1,453 results on '"Bridged Bicyclo Compounds chemistry"'
Search Results
2. RIFM fragrance ingredient safety assessment, exo-2-[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]ethanol, CAS Registry Number 7070-15-7.
- Author
-
Api AM, Bartlett A, Belsito D, Botelho D, Bruze M, Bryant-Freidrich A, Burton GA Jr, Cancellieri MA, Chon H, Dagli ML, Dekant W, Deodhar C, Farrell K, Fryer AD, Jones L, Joshi K, Lapczynski A, Lavelle M, Lee I, Moustakas H, Muldoon J, Penning TM, Ritacco G, Sadekar N, Schember I, Schultz TW, Siddiqi F, Sipes IG, Sullivan G, Thakkar Y, and Tokura Y
- Subjects
- Humans, Animals, Risk Assessment, Odorants, Toxicity Tests, Endpoint Determination, Consumer Product Safety, Bridged Bicyclo Compounds toxicity, Bridged Bicyclo Compounds chemistry, Databases, Chemical, Perfume toxicity, Perfume chemistry
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.
- Published
- 2024
- Full Text
- View/download PDF
3. Synthesis of (2 R ,4 S )-4-Amino-5-hydroxybicyclo[3.1.1]heptane-2-carboxylic Acid via an Asymmetric Intramolecular Mannich Reaction.
- Author
-
Dukes AO, Weerawarna PM, Devitt AN, and Silverman RB
- Subjects
- Stereoisomerism, Molecular Structure, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds chemical synthesis, Humans, Carboxylic Acids chemistry
- Abstract
Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The proposed inactivation mechanism involves a novel α-iminol rearrangement. The synthesis of the proposed inhibitor features an asymmetric intramolecular Mannich reaction, utilizing a chiral sulfinamide. This study presents a novel approach toward the synthesis of functionalized bicyclo[3.1.1]heptanes and highlights an underutilized method to access enantiopure exocyclic amines.
- Published
- 2024
- Full Text
- View/download PDF
4. Anticholinesterases activity of Murraya koenigii (L.) Spreng. and Murraya paniculata (L.) Jacq. essential oils with GC/MS analysis and molecular docking.
- Author
-
El-Shiekh RA, Kassem HAH, Khaleel AE, and Abd El-Mageed MMA
- Subjects
- Sesquiterpenes, Germacrane chemistry, Polycyclic Sesquiterpenes chemistry, Polycyclic Sesquiterpenes pharmacology, Sesquiterpenes chemistry, Sesquiterpenes pharmacology, Acetylcholinesterase metabolism, Acetylcholinesterase drug effects, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacology, Cyclohexane Monoterpenes, Bicyclic Monoterpenes, Murraya chemistry, Plant Leaves chemistry, Oils, Volatile chemistry, Oils, Volatile pharmacology, Molecular Docking Simulation, Gas Chromatography-Mass Spectrometry, Cholinesterase Inhibitors pharmacology, Cholinesterase Inhibitors chemistry
- Abstract
GC/MS analysis of Murraya koenigii (L.) Spreng. and Murraya paniculata (L.) Jacq. leaves revealed the identification of 73 components, with an evident greater contribution of monoterpenes hydrocarbons to their total volatiles. α-Pinene (37.5%) and β-caryophyllene (27.4%) were the most abundant compounds in M. koenigii leaves and β-phellandrene (40.7%) in M. paniculata leaves, using headspace. β-Phellandrene (33.7%) was the major constituent by M. koenigii leaves where germacrene D (23.8%), and δ-elemene (22.0%) were predominant in M. paniculata leaves, using steam distillation. M. koenigii leaves oil showed quite remarkable cholinesterase inhibitory activity, where oil of M. paniculata leaves showed strong inhibitory activity against AChE (IC
50 =13.2 ± 0.9 µg/mL) and BChE (IC50 =5.1 ± 0.3 µg/mL). Germacrene D, α-zingiberene, and δ-elemene showed higher affinity to BChE than AChE as revealed from docking scores (S = -5.65 to -6.03 Kcal/mol) for BChE and (S = -5.56 to -6.25 Kcal/mol) for AChE.- Published
- 2024
- Full Text
- View/download PDF
5. Regiodivergent biosynthesis of bridged bicyclononanes.
- Author
-
Ernst L, Lyu H, Liu P, Paetz C, Sayed HMB, Meents T, Ma H, Beerhues L, El-Awaad I, and Liu B
- Subjects
- Bridged Bicyclo Compounds metabolism, Bridged Bicyclo Compounds chemistry, Plant Proteins metabolism, Plant Proteins genetics, Molecular Docking Simulation, Phloroglucinol metabolism, Phloroglucinol analogs & derivatives, Phloroglucinol chemistry, Alkanes metabolism, Alkanes chemistry, Catalytic Domain, Terpenes metabolism, Terpenes chemistry, Models, Molecular, Hypericum metabolism, Hypericum genetics, Hypericum chemistry
- Abstract
Medicinal compounds from plants include bicyclo[3.3.1]nonane derivatives, the majority of which are polycyclic polyprenylated acylphloroglucinols (PPAPs). Prototype molecules are hyperforin, the antidepressant constituent of St. John's wort, and garcinol, a potential anticancer compound. Their complex structures have inspired innovative chemical syntheses, however, their biosynthesis in plants is still enigmatic. PPAPs are divided into two subclasses, named type A and B. Here we identify both types in Hypericum sampsonii plants and isolate two enzymes that regiodivergently convert a common precursor to pivotal type A and B products. Molecular modelling and substrate docking studies reveal inverted substrate binding modes in the two active site cavities. We identify amino acids that stabilize these alternative binding scenarios and use reciprocal mutagenesis to interconvert the enzymatic activities. Our studies elucidate the unique biochemistry that yields type A and B bicyclo[3.3.1]nonane cores in plants, thereby providing key building blocks for biotechnological efforts to sustainably produce these complex compounds for preclinical development., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
6. RIFM fragrance ingredient safety assessment, 1,5-dimethylbicyclo[3.2.1]octan-8-one-oxime, CAS Registry Number 75147-23-8.
- Author
-
Api AM, Belsito D, Botelho D, Bruze M, Burton GA Jr, Cancellieri MA, Chon H, Dagli ML, Dekant W, Deodhar C, Fryer AD, Jones L, Joshi K, Kumar M, Lapczynski A, Lavelle M, Lee I, Liebler DC, Moustakas H, Na M, Penning TM, Ritacco G, Romine J, Sadekar N, Schultz TW, Selechnik D, Siddiqi F, Sipes IG, Sullivan G, Thakkar Y, and Tokura Y
- Subjects
- Octanes chemistry, Octanes toxicity, Oximes chemistry, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds toxicity, Odorants
- Abstract
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. RIFM staff are employees of the Research Institute for Fragrance Materials, Inc. (RIFM). The Expert Panel receives a small honorarium for time spent reviewing the subject work.
- Published
- 2024
- Full Text
- View/download PDF
7. Discovery of a novel anti-osteoporotic agent from marine fungus-derived structurally diverse sirenins.
- Author
-
Cai J, Gao L, Wang Y, Zheng Y, Lin X, Zhou P, Chen C, Liu K, Tang L, Liu Y, Tan Y, Jin M, and Zhou X
- Subjects
- Animals, Fungi metabolism, Macrophages, NF-kappa B metabolism, Zebrafish metabolism, Bridged Bicyclo Compounds chemistry, Osteoporosis drug therapy, Penicillium chemistry
- Abstract
Thirteen new sirenin derivatives named eupenicisirenins C-O (1-13), along with a biosynthetically related known one (14), were isolated from the mangrove sediment-derived fungus Penicillium sp. SCSIO 41410. The structures, which possessed a rare cyclopropane moiety, were confirmed by extensive analyses of the spectroscopic data, quantum chemical calculations, and X-ray diffraction. Among them, eupenicisirenin C (1) exhibited the strongest NF-κB inhibitory activities, as well as suppressing effects on cGAS-STING pathway. Moreover, 1 showed the significant inhibitory effect on RANKL-induced osteoclast differentiation in bone marrow macrophages cells, and also displayed the therapeutic potential on prednisolone-induced zebrafish osteoporosis. Transcriptome analysis and the following verification tests suggested that its anti-osteoporotic mechanism is related to the extracellular matrix receptor interaction-related pathways. This study provided a promising marine-derived anti-osteoporotic agent for the treatment of skeletal disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
8. Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes.
- Author
-
Zheng Y, Huang W, Dhungana RK, Granados A, Keess S, Makvandi M, and Molander GA
- Subjects
- Cycloaddition Reaction, Hexanes chemistry, Butanes, Bridged Bicyclo Compounds chemistry, Heptanes chemistry
- Abstract
The development of synthetic strategies for the preparation of bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous strategies have been developed for the synthesis of bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on the synthesis of bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not been previously explored. Herein, we disclose the first photoinduced [3σ + 2σ] cycloaddition for the synthesis of trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes and cyclopropylamines. This transformation not only uses mild and operationally simple conditions but also provides unique meta-substituted arene bioisosteres. The applicability of this method is showcased by simple derivatization reactions.
- Published
- 2022
- Full Text
- View/download PDF
9. Enantioselective Michael Addition/Cyclization/Desymmetrization Sequence of Prochiral Cyclic Hemiacetals and Nitroolefins: Synthesis of Chiral Oxygen-Bridged Bicyclic Compounds.
- Author
-
Li YJ, Lv XJ, and Liu YK
- Subjects
- Cyclization, Stereoisomerism, Catalysis, Oxygen, Bridged Bicyclo Compounds chemistry
- Abstract
The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.
