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Made available in DSpace on 2022-04-28T19:47:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Dopamine is an important neurotransmitter that regulates numerous essential functions, including cognition and voluntary movement. As such, it serves as an important scaffold for synthesis of novel analogues as part of drug development effort to obtain drugs for treatment of neurodegenerative diseases, such as Parkinson's disease. To that end, similarity search of the ZINC database based on two known dopamine-1 receptor (D1R) agonists, dihydrexidine (DHX) and SKF 38393, respectively, was used to predict novel chemical entities with potential binding to D1R. Three compounds that showed the highest similarity index were selected for synthesis and bioactivity profiling. All main synthesis products as well as the isolated intermediates, were properly characterized. The physico-chemical analyses were performed using HRESIMS, GC/MS, LC/MS with UV–Vis detection, and FTIR, 1H NMR and 13C NMR spectroscopy. Binding to D1 and D2 receptors and inhibition of dopamine reuptake via dopamine transporter were measured for the synthesized analogues of DHX and SKF 38393. Laboratory of Fine Organic Chemistry Department of Chemistry and Biochemistry Faculty of Sciences and Technology of São Paulo State University, São Paulo Department of Pharmaceutical Chemistry Faculty of Life Sciences University of Vienna, Althanstraße 14 Mass Spectrometry Centre Faculty of Chemistry University of Vienna, Währinger Straße 38 Department of Analytical Chemistry Faculty of Chemistry University of Vienna, Währinger Straße 38 Centre for X-Ray Structure Analysis at Faculty of Chemistry University of Vienna, Währinger Straße 40-42 Department of Chemistry Faculty of Philosophy Sciences and Letters of Ribeirão Preto University of São Paulo, Avenida dos Bandeirantes, 3900, SP Department of Molecular Neurosciences Centre for Brain Research Medical University of Vienna, Spitalgasse 4 Department of Neuroproteomics Paracelsus Medical University Laboratory of Fine Organic Chemistry Department of Chemistry and Biochemistry Faculty of Sciences and Technology of São Paulo State University, São Paulo FAPESP: 2016/10149-0

Naturally occurring γ-butyrolactones and their synthetic analogues display a wide range of bioactivities. Here, the multicomponent reaction of dimethyl 2-benzyl-3-methylenesuccinate with bromobenzene and benzaldehyde catalyzed by cobalt (II) bromide afforded a maculalactone derivative with three stereogenic centers. This reaction presented moderate diastereoselectivity and yielded different proportions of all the four possible diastereoisomers. The anti:anti (majority), anti:syn, syn:anti, and syn:syn diastereoisomers were isolated and characterized by 1D and 2D NMR experiments. Because the stereochemical assignment of all the diastereoisomers by Nuclear Overhauser Effect Difference (NOEDiff) experiments was not definitive, the 1H and 13C NMR chemical shifts were predicted by theoretical calculations with the density functional theory at the B3LYP/6-31G(d) level. The relative configurations of all the four diastereoisomers were assigned by using the CP3 parameter to compare the experimental and the calculated data and by determining the CP3 probability, which provided high level of confidence.

The possibility of determining enantiomeric excess (ee) in chiral compounds by nuclear magnetic resonance (NMR) was discovered half a century ago and remains an important strategy nowadays. One way to determine ee in chiral compounds is to obtain diastereoisomers by using chiral derivatization agents (CDAs). CDAs bearing an aldehyde function have helped to discriminate primary chiral amines through a reaction that promptly yields imines. To the best of our knowledge, acyclic terpenes displaying an aldehyde function like S-citronellal have not been used in this context yet. In this study, we obtained excellent accuracy when we quantified aliphatic and aromatic amines by 1H and 13C NMR using S-citronellal as CDA. This analytical method proved to be fast and useful to quantify primary chiral amines.

