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A new mesembrine-type alkaloid, named sarniensine, was isolated together with tazettine, lycorine, the main alkaloid, and 3-epimacronine from Nerine sarniensis, with the last two produced for the first time by this plant. This Amaryllidaceae, which is indigenous of South Africa, was investigated for its alkaloid content, because the organic extract of its bulbs showed strong larvicidal activity with an LC 50 value of 0.008μgμL -1 against first instar Aedes aegypti larvae and with an LD 50 value 4.6μg/mosquito against adult female Ae. aegypti, which is the major vector for dengue, yellow fever and the Zika virus. The extract did not show repellency at MED value of 0.375mgcm 2 against adult Ae. aegypti. Sarniensine was characterized using spectroscopic and chiroptical methods as (3aR,4Z,6S,7aS)-6-methoxy-3a-(2'-methoxymethyl-benzo [1,3]dioxol-1'-yl)-1-methyl-2,3,3a,6,7,7a-hexahydro-1H-indole. It was less effective against larva at the lowest concentration of 0.1μgμL -1 , however it showed strong adulticidal activity with an LD 50 value of 1.38±0.056μgmosquito -1 ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Two new Amaryllidaceae alkaloids, belonging to the mesembrine- and crinine-types, named crinsarnine ( 1 ) and sarniensinol ( 2 ), were isolated from the dried bulbs of Nerine sarniensis together with bowdensine ( 3 ), sarniensine ( 4 ), hippadine ( 5 ) and 1- O -acetyl-lycorine ( 6 ). Crinsarnine ( 1 ) and sarniensinol ( 2 ) were characterized using spectroscopic and chiroptical methods as (1 S ,2 S ,4a R ,10b S )-2,7-dimethoxy-1,2,3,4,4a,6-hexahydro-5,11b-ethano[1,3]dioxolo-[4,5- j ]phenanthridin-1-yl acetate and (6-(3a R ,4 Z ,6 S ,7a S )-6-methoxy-1-methyl-2,3,3a,6,7,7a-hexa-hydro-1 H -indol-3a-yl)benzo[ d ][1,3]dioxol-5-yl)methanol, respectively. Furthermore, the complete spectroscopic characterization of bowdensine ( 3 ) is reported for the first time. Compounds 1 - 6 were evaluated against the Orlando reference strain of Aedes aegypti . None of compounds showed mortality against 1st instar Ae. aegypti larvae at the concentrations tested. In adult topical bioassays, only 1 displayed adulticidal activity with an LD 50 = 2.29 ± 0.049 μg/mosquito. As regards the structure-activity relationship, the pretazettine and crinine scaffold in 2 and 4 and in 1 and 3 respectively, proved to be important for their activity, while the pyrrole[ de ]phenanthridine scaffold present in 5 and 6 was important for their reactivity. Among the pretazettine group compounds, opening of the B ring or the presence of a B ring lactone as well as the trans -stereochemistry of the A/B ring junction, appears to be important for activity, while in crinine-type alkaloids, the substituent at C-2 seems to play a role in their activity.

The development of novel anti-HIV agents remains an important medicinal chemistry challenge given that no cure for the disease is imminent, and the continued use of current NNRTIs inevitably leads to problems associated with resistance. Inspired by the pyrazole-containing NNRTI lersivirine (LSV), we embarked upon a study to establish whether 1,2,3-triazole heterocycles could be used as a new scaffold for the creation of novel NNRTIs. An especially attractive feature of triazoles used for this purpose is the versatility in accessing variously functionalised systems using either the thermally regulated Huisgen cycloaddition, or the related 'click' reaction. Employing three alternative forms of these reactions, we were able to synthesise a range of triazole compounds and evaluate their efficacy in a phenotypic HIV assay. To our astonishment, even compounds closely mimicking LSV were only moderately effective against HIV., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Seventeen silyl- and trityl-modified (5'-O- and 3',5'-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100μM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI50 values, with the best results being values of ∼25μM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Docking studies of tubulin-targeting C2-substituted 7-deazahypoxanthine analogues of marine alkaloid rigidins led to the design and synthesis of compounds containing linear C2-substituents. The C2-alkynyl analogue was found to have double- to single-digit nanomolar antiproliferative IC50 values and showed statistically significant tumor size reduction in a colon cancer mouse model at nontoxic concentrations. These results provide impetus and further guidance for the development of these rigidin analogues as anticancer agents.