- Published
- 2022
- Full Text
- View/download PDF
10. Preparation of new bicyclo[2.1.1]hexane compact modules: an opening towards novel sp 3 -rich chemical space.
- Author
-
Herter L, Koutsopetras I, Turelli L, Fessard T, and Salomé C
- Subjects
- Cycloaddition Reaction, Hexanes chemistry, Bridged Bicyclo Compounds chemistry
- Abstract
Among the valuable saturated bicyclic structures incorporated in newly developed bio-active compounds, bicyclo[2.1.1]hexanes are playing an increasingly important role, while being still underexplored from a synthetic accessibility point of view. Here, we disclose an efficient and modular approach toward new 1,2-disubstituted bicyclo[2.1.1]hexane modules. Our strategy is based on the use of photochemistry to access new building blocks via [2 + 2] cycloaddition. The system can readily be derivatized with numerous transformations, opening the gate to sp
3 -rich new chemical space.- Published
- 2022
- Full Text
- View/download PDF
11. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.
- Author
-
Frank N, Nugent J, Shire BR, Pickford HD, Rabe P, Sterling AJ, Zarganes-Tzitzikas T, Grimes T, Thompson AL, Smith RC, Schofield CJ, Brennan PE, Duarte F, and Anderson EA
- Subjects
- Anions chemistry, Benzene chemistry, Drug Discovery, Pentanes chemical synthesis, Pentanes chemistry, Solubility, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Drug Design, Heptanes chemical synthesis, Heptanes chemistry
- Abstract
Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design
1 . The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3 . A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4 . By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5 . Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3 -rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
- Full Text
- View/download PDF
12. Investigating Bicyclobutane-Triazolinedione Cycloadditions as a Tool for Peptide Modification.
- Author
-
Schwartz BD, Smyth AP, Nashar PE, Gardiner MG, and Malins LR
- Subjects
- Amino Acids chemistry, Cycloaddition Reaction, Molecular Structure, Bridged Bicyclo Compounds chemistry, Peptides chemistry, Triazoles chemistry
- Abstract
Acyl bicyclobutanes are shown to engage in strain-promoted cycloaddition reactions with a diverse array of triazolinedione reagents. The synthesis of an orthogonally protected urazole building block enabled the facile preparation of amino acid- and peptide-derived triazolinediones that undergo cycloaddition reactions to afford novel peptide conjugates. The additive-free and fully atom-economical nature of the transformation is a promising starting point for the generalization of this cycloaddition reaction for the functionalization of biomolecules.
- Published
- 2022
- Full Text
- View/download PDF
13. Bicyclic Picomolar OGA Inhibitors Enable Chemoproteomic Mapping of Its Endogenous Post-translational Modifications.
- Author
-
González-Cuesta M, Sidhu P, Ashmus RA, Males A, Proceviat C, Madden Z, Rogalski JC, Busmann JA, Foster LJ, García Fernández JM, Davies GJ, Ortiz Mellet C, and Vocadlo DJ
- Subjects
- Amino Acid Sequence, Brain metabolism, Bridged Bicyclo Compounds metabolism, Catalytic Domain, Chromatography, High Pressure Liquid, Enzyme Inhibitors metabolism, Histone Acetyltransferases antagonists & inhibitors, Humans, Hyaluronoglucosaminidase antagonists & inhibitors, Mass Spectrometry, Peptides analysis, Peptides chemistry, Protein Processing, Post-Translational, Proteomics methods, Structure-Activity Relationship, Thiazolidines chemistry, Thiazolidines metabolism, beta-Hexosaminidase alpha Chain antagonists & inhibitors, beta-Hexosaminidase alpha Chain metabolism, Antigens, Neoplasm metabolism, Bridged Bicyclo Compounds chemistry, Enzyme Inhibitors chemistry, Histone Acetyltransferases metabolism, Hyaluronoglucosaminidase metabolism
- Abstract
Owing to its roles in human health and disease, the modification of nuclear, cytoplasmic, and mitochondrial proteins with O-linked N -acetylglucosamine residues (O-GlcNAc) has emerged as a topic of great interest. Despite the presence of O-GlcNAc on hundreds of proteins within cells, only two enzymes regulate this modification. One of these enzymes is O-GlcNAcase (OGA), a dimeric glycoside hydrolase that has a deep active site cleft in which diverse substrates are accommodated. Chemical tools to control OGA are emerging as essential resources for helping to decode the biochemical and cellular functions of the O-GlcNAc pathway. Here we describe rationally designed bicyclic thiazolidine inhibitors that exhibit superb selectivity and picomolar inhibition of human OGA. Structures of these inhibitors in complex with human OGA reveal the basis for their exceptional potency and show that they extend out of the enzyme active site cleft. Leveraging this structure, we create a high affinity chemoproteomic probe that enables simple one-step purification of endogenous OGA from brain and targeted proteomic mapping of its post-translational modifications. These data uncover a range of new modifications, including some that are less-known, such as O-ubiquitination and N-formylation. We expect that these inhibitors and chemoproteomics probes will prove useful as fundamental tools to decipher the mechanisms by which OGA is regulated and directed to its diverse cellular substrates. Moreover, the inhibitors and structures described here lay out a blueprint that will enable the creation of chemical probes and tools to interrogate OGA and other carbohydrate active enzymes.
- Published
- 2022
- Full Text
- View/download PDF
14. Synthesis of sp 3 -rich chiral bicyclo[3.3.1]nonanes for chemical space expansion and study of biological activities.
- Author
-
Ueda H, Wipf P, and Nakamura H
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Cell Hypoxia drug effects, Cell Proliferation drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Ligands, Models, Molecular, Molecular Structure, RNA, Messenger antagonists & inhibitors, RNA, Messenger metabolism, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Bridged Bicyclo Compounds pharmacology, Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
- Abstract
Chiral sp
3 -rich bicyclo[3.3.1]nonane scaffolds 10-12 were synthesized as single diastereomers from aldehyde 9, which was prepared from 4,4-dimethoxycyclohexa-2,5-dienone through a copper-catalyzed enantioselective reduction. Three different types of intramolecular addition reactions were studied: SmI2 -mediated reductive cyclization, base-promoted aldol reaction, and one-pot Mannich reaction. We succeeded in introducing three side-chains to scaffold 11 and construct an sp3 -rich compound library in both enantiomeric variants by simply changing the chirality of the ligands. The biological evaluation revealed that all synthesized compounds exhibited a concentration-dependent inhibition of hypoxia-inducible factor-1 (HIF-1) transcriptional activity, with IC50 values in the range of 17.2-31.7 µM, whereas their effects on cell viability were varied (IC50 = 3.5 to > 100 µM). The most active compound 16f inhibits the accumulation of HIF-1α protein and mRNA in hypoxia, indicating that it has a mechanism of action distinctly different from other known compounds bearing the common bicyclo[3.3.1]nonane skeleton., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
15. Superfast Tetrazole-BCN Cycloaddition Reaction for Bioorthogonal Protein Labeling on Live Cells.
- Author
-
Kumar GS, Racioppi S, Zurek E, and Lin Q
- Subjects
- Humans, Bridged Bicyclo Compounds chemistry, Molecular Structure, Tetrazoles chemistry, Cycloaddition Reaction
- Abstract
Here we report the design of a superfast bioorthogonal ligation reactant pair comprising a sterically shielded, sulfonated tetrazole and bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN). The design involves placing a pair of water-soluble N -sulfonylpyrrole substituents at the C-phenyl ring of diphenyltetrazoles to favor the photoinduced cycloaddition reaction over the competing nucleophilic additions. First-principles computations provide vital insights into the origin of the tetrazole-BCN cycloaddition's superior kinetics compared to the tetrazole-spirohexene cycloaddition. The tetrazole-BCN cycloaddition also enabled rapid bioorthogonal labeling of glucagon receptors on live cells in as little as 15 s.
- Published
- 2022
- Full Text
- View/download PDF
16. Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes.
- Author
-
Harmata AS, Spiller TE, Sowden MJ, and Stephenson CRJ
- Subjects
- Cycloaddition Reaction, Hydrolysis, Pentanes chemistry, Stereoisomerism, Alkenes chemistry, Bridged Bicyclo Compounds chemistry, Imines chemistry
- Abstract
Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp
3 -rich primary amine building blocks.- Published
- 2021
- Full Text
- View/download PDF
17. Synthesis of the Bridged [5-7-7] Tricyclic Core of Eurifoloid A.
- Author
-
Hou BL, Li LX, and Li CC
- Subjects
- Bridged Bicyclo Compounds chemistry, Catalysis, Cycloaddition Reaction, Diterpenes chemistry, Molecular Structure, Rhodium chemistry, Bridged Bicyclo Compounds chemical synthesis, Diterpenes chemical synthesis
- Abstract
We herein describe a new approach for the efficient and asymmetric construction of the tricyclic core of eurifoloid A, which possesses a unique and highly strained bicyclo[4.4.1] ring system. A rhodium-catalyzed intramolecular [3 + 2] dipolar cycloaddition was developed to install synthetically challenging bridged bicyclo[4.3.1] ring systems. The reported chemistry shows the feasibility of constructing the eurifoloid A framework using a diastereoselective intramolecular [3 + 2] cycloaddition and a ring enlargement.