Made available in DSpace on 2019-10-06T16:21:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-06-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000–30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, 1H and 13C NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 μM; SI = 131.8) and LQOF-G7 (IC50-ama 7.1 μM; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis. Laboratório de Química Orgânica Fina Departamento de Química e Biologia Faculdade de Ciências e Tecnologia Universidade Estadual Paulista – UNESP, Campus de Presidente Prudente, Rua Roberto Simonsen, 305 Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT) Universidade Estadual Paulista – UNESP Departamento de Análises Clínicas Faculdade de Ciências Farmacêuticas Universidade Estadual Paulista – UNESP Campus de Araraquara, Rodovia Araraquara-Jaú km1 Department of Pharmaceutical Chemistry Faculty of Life Sciences University of Vienna, Althanstraße 14 Laboratório ThoMSon de Espectrometria de Massas Instituto de Química Universidade de Campinas – UNICAMP Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo – USP, Avenida dos Bandeirantes, 3900 Department of Analytical Chemistry Faculty of Chemistry University of Vienna, Währinger Straße 38 Department of Neuroproteomics Paracelsus Medical University Laboratório de Química Orgânica Fina Departamento de Química e Biologia Faculdade de Ciências e Tecnologia Universidade Estadual Paulista – UNESP, Campus de Presidente Prudente, Rua Roberto Simonsen, 305 Programa de Pós-Graduação em Ciência e Tecnologia de Materiais (POSMAT) Universidade Estadual Paulista – UNESP Departamento de Análises Clínicas Faculdade de Ciências Farmacêuticas Universidade Estadual Paulista – UNESP Campus de Araraquara, Rodovia Araraquara-Jaú km1 FAPESP: 2013/08248-1 FAPESP: 2013/24487-6 FAPESP: 2016/19289-9 FAPESP: 2017/03552-5

This Letter describes the use of NbCl5 as the Lewis acid in Friedel–Crafts reactions, in which a bifunctional electrophile reacts inter- and intramolecularly with an aromatic ring to produce a number of indanones in a single step, maintaining mild conditions and good yields.

Phytochemical investigation of Pogonopus tubulosus trunk led to the isolation of isotubulosine and alangiside, tetrahydroisoquinoline indolic monoterpene alkaloids reported here for the first time for the family Rubiaceae and the genus Pogonopus, respectively. Isotubulosine proved cytotoxic against MCF-7, PC-3, 786-0, HT-29, and HL-60 human cancer cell lines, with GI50 values ranging from 5.26 to 20.61 μM, in addition to causing G2/M arrest, possibly by inhibiting DNA topoisomerase IIα. Alangiside showed weak cytotoxicity against MCF-7 and HL-60 and proved inactive against PC-3, HT-29, and 786-0 cell lines, with no sign of apoptosis. The alkaloid structures were established on the basis of 1D- and/or 2D-NMR, optical rotation, and HR ESIMS data. Complete 1H NMR assignments of isotubulosine were also performed, using 1H-1H COSY, HSQC, HMBC, NOESY, and 1H J-resolved techniques and employing experimental and calculated values of homonuclear coupling constants based on the lowest energy conformations. The foregoing results provide new information on the cytotoxicity and mechanism of action of tetrahydroisoquinoline indole monoterpene-type alkaloids and reveal isotubulosine to merit further studies as a potential anticancer agent.

We describe here the dynamic 1 H NMR studies of dimethyl 2-(triphenylphosphoranylidene) succinate ( 1 ). Phosphorane 1 has a bond presenting slow (in the 1 H NMR time scale) rotation which results in spectra of two isomers at the same time. From the spectral data were calculated the rate constant and thermodynamic parameters for the rotational process.

The direct E/Z configuration assignment of tri- and tetra-substituted stilbenes (and other analogous olefins) when only one of the isomers is available is a quite challenging task. Sometimes, a chemical transformation or some other tedious method is necessary for determination of the double bond substitution pattern. In this paper, we relied on theoretical calculation of chemical shifts as a complementary tool for 1H NMR determination of the configuration of an α-phenylcinnamic acid prepared as a unique isomer by the Perkin reaction.

2D DOSY 1H NMR has proved to be a useful technique in the identification of the molecular skeleton of the four major compounds of ethyl acetate extract of aerial parts of Bidens sulphurea (Asteraceae). The combination of this technique with HPLC, mass spectrometry and other NMR techniques enabled the identification of four flavonoid glycosides: quercetin-3-O-β-D-galactopyranoside, quercetin-3-O-β-D-glycopyranoside, quercetin-3-O-α-L-arabinofuranoside and quercetin-3-O-β-D-rhamnopyranoside. Copyright © 2009 John Wiley & Sons, Ltd.