Background: Use of nucleic acids to treat acquired or inherited hepatic diseases has considerable potential. Although recombinant viruses are popular vectors, interest in cheaper, often less immunogenic, non-viral modalities, is increasing. Thus hepatotropic, galactosylated lipoplexes directed to the hepatic asialoglycoprotein receptor (ASGP-R) are promising candidates., Objective: Here we examine the effect that galactosyl ligand spacer length has on the transfection activity of ASGP-Rtargeted lipoplexes in the human hepatoma cell line HepG2., Methods: Galactosyl ligands with spacer lengths in the range 2.4-24.1 Å were prepared and formulated into lipoplexes that were characterized by cryo-TEM, band shift, dye displacement and nuclease digestion assays. Cytotoxicity and transfection profiles were determined in liver-derived HepG2 cells and the renal ASGP-R-negative HEK293 line., Results: Lipoplexes, which formed at endpoint +/- charge ratios in the range 1:1-3:1, accorded cargo DNA good protection from serum nuclease digestion and were well-tolerated by both cell lines. Transfection activities in the hepatoma cell line decreased markedly in the presence of a competing ASGP-R cognate ligand and also as the ligand spacer length increased, while activities in HEK293 cells were significantly lower (P <0.05-0.001)., Conclusion: Targeted lipoplexes enter HepG2 cells by receptor mediation and the uptake of transfecting complexes and those displaying more rigid short and medium length spacers is more efficient. This observation will inform the design of hepatotropic lipoplexes that are suitable for applications in vivo.

Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiper L., is a known agonist of the transient receptor potential vanilloid 1 (TRPV1). In this investigation a series of polygodial analogues were prepared and investigated for TRPV1-agonist and anticancer activities. These experiments led to the identification of 9-epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9-Epipolygodial was found to maintain potency against apoptosis-resistant cancer cells as well as those displaying the multidrug-resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal-Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a sesquiterpenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Although fungi produce highly structurally diverse metabolites, many of which have served as excellent sources of pharmaceuticals, no fungi-derived agent has been approved as a cancer drug so far. This is despite a tremendous amount of research being aimed at the identification of fungal metabolites with promising anticancer activities. This review discusses the results of clinical testing of fungal metabolites and their synthetic derivatives, with the goal to evaluate how far we are from an approved cancer drug of fungal origin. Also, because in vivo studies in animal models are predictive of the efficacy and toxicity of a given compound in a clinical situation, literature describing animal cancer testing of compounds of fungal origin is reviewed as well. Agents showing the potential to advance to clinical trials are also identified. Finally, the technological challenges involved in the exploitation of fungal biodiversity and procurement of sufficient quantities of clinical candidates are discussed, and potential solutions that could be pursued by researchers are highlighted., (© 2015 Wiley Periodicals, Inc.)

Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homology (PH) domain-dependent covalent-allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chemical biology and medicinal chemistry research., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mono-antennary galacto derivatives of cholesterol are being actively developed to direct lipoplexes to the asialoglycoprotein receptor (ASGP-R) on hepatocytes. Here we report on a novel ASGP-R ligand cholest-5-en-3-yl [1-(β-D-galactopyranosyl)-1H-1,2,3-triazol-4-yl]methylcarbamate (4), assembled by a copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry), and compare it with cholest-5-en-3-yl-β-D-galactopyranoside (2) and cholest-5-en-3-yl [1-(β-D-galactopyranosyl-1'-oxy)phen-4-yl]carbamate (3), in liposome formulations with or without 5 mol% distearoylphosphatidylethanolamine poly(ethylene glycol)2000, intended for DNA delivery to ASGP-R-positive hepatocyte-derived HepG2 cells and the ASGP-R-negative embryo kidney cell line HEK293. Transfection levels attained with lipoplex 4 were 100 and 300% greater than those for lipoplexes 2 and 3 respectively in HepG2 cells, while competition assays reduced transfection levels by up to 98%. Transfection activities achieved in HEK293 cells were up to three orders of magnitude lower. Therefore, 4 is representative of a new class of promising hepatotropic ligands for gene delivery.