- Published
- 2021
- Full Text
- View/download PDF
18. Enantioselective Total Synthesis of (+)-Garsubellin A.
- Author
-
Jang D, Choi M, Chen J, and Lee C
- Subjects
- Biological Products chemical synthesis, Biological Products chemistry, Bridged Bicyclo Compounds chemistry, Crystallography, X-Ray, Cyclization, Molecular Conformation, Stereoisomerism, Terpenes chemistry, Terpenes chemical synthesis
- Abstract
Garsubellin A is a meroterpene capable of enhancing the enzyme choline acetyltransferase whose decreased level is believed to play a central role in the symptoms of Alzheimer's disease. Due to the potentially useful biological activity together with the novel bridged and fused cyclic molecular architecture, garsubellin A has garnered substantial synthetic interest, but its absolute stereostructure has been undetermined. We report here the first enantioselective total synthesis of (+)-garsubellin A. Our synthesis relies on stereoselective fashioning of a cyclohexanone framework and double conjugate addition of 1,2-ethanedithiol that promotes aldol cyclization to build the bicyclic [3.3.1] skeleton. The twelve-step, protecting group-free synthetic route has enabled the syntheses of both the natural (-)-garsubellin A and its unnatural (+)-antipode for biological evaluations., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
- Published
- 2021
- Full Text
- View/download PDF
19. Synthesis and pharmacological evaluation of enantiomerically pure endo -configured KOR agonists with 2-azabicyclo[3.2.1]octane scaffold.
- Author
-
Jonas H, Aiello D, Frehland B, Lehmkuhl K, Schepmann D, Köhler J, Diana P, and Wünsch B
- Subjects
- Stereoisomerism, Animals, Structure-Activity Relationship, Humans, Azabicyclo Compounds chemistry, Azabicyclo Compounds pharmacology, Azabicyclo Compounds chemical synthesis, Molecular Structure, Dose-Response Relationship, Drug, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacology, Bridged Bicyclo Compounds chemical synthesis
- Abstract
Conformationally restricted bicyclic KOR agonists 10 with an endo -configured amino moiety were synthesized to analyze the bioactive conformation of conformationally flexible KOR agonists such as 2-5. A seven-step synthesis starting with ( S )-configured 4-oxopiperidine-2-carboxylate 13 was developed. cis - and trans -configured diesters 12 were obtained in a 3 : 1 ratio via hydrogenation of the α,β-unsaturated ester 14. After establishment of the bicyclic scaffold, a diastereoselective reductive amination of ketone 11 provided exclusively the endo -configured bicyclic amines 10a,b. The 3 : 1 mixtures of enantiomers were separated by chiral HPLC, respectively, leading to enantiomerically pure KOR agonists (1 S ,5 S ,7 R )-10a,b and (1 R ,5 R ,7 S )-10a,b ( ent -10a,b). The KOR affinity was determined in receptor binding studies with the radioligand [
3 H]U-69 593. The high KOR affinity of endo -configured amines 10a ( Ki = 7 nM) and 10b ( Ki = 13 nM) indicates that the dihedral angle of the KOR pharmacophoric element N(pyrrolidine)-C-C-N(phenylacetyl) of 42° is close to the bioactive conformation of more flexible KOR agonists. It should be noted that changing the configuration of potent and selective KOR agonists 10a and 10b led to potent and selective σ1 ligands ( e.g. ent -10a Ki ( σ1 ) = 10 nM).- Published
- 2021
- Full Text
- View/download PDF
20. A convenient fluorometric test method for skin sensitization using glutathione in chemico .
- Author
-
Kim GH, Cha DH, Nepal MR, and Jeong TC
- Subjects
- Skin physiopathology, Animal Testing Alternatives methods, Bridged Bicyclo Compounds chemistry, Fluorometry methods, Glutathione analysis, Skin drug effects
- Abstract
A convenient fluorometrical test method to identify skin sensitizers in chemico was developed using reactivity with glutathione (GSH), a low molecular weight endogenous substance. Following incubation of test chemicals with GSH, the remaining GSH was quantitated fluorometrically by using monobromobimane (mBBr), a thiol-detecting agent, for determining % depletion of this endogenous substance by test chemicals. The experimental conditions optimized were: (1) reactivity of thiol compounds including GSH with mBBr, (2) effects of vehicles on reactivity, (3) molar ratios of GSH to test chemicals, and (4) reactivity of endogenous substance with test substances under different incubation times. When an optimized condition with DMSO as a vehicle for test chemicals and in 1:60 ratio for 24 hr at 4°C was applied to classify 48 well-known skin sensitizers and non-sensitizers, the predictive capacity was as follows: 88.2% sensitivity, 78.6% specificity, and 85.4% accuracy with 95.8% consistency of three trials when 10.3% depletion of GSH was used as a cutoff value. Because the present method employed relatively simple GSH as an acceptor for sensitizers and/or a relatively convenient fluorometric detection system in 96-well plates for a high throughput test, it would be a useful test tool for screening skin sensitization potential of test chemicals.
- Published
- 2021
- Full Text
- View/download PDF
21. An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates.
- Author
-
Yang Y, Tsien J, Hughes JME, Peters BK, Merchant RR, and Qin T
- Subjects
- Boronic Acids chemistry, Bridged Bicyclo Compounds chemistry, Cyclization, Molecular Structure, Boronic Acids chemical synthesis
- Abstract
Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons., (© 2021. Merck Sharp & Dohme corp. under exclusive licence to Springer Nature Limited.)
- Published
- 2021
- Full Text
- View/download PDF
22. New β-ketophosphonates for the synthesis of prostaglandin analogues. 1. Phosphonates with a bicyclo[3.3.0]octene scaffold spaced by a methylene group from the β-ketone.
- Author
-
Tănase C, Căproiu MT, and Drăghici C
- Subjects
- Bridged Bicyclo Compounds chemistry, Ketones chemical synthesis, Ketones chemistry, Organophosphonates chemistry, Organophosphorus Compounds chemistry, Organophosphonates chemical synthesis, Prostaglandins, Synthetic chemical synthesis
- Abstract
The synthesis of β-ketophosphonates, linked by a methylene group to a bicyclo[3.3.0]octene fragment, was performed by the reaction of dimethyl methanephosphonate with the ester group of two intermediates with this scaffold. Starting from a diol, protected with good leaving groups (mesyl and tosyl), we performed a sequence of reactions with good yields: the carbon chain lengthening by reaction with KCN, the hydrolysis of the nitrile groups to carboxyl, the esterification of carboxyl to ester and finally the phosphonate synthesis, which gave one bis-β-ketophosphonate and two mono β-ketophosphonates. The new β-ketophosphonates are key intermediates for obtaining new prostaglandin analogues with a bicyclo[3.3.0]octene fragment in the ω-side chain. The bicyclo[3.3.0]octane scaffold, found in natural products and in anticancer compounds, are expected to keep their activity in PG analogs; the bulky scaffold, separated by a methylene group from the C-15 carbon atom, is expected to diminish the inactivation of the PG analog by enzyme oxidation of 15α-OH oxidation to 15-Keto via PGDH pathway., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
23. Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state.
- Author
-
Cao AM, Quast RB, Fatemi F, Rondard P, Pin JP, and Margeat E
- Subjects
- Allosteric Regulation drug effects, Allosteric Site, Amino Acids chemistry, Amino Acids pharmacology, Biphenyl Compounds chemistry, Biphenyl Compounds pharmacology, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacology, Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Catalytic Domain, Cell Membrane drug effects, Cell Membrane metabolism, Cholesterol Esters chemistry, Cholesterol Esters pharmacology, Diosgenin analogs & derivatives, Diosgenin chemistry, Diosgenin pharmacology, Disaccharides chemistry, Disaccharides pharmacology, Fluorescence Resonance Energy Transfer, Gene Expression, Glucosides chemistry, Glucosides pharmacology, Glycolipids chemistry, Glycolipids pharmacology, HEK293 Cells, Humans, Indans chemistry, Indans pharmacology, Micelles, Octoxynol chemistry, Octoxynol pharmacology, Protein Binding, Protein Conformation, Protein Multimerization, Receptors, Metabotropic Glutamate genetics, Receptors, Metabotropic Glutamate metabolism, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Single Molecule Imaging, Xanthenes chemistry, Xanthenes pharmacology, Glutamic Acid pharmacology, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate chemistry
- Abstract
Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the G
i protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states., (© 2021. The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
24. Total Synthesis and Assignment of the Absolute Configuration of (+)-Omphalic Acid.
- Author
-
Chen R, Qiu D, Lei X, Niu Y, Hua Y, Peng H, Zeng T, and Zhang Y
- Subjects
- Catalysis, Cycloaddition Reaction, Hydrogenation, Molecular Structure, Stereoisomerism, Bridged Bicyclo Compounds chemistry, Diterpenes chemistry, Octanes chemistry
- Abstract
Omphalane diterpenoids usually contain a cyclohexane-fused bicyclo[3.2.1]octane scaffold embedded with two continuous quaternary carbon centers, which pose considerable challenges to synthetic chemists. Herein, we reported the first total synthesis of omphalic acid with high stereochemical control, featuring an intermolecular Diels-Alder cycloaddition, ring reorganization through Criegee oxidative cleavage and programmed aldol condensations, conformationally controlled hydrogenation, and Pd-catalyzed carboxylation. The absolute configuration of omphalic acid was defined for the first time via the asymmetric total synthesis facilitated by a derivatization resolution protocol.