A highly efficient two-step method for the synthesis of pyranoquinoline derivatives from imino-Diels-Alder reactions be- tween aldimines and 3,4-dihydro-2H-pyran using niobium(V) chlo- ride as catalyst under mild conditions is described.

The behavior of several epoxides when treated with NbCl5 was studied. In general, the studied epoxides reacted rapidly with NbCl5, giving, in most cases, more than one product (chlorohydrins, products containing solvent residues, as well as rearrangement products). A detailed study was performed to verify the effects of the temperature (rt, 0°C, or −78°C) and of the NbCl5 molar concentration on the composition of the products, yield, and time required for the reactions.

The keto–enol tautomerization for 4,4-dimethyl-cyclohexane-1,3-dione ( 1 ) and for 4-methyl-cyclohexane-1,3-dione ( 2 ) was investigated. We observed that one of the possible keto-enolic forms for each compound is more stable than the other and thus was preferentially formed in the keto–enol tautomerism. This study was supported through NMR analysis, geometry optimization calculations and NBO analysis for keto-enolic forms ( 3 and 4 ) and ( 5a , b and 6a , b) .

This facile protocol allows the synthesis of indanones through Friedel—Crafts reaction of dimethylacrylic acid with toluene and xylenes.

Complex 1H NMR spectra multiplets that cannot be easily understood by simple inspection are rather frequent in the daily work of the organic chemistry analyst. The multiple and excellent new techniques available from modern instruments usually provide satisfactory solutions, but there are still many cases where a simulation is necessary, at least to obtain a final confirmation. It is extremely convincing to see that a graph, obtained by calculations with chemical-shift and coupling-constant values only, can be virtually identical to the experimental spectrum. This paper describes a computer program to make such calculations. The program is free and can be downloaded from http://artemis.ffclrp.usp.br/NMR.htm (click on SimEsp_NMR_Compil.zip). All routines are also available and may be used without any restrictions. The paper includes a fairly detailed discussion about how the calculations are made.

In this paper we present a complete 1H and 13C NMR spectral analysis of three lignan lactones (methylpluviatolide, dimethylmatairesinol and hinokinin) by the use of techniques such as COSY, HMQC, HMBC and J-resolved. Complete assignment and all homonuclear hydrogen coupling constant measurements were performed, providing enough data also to the confirmation of the relative stereochemistry.

Theoretical methods were used for the correct structure assignments of the natural products jungianol and mutisianthol. A three stage protocol for the calculation was used: a conformational search using molecular mechanics (MM3), a DFT (B3LYP) structure optimization and ab initio (HF/GIAO) or DFT (B3LYP/GIAO) calculation of magnetic properties.

A complete NMR analysis with full assignment for 1H and 13C NMR spectral data for 5-(acetyloxy)-3-hydroxy-9,10-dimethoxy-6-oxo-11-oxatricyclo[6.2.1.02,7]undec-2-yl acetate (8) is described. This compound was prepared by rapid hydrogenation of the unstable Diels–Alder adduct obtained from the reaction between 3,4-dimethoxyfuran (4) and 2,5-diacetoxy-1,4-benzoquinone (5). Full homonuclear hydrogen coupling constants measurements and molecular mechanics calculations were performed for the determination of the relative stereochemistry. Copyright © 2005 John Wiley & Sons, Ltd.

A detailed NMR analysis with total assignment of 1 H and 13 C NMR data for the endo and the exo adducts, obtained by Diels–Alder reaction between 2-cyclohexenone and cyclopentadiene, is described. The unequivocal assignment of the endo and exo structures was performed by 1 H and 13 C NMR. These assignments were supported by theoretical chemical shift calculations at GIAO/HF level using 6-311+g(2d,p) from optimized structures at the B3LYP/6-31g(d) level.

GIAO and CSGT models at Hartree–Fock and DFT/B3LYP levels of theory using different basis sets were employed for calculations of 1 H and 13 C NMR chemical shifts for para -X-substituted (X = H, CH 3 O and NO 2 ) aromatic carbonyl compounds. For these compounds the best choice to evaluate theoretical chemical shifts is B3LYP/cc-pVDZ using CSGT model.

We describe the complete 1H and 13C NMR analysis of three aryltetralin lignan lactones (polygamain, morelensin and 4,5-dimethoxymorelensin) using modern NMR techniques such as COSY, HMQC, HMBC, 2D-J-resolved and NOE experiments. The relative stereochemistry of these compounds, which is very important with regard to their biological activity, was completely determined. Copyright © 2004 John Wiley & Sons, Ltd.