Using 2,8-bis(trifluoromethyl)quinoline, the pharmacophore of mefloquine, as scaffold, eleven novel triazole-linked compounds have been synthesised by the application of CuAAC chemistry. The in vitro biological activity of the compounds on the Plasmodium falciparum chloroquine-sensitive strain NF54 was then determined. The compounds all showed IC50s in the lower μM range with (1R,3S,5R)-N-{[1-(2,8-bis(trifluoromethyl)quinoline-4-yl)-1H-1,2,3-triazol-4-yl]methyl}adamantan-2-amine (29) exhibiting the best activity of 1.00 μM., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

As a continuation of the studies aimed at the development of new anticancer agents derived from the Amaryllidaceae alkaloid lycorine, 35 C1,C2-ether analogues of this natural product were synthesized. The compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines with varied levels of apoptosis resistance. A strong correlation between the compound lipophilicity and anticancer activity was observed, indicating that cell permeability properties must be an important determinant in the design of lycorine-based anticancer agents. A theoretical docking model, consistent with the experimental observations, is presented., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In the attempt to discover novel chemical scaffolds that can modulate the activity of disease-associated enzymes, such as kinases, biochemical assays are usually deployed in high-throughput screenings. First-line assays, such as activity-based assays, often rely on fluorescent molecules by measuring a change in the total emission intensity, polarization state, or energy transfer to another fluorescent molecule. However, under certain conditions, intrinsic compound fluorescence can lead to difficult data analysis and to false-positive, as well as false-negative, hits. We have reported previously on a powerful direct binding assay called fluorescent labels in kinases ('FLiK'), which enables a sensitive measurement of conformational changes in kinases upon ligand binding. In this assay system, changes in the emission spectrum of the fluorophore acrylodan, induced by the binding of a ligand, are translated into a robust assay readout. However, under the excitation conditions of acrylodan, intrinsic compound fluorescence derived from highly conjugated compounds complicates data analysis. We therefore optimized this method by identifying novel fluorophores that excite in the far red, thereby avoiding compound fluorescence. With this advancement, even rigid compounds with multiple π-conjugated ring systems can now be measured reliably. This study was performed on three different kinase constructs with three different labeling sites, each undergoing distinct conformational changes upon ligand binding. It may therefore serve as a guideline for the establishment of novel fluorescence-based detection assays.

The human immunodeficiency virus (HIV) causes AIDS (acquired immune deficiency syndrome), a disease in which the immune system progressively deteriorates, making sufferers vulnerable to all manner of opportunistic infections. Currently, world-wide there are estimated to be 34 million people living with HIV, with the vast majority of these living in sub-Saharan Africa. Therefore, an important research focus is development of new drugs that can be used in the treatment of HIV/AIDS. This review gives an overview of the disease and addresses the drugs currently used for treatment, with specific emphasis on new developments within the class of allosteric non-nucleoside reverse transcriptase inhibitors (NNRTIs).

The HIV pandemic represents one of the most serious diseases to face mankind in both a social and economic context, with many developing nations being the worst afflicted. Due to ongoing resistance issues associated with the disease, the design and synthesis of anti-HIV agents presents a constant challenge for medicinal chemists. Utilizing molecular modeling, we have designed a series of novel cyclopropyl indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors and carried out their preparation. These compounds facilitate a double hydrogen bonding interaction to Lys101 and efficiently occupy the hydrophobic pockets in the regions of Tyr181/188 and Val179. Several of these compounds inhibited HIV replication as effectively as nevirapine when tested in a phenotypic assay.