- Published
- 2021
- Full Text
- View/download PDF
25. Discovery of novel antibacterial agents: Recent developments in D-alanyl-D-alanine ligase inhibitors.
- Author
-
Qin Y, Xu L, Teng Y, Wang Y, and Ma P
- Subjects
- Anti-Bacterial Agents metabolism, Anti-Bacterial Agents pharmacology, Bacteria drug effects, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds metabolism, Bridged Bicyclo Compounds pharmacology, Enzyme Inhibitors metabolism, Heterocyclic Compounds, 1-Ring chemistry, Heterocyclic Compounds, 1-Ring metabolism, Heterocyclic Compounds, 1-Ring pharmacology, Peptide Synthases metabolism, Peptidoglycan biosynthesis, Structure-Activity Relationship, Anti-Bacterial Agents chemistry, Drug Discovery, Enzyme Inhibitors chemistry, Peptide Synthases chemistry
- Abstract
Bacterial infections can cause serious problems that threaten public health over a long period of time. Moreover, the continuous emergence of drug-resistant bacteria necessitates the development of novel antibacterial agents. D-alanyl-D-alanine ligase (Ddl) is an indispensable adenosine triphosphate-dependent bacterial enzyme involved in the biosynthesis of peptidoglycan precursor, which catalyzes the ligation of two D-alanine molecules into one D-alanyl-D-alanine dipeptide. This dipeptide is an essential component of the intracellular peptidoglycan precursor, uridine diphospho-N-acetylmuramic acid (UDP-MurNAc)-pentapeptide, that maintains the integrity of the bacterial cell wall by cross-linking the peptidoglycan chain, and is crucial for the survival of pathogens. Consequently, Ddl is expected to be a promising target for the development of antibacterial agents. In this review, we present a brief introduction regarding the structure and function of Ddl, as well as an overview of the various Ddl inhibitors currently being used as antibacterial agents, specifically highlighting their inhibitory activities, structure-activity relationships and mechanisms of action., (© 2021 John Wiley & Sons A/S.)
- Published
- 2021
- Full Text
- View/download PDF
26. Sinusiaetone A, an Anti-inflammatory Norditerpenoid with a Bicyclo[11.3.0]hexadecane Nucleus from the Hainan Soft Coral Sinularia siaesensis .
- Author
-
Chen ZH, Li WS, Zhang ZY, Luo H, Wang JR, Zhang HY, Zeng ZR, Chen B, Li XW, and Guo YW
- Subjects
- Alkanes, Animals, Anti-Inflammatory Agents chemistry, Bridged Bicyclo Compounds chemistry, Lipopolysaccharides chemistry, Molecular Structure, Anthozoa chemistry, Anti-Inflammatory Agents pharmacology, Bridged Bicyclo Compounds pharmacology, Diterpenes chemistry, Lipopolysaccharides pharmacology
- Abstract
A novel norditerpenoid, sinusiaetone A ( 1 ), featuring an uncommon bicyclo[11.3.0]hexadecane carbon skeleton, and four polyoxygenated cembranoids ( 2-5 ) were isolated from the Hainan soft coral Sinularia siaesensis . Their structures were established by spectroscopic analysis, X-ray diffraction, quantum chemical computational approaches, and/or a modified Mosher's method. A plausible biosynthetic pathway of 1 and its biogenetic relationship with 2-5 were proposed. New compounds 1-3 displayed an interesting inhibitory activity against lipopolysaccharide-induced inflammation in BV-2 microglial cells.
- Published
- 2021
- Full Text
- View/download PDF
27. Discovery of a novel inhibitor of nitric oxide production with potential therapeutic effect on acute inflammation.
- Author
-
Zhu LQ, Fan XH, Li JF, Chen JH, Liang Y, Hu XL, Ma SM, Hao XY, Shi T, and Wang Z
- Subjects
- Acute Disease, Amides chemical synthesis, Amides chemistry, Animals, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal chemistry, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Carrageenan, Dose-Response Relationship, Drug, Edema chemically induced, Edema drug therapy, Inflammation metabolism, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Mice, Molecular Structure, Nitric Oxide biosynthesis, RAW 264.7 Cells, Structure-Activity Relationship, Amides pharmacology, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Bridged Bicyclo Compounds pharmacology, Drug Discovery, Inflammation drug therapy, Nitric Oxide antagonists & inhibitors
- Abstract
Inflammation as a host's excessive immune response to stimulation, is involved in the development of numerous diseases. To discover novel anti-inflammatory agents and based on our previous synthetic work on marine natural product Chrysamide B, it and a series of derivatives were synthesized and evaluated for their anti-inflammatory activity on inhibition of LPS-induced NO production. Then the preliminary structure-activity relationships were conducted. Among them, Chrysamide B is the most potent anti-inflammatory agent with low cytotoxicity and strong inhibition on the production of NO (IC
50 = 0.010 μM) and the activity of iNOS (IC50 = 0.082 μM) in LPS-stimulated RAW 264.7 cells. Primary studies suggested that the mechanism of action may be that it interfered the formation of active dimeric iNOS but not affected transcription and translation. Furthermore, its good performance of anti-inflammatory effect on LPS-induced multiple inflammatory cytokines production, carrageenan-induced paw edema, and endotoxin-induced septic mice, was observed. We believe that these findings would provide an idea for the further modification and research of these analogs in the future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
28. Semipinacol rearrangement of a bicyclo[7.2.0]undecane framework into a bicyclo[6.3.0]undecane skeleton: a model study on the biosynthesis of seiridiasteriscane A.
- Author
-
Ishibashi O, Nishiyama M, Kwon E, Hashimoto M, Kuwahara S, and Enomoto M
- Subjects
- Spectrum Analysis methods, Alkanes chemistry, Bridged Bicyclo Compounds chemistry, Cyclohexenes chemistry, Models, Chemical
- Abstract
Seiridiasteriscane A is an asteriscane-type sesquiterpenoid bearing a trans-fused bicyclo[6.3.0]undecane skeleton. Although its biosynthesis has been proposed to involve a semipinacol rearrangement of a putative intermediary acetate bearing a bicyclo[7.2.0]undecane ring system (presumably derived from coisolated pestalotiopsin M) followed by epimerization of the resulting cis-fused seiridiasteriscane B, such a type of semipinacol rearrangement has never been reported so far. Our model study revealed that a 1-hydroxybicyclo[7.2.0]undecan-2-yl acetate underwent a smooth and stereospecific semipinacol rearrangement with the assistance of Et2AlCl to give the corresponding bicyclo[6.3.0]undecane-9-one. In addition, the resulting cis-fused 5,8-bicyclic ketone was partially epimerized to the corresponding trans-fused ketone by prolonged adsorption onto a silica gel plate. These results may support a recently proposed biosynthetic pathway of seiridiasteriscane A., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)
- Published
- 2021
- Full Text
- View/download PDF
29. Simultaneous Determination of Human Serum Albumin and Low-Molecular-Weight Thiols after Derivatization with Monobromobimane.
- Author
-
Kurpet K, Głowacki R, and Chwatko G
- Subjects
- Chromatography, Reverse-Phase, Humans, Molecular Weight, Oxidation-Reduction, Serum Albumin, Human chemistry, Sulfhydryl Compounds chemistry, Bridged Bicyclo Compounds chemistry, Serum Albumin, Human analysis, Sulfhydryl Compounds analysis
- Abstract
Biothiols are extremely powerful antioxidants that protect cells against the effects of oxidative stress. They are also considered relevant disease biomarkers, specifically risk factors for cardiovascular disease. In this paper, a new procedure for the simultaneous determination of human serum albumin and low-molecular-weight thiols in plasma is described. The method is based on the pre-column derivatization of analytes with a thiol-specific fluorescence labeling reagent, monobromobimane, followed by separation and quantification through reversed-phase high-performance liquid chromatography with fluorescence detection (excitation, 378 nm; emission, 492 nm). Prior to the derivatization step, the oxidized thiols are converted to their reduced forms by reductive cleavage with sodium borohydride. Linearity in the detector response for total thiols was observed in the following ranges: 1.76-30.0 mg mL
-1 for human serum albumin, 0.29-5.0 nmol mL-1 for α-lipoic acid, 1.16-35 nmol mL-1 for glutathione, 9.83-450.0 nmol mL-1 for cysteine, 0.55-40.0 nmol mL-1 for homocysteine, 0.34-50.0 nmol mL-1 for N-acetyl-L-cysteine, and 1.45-45.0 nmol mL-1 for cysteinylglycine. Recovery values of 85.16-119.48% were recorded for all the analytes. The developed method is sensitive, repeatable, and linear within the expected ranges of total thiols. The devised procedure can be applied to plasma samples to monitor biochemical processes in various pathophysiological states.- Published
- 2021
- Full Text
- View/download PDF
30. Design, synthesis and antitumor activity evaluation of Chrysamide B derivatives.
- Author
-
Zhu L, Li J, Fan X, Hu X, Chen J, Liu Y, Hao X, Shi T, Wang Z, and Zhao Q
- Subjects
- Amides chemical synthesis, Amides chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Cell Movement drug effects, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Structure-Activity Relationship, Tumor Cells, Cultured, Amides pharmacology, Antineoplastic Agents pharmacology, Bridged Bicyclo Compounds pharmacology, Drug Design
- Abstract
Marine natural products derived from special or extreme environment provide an important source for the development of anti-tumor drugs due to their special skeletons and functional groups. In this study, based on our previous work on the total synthesis and structure revision of the novel marine natural product Chrysamide B, a group of its derivatives were designed, synthesized, and subsequently of which the anti-cancer activity, structure-activity relationships and cellular mechanism were explored for the first time. Compared with Chrysamide B, better anti-cancer performance of some derivatives against five human cancer cell lines (SGC-7901, MGC-803, HepG2, HCT-116, MCF-7) was observed, especially for compound b-9 on MGC-803 and SGC-7901 cells with the IC
50 values of 7.88 ± 0.81 and 10.08 ± 1.08 μM, respectively. Subsequently, cellular mechanism study suggested that compound b-9 treatment could inhibit the cellular proliferation, reduce the migration and invasion ability of cells, and induce mitochondrial-dependent apoptosis in gastric cancer MGC-803 and SGC-7901 cells. Furthermore, the mitochondrial-dependent apoptosis induced by compound b-9 is related with the JAK2/STAT3/Bcl-2 signaling pathway. To conclude, our results offer a new structure for the discovery of anti-tumor lead compounds from marine natural products., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
31. Development and Application of Subtype-Selective Fluorescent Antagonists for the Study of the Human Adenosine A 1 Receptor in Living Cells.