2012Non-substituted B-ring flavonoids and anindole alkaloid from Piper aleyreanum(Piperaceae) BIOCHEMICAL SYSTEMATICS AND ECOLOGY, OXFORD, v. 45, n. 1, Special Issue, supl. 1, Part1, pp. 206-208, DEC, 2012http://www.producao.usp.br/handle/BDPI/37434 Downloaded from: Biblioteca Digital da Producao Intelectual - BDPI, Universidade de Sao Paulo

The present phytochemical investigation on Maytenus guianensis led to the isolations of nine triterpenes, including friedelanes, friedo-nor-oleanane, oleanane and ursane and one steroid. All of them were isolated from this plant for the first time. The presences of friedo-nor-oleanane triterpenoids might be employed as the common characteristic constituents of both Hippocrateaceae and Celastraceae family.

In this paper we describe an approach for teaching the relation between chemical equilibrium and free energy that is, according to our experience, very efficient and enlightening. This approach has a strong visual appeal and can be used at different levels, from simple presentation of the results as graphs of free energy versus reaction mixture composition, up to full derivation of formulas to find the equations of the curves.

In this paper we describe the synthesis of a γ,δ-unsaturated aldehyde from a bicyclic Diels-Alder adduct, to be used in future electrocyclic reaction studies. A number of reactions produced undesired materials resulting from the interaction between functions, forcing the use of partial protection to accomplish a synthesis that would be otherwise straightforward. Suggestions to account for the results are given.

Purification and bioassay-guided fractionation were employed to isolate proanthocyanidins with antioxidant activity from peanut skin (Arachis hypogaea Runner 886). The crude extract was prepared with acetone (60% v/v) and purified using chromatographic methods, including a semipreparative HPLC technique. As a result, two proanthocyanidins were isolated and identified using NMR, epicatechin-(2 β → O → 7, 4 β → 8)-catechin (proanthocyanidin A1) and epicatechin-(β → 2 O → 7, 4 β → 8)-epicatechin (proanthocyanidin A2). Despite the structural similarity, differences were observed in their antioxidant activity. Proanthocyanidin A1 proved to be more active, with EC50 value for DPPH radical scavenging of 18.25 μg/mL and reduction of Fe(3+)-TPTZ complex of 7.59 mmol/g, higher than that of synthetic antioxidant BHT. This compound evaluated by ABTS(+) was similar to that of natural quercetin. Therefore, peanut skin is an important source of bioactive compounds that may be used as a mild antioxidant for food preservation.

A bicyclo[6.2.1]undecane model compound (VI) of the core structure of the biologically active furanoheliangolide sesquiterpene is synthesized.

The long-range ( 4 J HH ) coupling constants of 28 compounds, cyclopentane and cyclohexane derivatives, have been analyzed by means of principal component analysis (PCA). The corresponding dihedral angles ( θ 1 and θ 2 ) and cos 2 θ 1 cos 2 θ 2 , besides the ‘ W ’ constants, were utilized as variables in multivariable data analysis. Dihedral (torsion) angles were calculated utilizing three different methods: PC Model, CS Mopac Pro and gaussian98 , to improve data reliability. The measured 4 J HH showed a clear tendency of increasing with the variations in torsion angles from approximately 90–180°, as expected. PCA allowed discrimination of the behaviour of various compounds. It was noted that the compounds analyzed exhibit strong clustering due to structural similarities. Particularly interesting results were obtained in the PCA of gaussian98 data, where seven different clusters of compounds were found.

NMR chemical shifts have been experimentally measured and theoretically estimated for all the carbon atoms of (1R,3S,4S,8S)-p-menthane-3,9-diol in chloroform solution. Theoretical estimations were performed using a combination of molecular dynamics simulations and quantum mechanical calculations. Molecular dynamics simulations were used to obtain the most populated conformations of the (1R,3S:4S,8S)-p-menthane-3,9-diol as well as the distribution of the solvent molecules around it. Quantum mechanical calculations of NMR chemical shifts were performed on the most relevant conformations employing the GIAO-DFT formalism. A special emphasis was put in evaluating the effects of the surrounding solvent molecules. For this purpose, supermolecule calculations were performed on complexes constituted by the solute and n chloroform molecules, where n ranges from 3 to 16. An excellent agreement with experimental data has been obtained following this computational strategy.