The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine's natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to pro-apoptotic stimuli. Bulbispermine, haemanthamine, and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited notable growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion; they displayed similar potencies in both cell types, indicating that the induction of apoptosis is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this paper, we present the structure-based design, synthesis and biological activity of N-pyrazole, N'-thiazole-ureas as potent inhibitors of p38α mitogen-activated protein kinase (p38α MAPK). Guided by complex crystal structures, we employed the initially identified N-aryl, N'-thiazole urea scaffold and introduced key structural elements that allowed the formation of novel hydrogen bonding interactions within the allosteric site of p38α, resulting in potent type III inhibitors. [4-(3-tert-Butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl)-phenyl]acetic acid 18c was found to be the most potent compound within this series and inhibited p38α activity with an IC(50) of 135 ± 21 nM. Its closest analog, ethyl [4-(3-tert-butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]acetate 18b, effectively inhibited p38α mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The vast majority of small molecules known to modulate kinase activity, target the highly conserved ATP-pocket. Consequently, such ligands are often less specific and in case of inhibitors, this leads to the inhibition of multiple kinases. Thus, selective modulation of kinase function remains a major hurdle. One of the next great challenges in kinase research is the identification of ligands which bind to less conserved sites and target the non-catalytic functions of protein kinases. However, approaches that allow for the unambiguous identification of molecules that bind to these less conserved sites are few in number. We have previously reported the use of fluorescent labels in kinases (FLiK) to develop direct kinase binding assays that exclusively detect ligands which stabilize inactive (DFG-out) kinase conformations. Here, we present the successful application of the FLiK approach to develop a high-throughput binding assay capable of directly monitoring ligand binding to a remote site within the MAPK insert of p38α mitogen-activated protein kinase (MAPK). Guided by the crystal structure of an initially identified hit molecule in complex with p38α, we developed a tight binding ligand which may serve as an ideal starting point for further investigations of the biological function of the MAPK insert in regulating the p38α signaling pathway.

As a continuation of our studies aimed at the development of a new cytostatic agent derived from an Amaryllidaceae alkaloid lycorine, we synthesized 32 analogues of this natural product. This set of synthetic analogues included compounds incorporating selective derivatization of the C1 versus C2 hydroxyl groups, aromatized ring C, lactamized N6 nitrogen, dihydroxylated C3-C3a olefin functionality, transposed olefin from C3-C3a to C2-C3 or C3a-C4, and C1 long-chain fatty esters. All synthesized compounds were evaluated for antiproliferative activities in vitro in a panel of tumor cell lines including those exhibiting resistance to proapoptotic stimuli and representing solid cancers associated with dismal prognoses, such as melanoma, glioblastoma, and non-small-cell lung cancer. Most active analogues were not discriminatory between cancer cells displaying resistance or sensitivity to apoptosis, indicating that these compounds are thus able to overcome the intrinsic resistance of cancer cells to pro-apoptotic stimuli. 1,2-Di-O-allyllycorine was identified as a lycorine analogue, which is 100 times more potent against a U373 human glioblastoma model than the parent natural product. Furthermore, a number of synthetic analogues were identified as promising for the forthcoming in vivo studies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We investigate the chemical sensing behavior of composites prepared with polyvinyl alcohol and carbon materials (undoped multiwalled carbon nanotubes, nitrogen-doped multiwalled carbon nanotubes and carbon nanocoils). We determine the sensitivity of thin films of these composites for ethanol, methanol and toluene vapor, comparing their conductance and capacitance responses. The composite that exhibits highest sensitivity depends on specific vapor, vapor concentration and measured electrical response, showing that the interactivity of the carbon structure with chemical species depend on structural specificities of the carbon structure and doping.

Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on β-tubulin, provided a theoretical understanding of these successful experimental findings.

A library of small tetrahydroisoquinoline ligands, previously identified via structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements, has been generated as novel estrogen receptor agonistic fragments via traditional medicinal chemistry exploration. The approach described has allowed for the rapid evaluation of a structure-activity relationship of the ligands concerning estrogen receptor affinity and estrogen receptor β subtype selectivity. The structural biological insights obtained from the fragments aid the understanding of larger analogues and constitute attractive starting points for further optimization.

Reaction of (2,4,5-trimethoxyphenyl)(2-hydroxyphenyl)methanone with ceric ammonium nitrate furnished the xanthone, 2,3-dimethoxy-9H-xanthen-9-one. Under the same conditions the related (1,4-dimethoxynaphthalen-2-yl)(2-hydroxyphenyl)methanone resulted in the formation of 12a-methoxy-5H-benzo[c]xanthenes 5,7(12aH)-dione. Other examples of this novel transformation are also outlined.