- Author
-
Comeo E, Trinh P, Nguyen AT, Nowell CJ, Kindon ND, Soave M, Stoddart LA, White JM, Hill SJ, Kellam B, Halls ML, May LT, and Scammells PJ
- Subjects
- Adenosine A1 Receptor Antagonists metabolism, Bridged Bicyclo Compounds chemistry, Drug Design, Fluorescence Resonance Energy Transfer, Fluorescent Dyes metabolism, HEK293 Cells, Humans, Kinetics, Ligands, Octanes chemistry, Receptor, Adenosine A1 metabolism, Structure-Activity Relationship, Xanthine chemistry, Xanthine metabolism, Adenosine A1 Receptor Antagonists chemical synthesis, Fluorescent Dyes chemistry, Receptor, Adenosine A1 chemistry
- Abstract
The adenosine A
1 receptor (A1 AR) is a G-protein-coupled receptor (GPCR) that provides important therapeutic opportunities for a number of conditions including congestive heart failure, tachycardia, and neuropathic pain. The development of A1 AR-selective fluorescent ligands will enhance our understanding of the subcellular mechanisms underlying A1 AR pharmacology facilitating the development of more efficacious and selective therapies. Herein, we report the design, synthesis, and application of a novel series of A1 AR-selective fluorescent probes based on 8-functionalized bicyclo[2.2.2]octylxanthine and 3-functionalized 8-(adamant-1-yl) xanthine scaffolds. These fluorescent conjugates allowed quantification of kinetic and equilibrium ligand binding parameters using NanoBRET and visualization of specific receptor distribution patterns in living cells by confocal imaging and total internal reflection fluorescence (TIRF) microscopy. As such, the novel A1 AR-selective fluorescent antagonists described herein can be applied in conjunction with a series of fluorescence-based techniques to foster understanding of A1 AR molecular pharmacology and signaling in living cells.- Published
- 2021
- Full Text
- View/download PDF
32. Photoinduced oxidative cyclopropanation of ene-ynamides: synthesis of 3-aza[ n .1.0]bicycles via vinyl radicals.
- Author
-
Deng Y, Zhang J, Bankhead B, Markham JP, and Zeller M
- Subjects
- Aza Compounds chemistry, Bridged Bicyclo Compounds chemistry, Molecular Structure, Oxidation-Reduction, Photochemical Processes, Alkynes chemistry, Amides chemistry, Aza Compounds chemical synthesis, Bridged Bicyclo Compounds chemical synthesis, Cyclopropanes chemistry
- Abstract
The first photoinduced synthesis of polyfunctionalized 3-aza[n.1.0]bicycles from readily available ene-ynamides and 2,6-lutidine N-oxide using an organic acridinium photocatalyst is reported. Applying a photocatalytic strategy to the reactive distonic cation vinyl radical intermediate from ynamide, a series of bio-valuable 3-azabicycles, including diverse 3-azabicyclio[4.1.0]heptanes and 3-azabicyclo[5.1.0]octanes that are challenging to accomplish using traditional methods, have been successfully synthesized in good to high yields under mild and metal-free conditions. Mechanistic studies are consistent with the photocatalyzed single-electron oxidation of ene-ynamide and the intermediacy of a putative cationic vinyl radical in this transformation. Importantly, this strategy provides new access to the development of photocatalytic vinyl radical cascades for the synthesis of structurally sophisticated substrates.
- Published
- 2021
- Full Text
- View/download PDF
33. Three-Component 1,2-Carboamidation of Bridged Bicyclic Alkenes via Rh III -Catalyzed Addition of C-H Bonds and Amidating Reagents.
- Author
-
Brandes DS, Sirvent A, Mercado BQ, and Ellman JA
- Subjects
- Amides chemistry, Bridged Bicyclo Compounds chemical synthesis, Catalysis, Indicators and Reagents, Lactams chemistry, Molecular Structure, Pyrazoles chemistry, Alkenes chemistry, Bridged Bicyclo Compounds chemistry, Rhodium chemistry
- Abstract
A three-component method is described for the preparation of syn -1,2-disubstituted bridged bicyclic compounds. The reaction was demonstrated for readily available aromatic and heteroaromatic C-H bond substrates with tertiary and secondary amide, lactam, pyrazole, and triazole directing groups and a variety of bridged bicyclic alkenes, including norbornene, benzonorbornadiene, oxygen- and nitrogen-bridged analogs, and an unsaturated tropinone. A broad dioxazolone scope was also observed. The use of a chiral Cp-derived Rh
III catalyst enables asymmetric synthesis of products.- Published
- 2021
- Full Text
- View/download PDF
34. Ferutinin: A phytoestrogen from ferula and its anticancer, antioxidant, and toxicity properties.
- Author
-
Naji Reyhani Garmroudi S, Karimi E, Oskoueian E, Homayouni-Tabrizi M, and Iranshahi M
- Subjects
- Animals, Antineoplastic Agents, Phytogenic chemistry, Antioxidants chemistry, Benzoates chemistry, Breast Neoplasms metabolism, Breast Neoplasms pathology, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacology, Cycloheptanes chemistry, Drug Screening Assays, Antitumor, Female, Humans, MCF-7 Cells, Male, Mice, Mice, Inbred BALB C, Phytoestrogens chemistry, Sesquiterpenes chemistry, Antineoplastic Agents, Phytogenic pharmacology, Antioxidants pharmacology, Benzoates pharmacology, Breast Neoplasms drug therapy, Cycloheptanes pharmacology, Ferula chemistry, Phytoestrogens pharmacology, Sesquiterpenes pharmacology
- Abstract
This study was performed to evaluate the antioxidant, anticancer, and toxicity properties of ferutinin, a phytoestrogen derived from Ferula species. The human Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line and normal human fibroblast (HDF) were cultured and treated with different ferutinin concentrations. The cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death-defining tests (a comparative real-time polymerase chain reaction [for Bax and Bcl-2 genes], flow cytometry, and acridine orange/propidium iodide cell staining). Moreover, 15 white male balb/c mice were divided into three groups of five (one untreated control group and two groups), which received different doses of ferutinin-supplemented water (500 and 1000 µg/kg mice weight) to check the mice liver and kidney pathomorphological alterations and to determine the antioxidant enzymes' expression profile (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase) in the mentioned tissues. Finally, the liver lipid peroxidation of mice was analyzed. The results of MTT and cell death-defining tests indicate the significant reduction in cell viability and induction of apoptotic death in MCF-7 cells (enhanced sub-G1 peaks, Bax overexpression, Bcl-2 downregulation, and increased apoptotic cells). The antioxidant enzymes (SOD and CAT) in the mice liver and kidney cells were found to be upregulated (p < .05) in response to the increasing doses of ferutinin. Besides, the lipid peroxidation of the liver tissue of mice was significantly reduced. According to the results, we suggest that ferutinin has the potential to be served as a selective anticancer compound for breast cancer treatment., (© 2021 Wiley Periodicals LLC.)
- Published
- 2021
- Full Text
- View/download PDF
35. [3,3] Ring Rearrangement of Oxo- or Aza-Bridged Bicyclo[3.2.1]octene-Based 1,5-Dienes.
- Author
-
Semenova E, Lahtigui O, Ghiviriga I, and Grenning AJ
- Subjects
- Biochemical Phenomena, Catalysis, Molecular Structure, Bridged Bicyclo Compounds chemistry, Furans chemistry, Polyenes chemistry
- Abstract
We report that oxo- or aza-bridged alkylidenemalononitrile-cycloheptenes undergo a [3,3] ring rearrangement to yield cyclopenta-fused dihydro-furans or pyrroles. Described herein are the origins of the serendipitous discovery, scope studies, and representative functional group interconversion chemistry.
- Published
- 2021
- Full Text
- View/download PDF
36. Synthesis, Antifungal Activity, and 3D-QSAR Study of Novel Nopol-Derived 1,3,4-Thiadiazole-Thiourea Compounds.
- Author
-
Chen M, Duan WG, Lin GS, Fan ZT, and Wang X
- Subjects
- Antifungal Agents chemistry, Bridged Bicyclo Compounds chemistry, Drug Design, Fungi drug effects, Fungicides, Industrial chemical synthesis, Fungicides, Industrial chemistry, Fungicides, Industrial pharmacology, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Quantitative Structure-Activity Relationship, Static Electricity, Thiadiazoles chemistry, Thiourea chemistry, Thiourea pharmacokinetics, Antifungal Agents chemical synthesis, Antifungal Agents pharmacology, Bridged Bicyclo Compounds pharmacology, Thiadiazoles pharmacology, Thiourea analogs & derivatives
- Abstract
A series of novel nopol derivatives bearing the 1,3,4-thiadiazole-thiourea moiety were designed and synthesized by multi-step reactions in search of potent natural product-based antifungal agents. Their structures were confirmed by FT-IR, NMR, ESI-MS, and elemental analysis. Antifungal activity of the target compounds was preliminarily evaluated by in vitro methods against Fusarium oxysporum f. sp. cucumerinum , Cercospora arachidicola , Physalospora piricola , Alternaria solani , Gibberella zeae , Rhizoeotnia solani , Bipolaris maydis , and Colleterichum orbicalare at 50 µg/mL. All the target compounds exhibited better antifungal activity against P. piricola , C. arachidicola , and A. solani . Compound 6j (R = m , p -Cl Ph) showed the best broad-spectrum antifungal activity against all the tested fungi. Compounds 6c (R = m -Me Ph), 6q (R = i -Pr), and 6i (R = p -Cl Ph) had inhibition rates of 86.1%, 86.1%, and 80.2%, respectively, against P. piricola , much better than that of the positive control chlorothalonil. Moreover, compounds 6h (R = m -Cl Ph) and 6n (R = o -CF
3 Ph) held inhibition rates of 80.6% and 79.0% against C. arachidicola and G. zeae , respectively, much better than that of the commercial fungicide chlorothalonil. In order to design more effective antifungal compounds against A. solani , analysis of the three-dimensional quantitative structure-activity relationship (3D-QSAR) was carried out using the CoMFA method, and a reasonable and effective 3D-QSAR model ( r2 = 0.992, q2 = 0.753) has been established. Furthermore, some intriguing structure-activity relationships were found and are discussed by theoretical calculation.- Published
- 2021
- Full Text
- View/download PDF
37. Identification of sulfenylation patterns in trophozoite stage Plasmodium falciparum using a non-dimedone based probe.