Several benzofuranofuran derivatives were synthesized employing intramolecular cycloaddition reactions of ketenes with alkenes. (Alkenyloxy)ketenes, prepared from the tosylate by treatment with triethylamine, easily undergo intramolecular [2 + 2] cycloaddition to give tricyclic benzocyclobutafuranones. Baeyer-Villiger oxidation of the cycloadducts gives benzofurano-furanones, which are closely related to natural products with anticoagulant and antimalarial properties.

A set of amphiphilic p-menthan-3,9-diols have been investigated by molecular dynamics simulations. These are four stereoisomers than can be specifically obtained from two terpenoids widely used in biorganic chemistry. For this purpose, the p-menthan-3,9-diols have been explicitly parametrized using both semiempirical and ab initio quantum mechanical calculations. The reliability of these parameters has been validated by predicting different molecular and thermodynamic properties. Molecular dynamics simulations in aqueous solution have been performed with the new parameters. The results provide useful insights about the conformational properties of this family of compounds and the formation of intra- and intermolecular hydrogen bonds.

In this paper we describe the peculiar properties of a polycyclic compound (2), derived from a Diels–Alder adduct, which undergoes spontaneous cyclization to 3 when kept in chloroform solution. Stable intermediates needed for our studies on the synthesis of heliangolides were obtained only after reduction of the double bonds of 2.

The conformational preferences of p-menthan-3,9-diols in both aqueous and chloroform solutions have been investigated by molecular dynamics simulations. The effects of changing the stereochemistry at the C3 atom on the dynamics of these compounds have been studied by considering the two epimers. The results reveal a strong dependence of conformation on both the stereochemistry and the environment. In some cases the formation of an intramolecular hydrogen bond stabilises unusual conformations for the cyclohexane ring.

Goyazensolide, a biologically active natural product classified as a furoheliangolide, was transformed in a phthalimide derivative that showed an enhanced biological activity against Tripanosoma cruzi. The complex natural product was also reduced with high stereoselectivity by hydrogen/Wilkinson’s catalyst, an epimer of this product was obtained in the reduction with hydrogen/Pd-C.

The synthesis of 2-methoxy-4-methylpyridine-3-carbonitrile (3) and its conversion, by way of alkylation of the C(4) methyl group, into the pyrodyl acetic acid ester 6 is described.

The core structure of the natural sesquiterpene lactones furanoheliangolides, an 11-oxabicyclo[6.2.1]undecane system, was synthesized through a pathway involving two Diels–Alder reactions.

A rationalization is suggested which can help organic chemists in realizing analyses of the relative stereochemistry of substituted cyclopentanes by proton NMR, through the coupling constants between vicinal hydrogens. Some useful generalizations, derived from the dihedral angles found for cyclopentane through a molecular mechanics program, are given.

Abstract: In this paper we describe a very short stereoselective synthesis of the β-ethoxylactone 13, a model structure for compounds isolated from Otoba parvifolia. The method, which also produces β-hydroxy-esters and β-hydroxy-lactones, is based on a chemo- and stereoselective Reformatsky reaction.

Over the years researchers have been increasingly interested in the Michael addition [1], because this is one of the most useful reactions for the construction of carbon-carbon bonds, particularly in the synthesis of naturally occurring products and compounds with biological and pharmacological activity [2]. We report here some experimental results involving NbCl5 mediated Michael addition followed by cyclization to bicyclic systems. Bicyclic compounds are traditionally synthesized through Diels Alder reactions. In this work, bicyclo[2.2.2]octan-2-ones have been synthesized using cross-conjugate dienes derived from cyclohexenones [3].

Lewis acid catalyzed ring opening of these epoxides usually follow some well defined paths: the intermediate carbocation is always formed in the carbon atom farther from the carbonyl group (III) (Scheme 1), because this group destabilizes positive charges in α-position. The carbocation can either undergo acyl migration or H + elimination (or hydrogen migration) to form a ring-contracted aldehyde (A) or an αdiketone (B) (Scheme 1). Scheme 1: Lewis acid catalyzed rearrangement of cyclic 2,3-epoxy ketones.