Targeting protein kinases in cancer therapy with irreversible small-molecule inhibitors is moving to the forefront of kinase-inhibitor research and is thought to be an effective means of overcoming mutation-associated drug resistance in epidermal growth factor receptor kinase (EGFR). We generated a detection technique that allows direct measurements of covalent bond formation without relying on kinase activity, thereby allowing the straightforward investigation of the influence of steric clashes on covalent inhibitors in different resistant kinase mutants. The obtained results are discussed together with structural biology and biochemical studies of catalytic activity in both wild-type and gatekeeper mutated kinase variants to draw conclusions about the impact of steric hindrance and increased catalytic activity in drug-resistant kinase variants.

Chronic infection with the hepatitis B virus (HBV) occurs in approximately 6% of the world's population and carriers of the virus are at risk for complicating hepatocellular carcinoma. Current treatment options have limited efficacy and chronic HBV infection is likely to remain a significant global medical problem for many years to come. Silencing HBV gene expression by harnessing RNA interference (RNAi) presents an attractive option for development of novel and effective anti HBV agents. However, despite significant and rapid progress, further refinement of existing technologies is necessary before clinical application of RNAi-based HBV therapies is realized. Limiting off target effects, improvement of delivery efficiency, dose regulation and preventing reactivation of viral replication are some of the hurdles that need to be overcome. To address this, we assessed the usefulness of the recently described class of altritol-containing synthetic siRNAs (ANA siRNAs), which were administered as lipoplexes and tested in vivo in a stringent HBV transgenic mouse model. Our observations show that ANA siRNAs are capable of silencing of HBV replication in vivo. Importantly, non specific immunostimulation was observed with unmodified siRNAs and this undesirable effect was significantly attenuated by ANA modification. Inhibition of HBV replication of approximately 50% was achieved without evidence for induction of toxicity. These results augur well for future application of ANA siRNA therapeutic lipoplexes.

The mutant receptor tyrosine kinase EGFR is a validated and therapeutically amenable target for genotypically selected lung cancer patients. Here we present the synthesis and biological evaluation of a series of 6- and 7-substituted 4-anilinoquinolines as potent type I inhibitors of clinically relevant mutant variants of EGFR. Quinolines 3a and 3e were found to be highly active kinase inhibitors in biochemical assays and were further investigated for their biological effect on EGFR-dependent Ba/F3 cells and non-small cell lung cancer (NSCLC) cell lines.

Pancratistatin is a phenanthridone-type natural product isolated from several plants of the Amaryllidaceae family. Its potent antiproliferative, antivascular, antiviral, and antiparasitic properties have attracted the attention of synthetic, biological, and medicinal chemists. Pancratistatin's low natural availability and complex structure have steered many of these research projects toward the preparation of its simplified synthetic analogues with useful levels of activity. In this work we have developed synthetic chemistry aimed at the preparation of pancratistatin analogues with a truncated cyclitol portion of the molecule. The described synthetic pathways are based on a highly anti-diastereoselective arylcuprate conjugate addition to gamma-alkoxy-alpha,beta-enoates and syn-selective azidation at the alpha-position of ester enolates. Analogues with the formally cleaved C3-C4 bond, and thus containing an open ring C, as well as a compound containing a truncated lactol moiety in lieu of the cyclitol, were prepared. Several of the analogues exhibited weak antiproliferative activity, with the highest potency observed in the case of the lactol analogue. From these results implications for the design of future pancratistatin analogues are discussed. Furthermore, the synthetic pathways can be used to construct pancratistatin-mimetic libraries, in which the cyclitol moiety is replaced by other cyclic motifs.

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki-Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki-Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)(2) and NaBH(4) afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 microg/mL) against the Gram-positive micro-organism Bacillus cereus.

The structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements provides a valid, intuitive means to map and navigate chemical space. We demonstrate that scaffold trees built using bioactivity as the key selection criterion for structural simplification during tree construction allow efficient and intuitive mapping, visualization and navigation of the chemical space defined by a given library, which in turn allows correlation of this chemical space with the investigated bioactivity and further compound design. Brachiation along the branches of such trees from structurally complex to simple scaffolds with retained yet varying bioactivity is feasible at high frequency for the five major pharmaceutically relevant target classes and allows for the identification of new inhibitor types for a given target. We provide proof of principle by identifying new active scaffolds for 5-lipoxygenase and the estrogen receptor ERalpha.