- Author
-
Schipper S, Wu H, Furdui CM, Poole LB, Delahunty CM, Park R, Yates JR 3rd, Becker K, and Przyborski JM
- Subjects
- Cells, Cultured, Cysteine metabolism, Erythrocytes parasitology, Gene Ontology, Glutathione metabolism, Humans, Mass Spectrometry, Molecular Sequence Annotation, Nitroso Compounds metabolism, Oxidation-Reduction, Plasmodium falciparum genetics, Protozoan Proteins genetics, Staining and Labeling methods, Trophozoites genetics, Bridged Bicyclo Compounds chemistry, Molecular Probes chemistry, Plasmodium falciparum metabolism, Protein Processing, Post-Translational, Protozoan Proteins metabolism, Sulfenic Acids metabolism, Trophozoites metabolism
- Abstract
Plasmodium falciparum causes the deadliest form of malaria. Adequate redox control is crucial for this protozoan parasite to overcome oxidative and nitrosative challenges, thus enabling its survival. Sulfenylation is an oxidative post-translational modification, which acts as a molecular on/off switch, regulating protein activity. To obtain a better understanding of which proteins are redox regulated in malaria parasites, we established an optimized affinity capture protocol coupled with mass spectrometry analysis for identification of in vivo sulfenylated proteins. The non-dimedone based probe BCN-Bio1 shows reaction rates over 100-times that of commonly used dimedone-based probes, allowing for a rapid trapping of sulfenylated proteins. Mass spectrometry analysis of BCN-Bio1 labeled proteins revealed the first insight into the Plasmodium falciparum trophozoite sulfenylome, identifying 102 proteins containing 152 sulfenylation sites. Comparison with Plasmodium proteins modified by S-glutathionylation and S-nitrosation showed a high overlap, suggesting a common core of proteins undergoing redox regulation by multiple mechanisms. Furthermore, parasite proteins which were identified as targets for sulfenylation were also identified as being sulfenylated in other organisms, especially proteins of the glycolytic cycle. This study suggests that a number of Plasmodium proteins are subject to redox regulation and it provides a basis for further investigations into the exact structural and biochemical basis of regulation, and a deeper understanding of cross-talk between post-translational modifications., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
38. Tetracyclic Diterpenoid Synthesis Facilitated by ODI-Cascade Approaches to Bicyclo[3.2.1]octane Skeletons.
- Author
-
Gao K, Hu J, and Ding H
- Subjects
- Cycloaddition Reaction, Diterpenes chemistry, Diterpenes, Kaurane chemical synthesis, Diterpenes, Kaurane chemistry, Drug Design, Oxidation-Reduction, Bridged Bicyclo Compounds chemistry, Diterpenes chemical synthesis, Octanes chemistry
- Abstract
Tetracyclic diterpenoids (C
20 ) mainly refer to the plant terpenoids bearing biogenetically related carbon skeletons derived from copalyl diphosphates ( ent -CPP and syn -CPP). This large family contains over 1600 known members that can be categorized into 11 major structural types. Among them, more than three-quarters share a bridged bicyclo[3.2.1]octane subunit, which is also an important branching point in biosynthesis en route to the other types of bicyclic scaffolds, such as bicyclo[2.2.2]-, bicyclo[3.3.0]-, and tricyclo[3.2.1.0]octanes. Combined with the significance of its stereochemical importance in biological activity, the assembly of the bicyclo[3.2.1]octane skeletons is critical to the success of the whole synthesis blueprint toward tetracyclic diterpenoids. Although a number of inspiring methodologies have been disclosed, general approaches by the incorporation of innovative cascade reactions permitting access to diverse structural types of tetracyclic diterpenoids remain limited and in urgent demand.Because of the long-standing interest in the synthesis of bridged diterpenoids, we have recently developed two complementary types of oxidative dearomatization induced (ODI) cascade approaches to the rapid and efficient construction of bicyclo[3.2.1]octane skeletons. In this Account, we summarize our original synthesis design, methodology development, and the application of these two strategies in tetracyclic diterpenoid synthesis during the past few years in our laboratory.First, we detail our preliminary investigation of the ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction, which showed a wide scope of vinylphenol substrates and led to cyclopentane and cyclohexane-fused bicyclo[3.2.1]octanes in good yields with excellent dr values. Next, we describe the utilization of this ODI-[5 + 2] cascade reaction which resulted in the asymmetric total syntheses of four highly oxygenated ent -kauranoids. The strategy concerning accurate stereochemical control in the ODI-[5 + 2] cycloaddition was then successfully transplanted to the total syntheses of three stemaranoids, thus providing a straightforward and diastereoselective route to C9-ethano-bridged tetracyclic diterpenoids. To access more complex diterpenoid rhodomollanol A, we exploited two additional biomimetic rearrangements, namely, the retro- Dieckmann fragmentation/vinylogous Dieckmann cyclization cascade and the photo-Nazarov cyclization/intramolecular cycloetherification cascade. Taken together with the ODI-[5 + 2] cascade, the asymmetric total synthesis of the target molecule was realized, which shed light on the biogenetic pathway of the unprecedented rhodomollane-type carbon framework. Finally, we describe an ODI-Diels-Alder/Beckwith-Dowd cascade approach as a valuable supplement to the ODI-[5 + 2] cascade for the fabrication of cycloheptane-fused bicyclo[3.2.1]octane skeletons. Its versatility was also demonstrated by the total syntheses of two challenging grayanane diterpenoids. In view of the high functional-group compatibility and scalability, we anticipate that the two novel cascade approaches will find further use in the field of complex natural product synthesis.- Published
- 2021
- Full Text
- View/download PDF
39. Nopol-Based Quinoline Derivatives as Antiplasmodial Agents.
- Author
-
Nyamwihura RJ, Zhang H, Collins JT, Crown O, and Ogungbe IV
- Subjects
- Antimalarials chemical synthesis, Antimalarials chemistry, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Hep G2 Cells, Humans, Quinolines chemical synthesis, Quinolines chemistry, Antimalarials pharmacology, Bridged Bicyclo Compounds pharmacology, Plasmodium drug effects, Quinolines pharmacology
- Abstract
Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum , one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides ( 2 - 4 ) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf 3D7 but inactive against chloroquine-resistant strains Pf K1 and Pf NF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC
50 in the Pf K1 strain. However, 8 was more than two orders of magnitude less active against Pf 3D7 and Pf NF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax .- Published
- 2021
- Full Text
- View/download PDF
40. Reaction mechanism of the farnesyl pyrophosphate C-methyltransferase towards the biosynthesis of pre-sodorifen pyrophosphate by Serratia plymuthica 4Rx13.
- Author
-
Lemfack MC, Brandt W, Krüger K, Gurowietz A, Djifack J, Jung JP, Hopf M, Noack H, Junker B, von Reuß S, and Piechulla B
- Subjects
- Amino Acid Motifs, Bacterial Proteins chemistry, Bacterial Proteins genetics, Binding Sites, Biocatalysis, Bridged Bicyclo Compounds chemistry, Cloning, Molecular, Cyclization, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, Methylation, Methyltransferases chemistry, Methyltransferases genetics, Molecular Docking Simulation, Mutagenesis, Site-Directed, Octanes chemistry, Polyisoprenyl Phosphates chemistry, Polyisoprenyl Phosphates metabolism, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Serratia chemistry, Serratia genetics, Sesquiterpenes chemistry, Sesquiterpenes metabolism, Substrate Specificity, Bacterial Proteins metabolism, Bridged Bicyclo Compounds metabolism, Methyltransferases metabolism, Octanes metabolism, Serratia enzymology
- Abstract
Classical terpenoid biosynthesis involves the cyclization of the linear prenyl pyrophosphate precursors geranyl-, farnesyl-, or geranylgeranyl pyrophosphate (GPP, FPP, GGPP) and their isomers, to produce a huge number of natural compounds. Recently, it was shown for the first time that the biosynthesis of the unique homo-sesquiterpene sodorifen by Serratia plymuthica 4Rx13 involves a methylated and cyclized intermediate as the substrate of the sodorifen synthase. To further support the proposed biosynthetic pathway, we now identified the cyclic prenyl pyrophosphate intermediate pre-sodorifen pyrophosphate (PSPP). Its absolute configuration (6R,7S,9S) was determined by comparison of calculated and experimental CD-spectra of its hydrolysis product and matches with those predicted by semi-empirical quantum calculations of the reaction mechanism. In silico modeling of the reaction mechanism of the FPP C-methyltransferase (FPPMT) revealed a S
N 2 mechanism for the methyl transfer followed by a cyclization cascade. The cyclization of FPP to PSPP is guided by a catalytic dyad of H191 and Y39 and involves an unprecedented cyclopropyl intermediate. W46, W306, F56, and L239 form the hydrophobic binding pocket and E42 and H45 complex a magnesium cation that interacts with the diphosphate moiety of FPP. Six additional amino acids turned out to be essential for product formation and the importance of these amino acids was subsequently confirmed by site-directed mutagenesis. Our results reveal the reaction mechanism involved in methyltransferase-catalyzed cyclization and demonstrate that this coupling of C-methylation and cyclization of FPP by the FPPMT represents an alternative route of terpene biosynthesis that could increase the terpenoid diversity and structural space.- Published
- 2021
- Full Text
- View/download PDF
41. Annulative Methods in the Synthesis of Complex Meroterpene Natural Products.
- Author
-
Shen X, Thach DQ, Ting CP, and Maimone TJ
- Subjects
- Biological Products chemistry, Bridged Bicyclo Compounds chemistry, Cyclization, Cycloaddition Reaction, Molecular Conformation, Oxidation-Reduction, Phloroglucinol analogs & derivatives, Phloroglucinol chemical synthesis, Phloroglucinol chemistry, Resorcinols chemical synthesis, Resorcinols chemistry, Stereoisomerism, Terpenes chemistry, Biological Products chemical synthesis, Terpenes chemical synthesis
- Abstract
From the venerable Robinson annulation to the irreplaceable Diels-Alder cycloaddition, annulation reactions have fueled the progression of the field of natural product synthesis throughout the past century. In broader terms, the ability to form a cyclic molecule directly from two or more simpler fragments has transformed virtually every aspect of the chemical sciences from the synthesis of organic materials to bioconjugation chemistry and drug discovery. In this Account, we describe the evolution of our meroterpene synthetic program over the past five years, enabled largely by the development of a tailored anionic annulation process for the synthesis of hydroxylated 1,3-cyclohexanediones from lithium enolates and the reactive β-lactone-containing feedstock chemical diketene.First, we provide details on short total syntheses of the prototypical polycyclic polyprenylated acylphloroglucinol (PPAP) natural products hyperforin and garsubellin A, which possess complex bicyclo[3.3.1]nonane architectures. Notably, these molecules have served as compelling synthetic targets for several decades and induce a number of biological effects of relevance to neuroscience and medicine. By merging our diketene annulation process with a hypervalent iodine-mediated oxidative ring expansion, bicyclo[3.3.1]nonane architectures can be easily prepared from simple 5,6-fused bicyclic diketones in only two chemical operations. Leveraging these two key chemical reactions in combination with various other stereoselective transformations allowed for these biologically active targets to be prepared in racemic form in only 10 steps.Next, we extend this strategy to the synthesis of complex fungal-derived meroterpenes generated biosynthetically from the coupling of 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate. A Ti(III)-mediated radical cyclization of a terminal epoxide was used to rapidly prepare a 6,6,5-fused tricyclic ketone which served as an input for our annulation/rearrangement process, ultimately enabling a total synthesis of protoaustinoid A, an important biosynthetic intermediate in DMOA-derived meroterpene synthesis, and its oxidation product berkeleyone A. Through a radical-based, abiotic rearrangement process, the bicyclo[3.3.1]nonane cores of these natural products could again be isomerized, resulting in the 6,5-fused ring systems of the andrastin family and ultimately delivering a total synthesis of andrastin D and preterrenoid. Notably, these isomerization transformations proved challenging when employing classic, acid-induced conditions for carbocation generation, thus highlighting the power of radical biomimicry in total synthesis. Finally, further oxidation and rearrangement allowed for access to terrenoid and the lactone-containing metabolite terretonin L.Overall, the merger of annulative diketene methodology with an oxidative rearrangement transformation has proven to be a broadly applicable strategy to synthesize bicyclo[3.3.1]nonane-containing natural products, a class of small molecules with over 1000 known members.
- Published
- 2021
- Full Text
- View/download PDF
42. In Pursuit of Synthetic Efficiency: Convergent Approaches.
- Author
-
Gao Y and Ma D
- Subjects
- Alkaloids chemical synthesis, Alkaloids chemistry, Biological Products chemistry, Bridged Bicyclo Compounds chemistry, Carbon chemistry, Cyclization, Cycloaddition Reaction, Diterpenes, Kaurane chemical synthesis, Diterpenes, Kaurane chemistry, Octanes chemistry, Oxidation-Reduction, Sesterterpenes chemical synthesis, Sesterterpenes chemistry, Stereoisomerism, Trabectedin chemical synthesis, Trabectedin chemistry, Zanamivir chemical synthesis, Zanamivir chemistry, Biological Products chemical synthesis
- Abstract
The field of total synthesis has reached a stage in which emphasis has been increasingly focused on synthetic efficiency rather than merely achieving the synthesis of a target molecule. The pursuit of synthetic efficiency, typically represented by step count and overall yield, is a rich source of inspiration and motivation for synthetic chemists to invent innovative strategies and methods. Among them, convergent strategy has been well recognized as an effective approach to improve efficiency. This strategy generally involves coupling of fragments with similar complexity to furnish the target molecule via subsequent cyclization or late-stage functionalization. Thus, methodologies that enable effective connection of fragments are critical to devising a convergent plan. In our laboratory, convergent strategy has served as a long-standing principle for pursuing efficient synthesis during the course of planning and implementing synthetic projects. In this Account, we summarize our endeavors in the convergent synthesis of natural products over the last ten years. We show how we identify reasonable bond disconnections and employ enabling synthetic methodologies to maximize convergency, leading to the efficient syntheses of over two-dozen highly complex molecules from eight disparate families.In detail, we categorize our work into three parts based on the diverse reaction types for fragment assembly. First, we demonstrate the application of a powerful single-electron reducing agent, SmI
2 , in a late-stage cyclization step, forging the polycyclic skeletons of structurally fascinating Galbulimima alkaloids and Leucosceptrum sesterterpenoids. Next, we showcase how three different types of cycloaddition reactions can simultaneously construct two challenging C-C bonds in a single step, providing concise entries to three distinct families, namely, spiroquinazoline alkaloids, gracilamine, and kaurane diterpenoids. In the third part, we describe convergent assembly of ent -kaurane diterpenoids, gelsedine-type alkaloids, and several drug molecules via employing some bifunctional synthons. To access highly oxidized ent -kaurane diterpenoids, we introduce the hallmark bicyclo[3.2.1]octane ring system at an early stage, and then execute coupling and cyclization by means of a Hoppe's homoaldol reaction and a Mukaiyama-Michael-type addition, respectively. Furthermore, we showcase how the orchestrated combination of an asymmetric Michael addition, a tandem oxidation-aldol reaction and a pinacol rearrangement can dramatically improve the efficiency in synthesizing gelsedine-type alkaloids, with nary a protecting group. Finally, to address the supply issue of several drugs, including anti-influenza drug zanamivir and antitumor agent Et-743, we exploit scalable and practical approaches to provide advantages over current routes in terms of cost, ease of execution, and efficiency.- Published
- 2021
- Full Text
- View/download PDF
43. Discovery of highly potent heme-displacing IDO1 inhibitors based on a spirofused bicyclic scaffold.
- Author
-
Kinzel O, Steeneck C, Anderhub S, Hornberger M, Pinto S, Morschhaeuser B, Albers M, Sonnek C, Wang Y, Mallinger A, Czekańska M, and Hoffmann T
- Subjects
- Amides chemical synthesis, Amides chemistry, Animals, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Kynurenine antagonists & inhibitors, Kynurenine biosynthesis, Lipopolysaccharides antagonists & inhibitors, Lipopolysaccharides pharmacology, Mice, Molecular Structure, Oxamic Acid chemical synthesis, Oxamic Acid chemistry, Structure-Activity Relationship, Amides pharmacology, Bridged Bicyclo Compounds pharmacology, Drug Discovery, Enzyme Inhibitors pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors, Oxamic Acid pharmacology
- Abstract
Through structural modification of an oxalamide derived chemotype, a novel class of highly potent, orally bioavailable IDO1-specific inhibitors was identified. Representative compound 18 inhibited human IDO1 with IC
50 values of 3.9 nM and 52 nM in a cellular and human whole blood assay, respectively. In vitro assessment of the ADME properties of 18 demonstrated very high metabolic stability. Pharmacokinetic profiling in mice showed a significantly reduced clearance compared to the oxalamides. In a mouse pharmacodynamic model 18 nearly completely suppressed lipopolysaccharide-induced kynurenine production. Hepatocyte data of 18 suggest the human clearance to be in a similar range to linrodostat (1)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
44. 2-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives: Simplification and modification of aconitine scaffold for the discovery of novel anticancer agents.
- Author
-
Zhang Y, Zhang TJ, Li XY, Liang JW, Tu S, Xu HL, Xue WH, Qian XH, Zhang ZH, Zhang X, and Meng FH
- Subjects
- Aconitine chemical synthesis, Aconitine chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Aza Compounds chemical synthesis, Aza Compounds chemistry, Aza Compounds pharmacology, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacology, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HSP90 Heat-Shock Proteins antagonists & inhibitors, Humans, Molecular Docking Simulation, Molecular Structure, Octanes chemical synthesis, Octanes chemistry, Octanes pharmacology, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Triazoles pharmacology, Aconitine pharmacology, Antineoplastic Agents pharmacology, Drug Discovery
- Abstract
The molecular chaperone heat shock protein 90 (Hsp90) is a promising target for cancer therapy. Natural product aconitine is a potential Hsp90 inhibitor reported in our previous work. In this study, we designed and synthesized a series of 2-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[3.2.1]octan-3-one derivatives as potent Hsp90 inhibitors by simplifying and modifying aconitine scaffold. Among these compounds, 14t exhibited an excellent antiproliferative activity against LoVo cells with an IC
50 value of 0.02 μM and a significant Hsp90α inhibitory activity with an IC50 value of 0.71 nM. Molecular docking studies provided a rational binding model of 14t in complex with Hsp90α. The following cell cycle and apoptosis assays revealed that compound 14t could arrest cell cycle at G1/S phase and induce cell apoptosis via up-regulation of bax and cleaved-caspase 3 protein expressions while inhibiting the expressions of bcl-2. Moreover, 14t could inhibit cell migration in LoVo and SW620 cell lines. Consistent with in vitro results, 14t significantly repressed tumor growth in the SW620 xenograft mouse model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
45. Cholesteryl ester transfer protein (CETP) inhibitors based on cyclic urea, bicyclic urea and bicyclic sulfamide cores.