To advance the use of cationic lipids for non-viral nucleic acid vector formulation, a panel of novel nitrogen heterocycle cholesteryl derivatives containing a biodegradable carbamate linker was synthesised. Optimally acting piperazine and cyclen compounds had nucleic acid-binding and lipoplex nanoparticle formation properties that were suitable for their use as non-viral vectors. It was found that the lipoplexes formed were capable of efficient non-toxic nucleic acid delivery to cells in culture. The chemical structure of individual cationic lipids, which is likely to influence lipoplex formation, affected efficiency of DNA or RNA transfection. The results indicated that the cyclen containing compound possessing two cholesteryl moieties resulted in efficient siRNA-mediated target gene silencing but was a poor reagent for DNA transfection.

Readily available 2,2',6,6'-tetramethoxy-1,1'-biphenyl was transformed in 14 synthetic steps into the natural product cardinalin 3 using a bidirectional approach. One of the key steps was the formation of the cis-1,3-dimethylnaphtho[2,3-c]pyran ring. (+/-)-1,1'-[6,6'-Diallyl-5,5'-bis(benzyloxy)-1,1',3,3'-tetramethoxy-2,2'-binaphthalene-7,7'-diyl]diethanol was treated with O(2) in the presence of CuCl(2) and catalytic PdCl(2) to afford 5,5'-bis(benzyloxy)-7,7',9,9'-tetramethoxy-1,1',3,3'-tetramethyl-1H,1'H-8,8'-bibenzo[g]isochromene. Hydrogenation of this compound afforded 7,7',9,9'-tetramethoxy-cis-1,3-cis-1',3'-tetramethyl-3,3',4,4'-tetrahydro-1H,1'H-8,8'-bibenzo[g]isochromene-5,5'-diol in quantitative yield, which was converted in 3 steps to cardinalin 3.

The title compound, C(20)H(19)NO(5)S(2), crystallizes as an almost 2:1 mixture of two molecular orientations (described as Orient-A and Orient-B). The consequences of these two orientations is the formation of three types of N-H...O hydrogen-bonded dimers in which the (Orient-A + Orient-A) dimers are likely to be the most stable, while the mixed (Orient-A + Orient-B) dimers are more frequent. Extra interactions in the form of C-H...O and C-H...pi interactions act to further stabilize these dimers and probably allow the less energetically favourable (Orient-A + Orient-B) and (Orient-B + Orient-B) hydrogen-bonded dimers to exist by preventing their conversion to (Orient-A + Orient-A)-only hydrogen-bonded dimers during the crystal-growth process.

The title compound, C(15)H(11)Cl(2)NO, was synthesized from N-benzyl isatin. The compound crystallizes as stacks of molecules running down the c axis. Molecules within each of these stacks interact with each other through pi-pi and C-H...pi interactions, and interact with neighbouring stacks through C-H...O interactions.

Prototypical thrombin inhibitors were synthesized based on a trisubstituted phenol as a core motif. A naphthylsulfonamide analogue showed excellent antithrombin activity. An X-ray co-crystal structure showed the expected interactions.

[reactions: see text] The metathesis reaction is used as a key step for the synthesis of the indolo[2,3-a]carbazole core of rebeccamycin 13 and the sulfur analog of furostifoline 21. Using the same methodology for the attempted synthesis of furostifoline, we unexpectedly formed tert-butyl-2a-methyl-1,2,2a,10c-tetrahydro-6H-cyclobuta[c]furo[3,2-a]carbazole-6-carboxylate 26 from the unstable diene, tert-butyl 2-(2-isopropenyl-3-furyl)-3-vinyl-1H-indole-1-carboxylate 25, presumably via a spontaneous pi8 electrocyclization reaction.

The synthesis of substituted polyaromatic compounds that contain at least four benzene rings fused together in an angular fashion is described. Suzuki coupling of 1-bromo-3,4-dihydronaphthalene-2-carbaldehyde with a number of aromatic boronic acids affords products such as 1-(1,4-dimethoxy-3-methyl-2-naphthyl)-3,4-dihydronaphthalene-2-carbaldehyde. Exposure of these dihydronaphthalenes to potassium tert-butoxide and DMF at 80 degrees C yields polyaromatic compounds such as 9,14-dimethoxynaphtho[1,2-a]anthracene.