- Author
-
Liu J, Shao PP, Guiadeen D, Krikorian A, Sun W, Deng Q, Cumiskey AM, Duffy RA, Murphy BA, Mitra K, Johns DG, Duffy JL, and Vachal P
- Subjects
- Animals, Anticholesteremic Agents metabolism, Anticholesteremic Agents therapeutic use, Cholesterol Ester Transfer Proteins metabolism, Cholesterol, HDL blood, Cyclization, Dyslipidemias drug therapy, Dyslipidemias pathology, Humans, Mice, Mice, Transgenic, Structure-Activity Relationship, Sulfonamides metabolism, Sulfonamides therapeutic use, Urea metabolism, Urea therapeutic use, Anticholesteremic Agents chemical synthesis, Bridged Bicyclo Compounds chemistry, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Sulfonamides chemistry, Urea analogs & derivatives
- Abstract
Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described., (Copyright © 2020. Published by Elsevier Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
46. Synthesis of Three-Dimensionally Fascinating Diterpenoid Alkaloids and Related Diterpenes.
- Author
-
Liu XY, Wang FP, and Qin Y
- Subjects
- Alkaloids chemistry, Biological Products chemistry, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Cyclization, Cycloaddition Reaction, Diterpenes chemical synthesis, Molecular Conformation, Oxidation-Reduction, Stereoisomerism, Alkaloids chemical synthesis, Biological Products chemical synthesis, Diterpenes chemistry
- Abstract
Three-dimensional cage-like natural products represent astounding and long-term challenges in the research endeavors of total synthesis. A central issue that synthetic chemists need to address lies in how to efficiently construct the polycyclic frameworks as well as to install the requisite substituent groups. The diterpenoid alkaloids that biogenetically originate from amination of diterpenes and diversify through late-stage skeletal reorganization belong to such a natural product category. As the characteristic components of the Aconitum and Delphinium species, these molecules display a rich array of biological activities, some of which are used as clinical drugs. More strikingly, their intricate and beautiful architectures have rendered the diterpenoid alkaloids elusive targets in the synthetic community. The successful preparation of these intriguing compounds relies on the development of innovative synthetic strategies.Our laboratory has explored the total synthesis of a variety of diterpenoid alkaloids and their biogenetically related diterpenes over the past decade. In doing so, we have accessed 6 different types of skeletons (atisine-, denudatine-, arcutane-, arcutine-, napelline-, and hetidine-type) and achieved the total synthesis of 6 natural products (isoazitine, dihydroajaconine, gymnandine, atropurpuran, arcutinine, and liangshanone). Strategically, an oxidative dearomatization/Diels-Alder (OD/DA) cycloaddition sequence was widely employed in our synthesis to form the ubiquitous [2.2.2]-bicyclic ring unit and its related ring-distorted derivatives in these complex target molecules. This protocol, in combination with additional bond-forming key steps, allowed us to prepare the corresponding polycyclic alkaloids and a biogenetically associated diterpene. For example, bioinspired C-H activation, aza -pinacol, and aza -Prins cyclizations were used toward a unified approach to the atisine-, denudatine-, and hetidine-type alkaloids via ajaconine intermediates in our first work. To pursue the synthesis of atropurpuran and related arcutine alkaloids, we harnessed a ketyl-olefin radical cyclization to assemble the carbocycle and an aza -Wacker cyclization to construct the unusual pyrrolidine ring. Furthermore, a one-pot alkene cleavage/Mannich cyclization tactic, sequential Robinson annulation, and intramolecular aldol addition were developed, which facilitated the formation of the napelline alkaloid scaffold and the first total synthesis of liangshanone. Finally, the utility of the Mannich cyclization and enyne cycloisomerization reactions allowed for access to the highly functionalized A/E and C/D ring fragments of aconitine (regarded as the "Holy Grail" of diterpenoid alkaloids). This Account provides insight into our synthetic designs and approaches used toward the synthesis of diterpenoid alkaloids and relevant diterpenes. These endeavors lay a foundation for uncovering the biological profiles of associated molecules and also serve as a reference for preparing other three-dimensionally fascinating natural products.
- Published
- 2021
- Full Text
- View/download PDF
47. Reaction of 3-Oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate with Dimethylsulfoxonium Methylide.
- Author
-
Hsieh YH, Iwasaki H, Iwai Y, Tanabe Y, Taketomo R, Yamanishi S, Tanaka Y, Kojima N, and Yamashita M
- Subjects
- Bridged Bicyclo Compounds chemical synthesis, Carboxylic Acids chemical synthesis, Crystallography, X-Ray, Cyclopropanes chemical synthesis, Cyclopropanes chemistry, Models, Molecular, Sulfonium Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Carboxylic Acids chemistry, Sulfonium Compounds chemistry
- Abstract
We have been interested in the reactivities of small-ring compounds and have reported reactions that proceed through cyclopropane intermediates starting from coumarin derivatives bearing an electron-withdrawing group at the 3-position or 2-oxo-2H-pyran-3-carboxylate derivatives and dimethylsulfoxonium methylide. This time, the reaction between 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate and dimethylsulfoxonium methylide has been investigated. 3a,4,5,7a-Tetrahydro-7-hydroxybenzofuran-6-carboxylate and/or 2-hydroxybicyclo[4.1.0]hept-2-ene-3-carboxylate were obtained. The compounds were characterized using various spectral and X-ray crystallographic techniques. A plausible reaction mechanism has been discussed. This reaction was applied to some 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate derivatives to clarify the generality.
- Published
- 2021
- Full Text
- View/download PDF
48. Molecular Transformation Based on an Innovative Catalytic System.
- Author
-
Takemoto Y
- Subjects
- Benzoic Acid chemistry, Boron chemistry, Bridged Bicyclo Compounds chemistry, Catalysis, Cyclopropanes chemistry, Hydrogen Bonding, Kinetics, Ligands, Molecular Structure, Bridged Bicyclo Compounds chemical synthesis, Cyclopropanes chemical synthesis, Thiourea chemistry
- Abstract
Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important pharmaceuticals and natural products. Benzothiadiazines possess a stronger hydrogen-bond donor ability compared to thioureas and exhibit remarkable catalytic performance for the activation of α,β-unsaturated amides. Hybrid thioureas (bearing an arylboronic acid and an ammonium salt) efficiently promote the hetero-Michael addition to α,β-unsaturated carboxylic acids and the O-alkylation of keto enols with 5-chlorofuran-2(5H)-one. These hybrid catalysts enable the first total synthesis of non-racemic avenaol, a noncanonical strigolactone, as well as the asymmetric synthesis of several pharmaceuticals. In addition, this study discovers unique chemical phenomena (i.e., the dual role of benzoic acid as a boron ligand and a proton shuttle, the chirality switch of products by solvent used, and the dynamic kinetic resolution of a racemic electrophile in an S
N 2-type reaction).- Published
- 2021
- Full Text
- View/download PDF
49. Ferula L. Plant Extracts and Dose-Dependent Activity of Natural Sesquiterpene Ferutinin: From Antioxidant Potential to Cytotoxic Effects.
- Author
-
Macrì R, Musolino V, Gliozzi M, Carresi C, Maiuolo J, Nucera S, Scicchitano M, Bosco F, Scarano F, Ruga S, Zito MC, Guarnieri L, Bombardelli E, and Mollace V
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Antioxidants chemistry, Antioxidants therapeutic use, Apoptosis drug effects, Benzoates chemistry, Benzoates therapeutic use, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacology, Bridged Bicyclo Compounds therapeutic use, Cell Line, Tumor, Cycloheptanes chemistry, Cycloheptanes therapeutic use, Dose-Response Relationship, Drug, Electron Transport drug effects, Hormone Replacement Therapy, Humans, Mitochondria drug effects, Mitochondria metabolism, Nitric Oxide metabolism, Phytochemicals chemistry, Phytochemicals pharmacology, Phytoestrogens chemistry, Phytoestrogens pharmacology, Plant Extracts chemistry, Plant Extracts therapeutic use, Reactive Oxygen Species metabolism, Sesquiterpenes chemistry, Sesquiterpenes therapeutic use, Antineoplastic Agents pharmacology, Antioxidants pharmacology, Benzoates pharmacology, Cycloheptanes pharmacology, Ferula chemistry, Plant Extracts pharmacology, Sesquiterpenes pharmacology
- Abstract
The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug.
- Published
- 2020
- Full Text
- View/download PDF
50. Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors.
- Author
-
Sun M, Cai S, Li P, Zhang F, Zhang H, and Zhou J
- Subjects
- Amides metabolism, Amides pharmacology, Binding Sites, Cell Line, Tumor, Cell Survival drug effects, Humans, Molecular Docking Simulation, Polymorphism, Single Nucleotide, Protein Kinase Inhibitors metabolism, Protein Kinase Inhibitors pharmacology, Receptor, trkA genetics, Receptor, trkA metabolism, Structure-Activity Relationship, Amides chemistry, Bridged Bicyclo Compounds chemistry, Drug Design, Protein Kinase Inhibitors chemical synthesis, Receptor, trkA antagonists & inhibitors
- Abstract
'precision medicine' is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC
50 = 1.3 nM, TRKAG595R IC50 = 6.1 nM), and I-10 (TRKA IC50 = 1.1 nM, TRKAG595R IC50 = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC50 = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC50 was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation., (Copyright © 2020. Published by Elsevier Ltd.)- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.