Resveratrol is a phytoalexin able to display an array of biological activities. We decided to replace the double bond with a triazole ring using the archetypical click reaction: the Huisgen [3 + 2] cycloaddition. Seventy-two triazole derivatives were synthesized via a parallel combinatorial approach. Preliminary data suggest that this procedure can lead to the synthesis of compounds that display some, but not all, of resveratrol's actions with increased potency.

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Over the last decade, 1,2,3-triazoles have received increasing attention in medicinal chemistry thanks to the discovery of the highly useful and widely applicable 1,3-dipolar cycloaddition reaction between azides and alkynes (click chemistry) catalyzed by copper salts and ruthenium complexes. After a decade of medicinal chemistry research on 1,2,3-triazoles, we feel that the time is ripe to demonstrate the real ability of this heterocycle to participate in important and pivotal binding interactions with biological targets while maintaining a good pharmacokinetic profile. In this study, we retrieved and analyzed X-ray crystal structures of complexes between 1,2,3-triazoles and either proteins or DNA to understand the pharmacophoric role of the triazole. Furthermore, the metabolic stability, the capacity to inhibit cytochromes, and the contribution of 1,2,3-triazoles to the overall aqueous solubility of compounds containing them have been analyzed. This information should furnish fresh insight for medicinal chemists in the design of novel bioactive molecules that contain the triazole nucleus.

ABSTRACT:The phase I biotransformation of combretastatin A-4 (CA-4) 1, a potent tubulin polymerization inhibitor with antivascular and antitumoral properties, was studied using rat and human liver subcellular fractions. The metabolites were separated by high-performance liquid chromatography and detected with simultaneous UV and electrospray ionization (ESI) mass spectrometry. The assignment of metabolite structures was based on ESI-tandem mass spectrometry experiments, and it was confirmed by comparison with reference samples obtained by synthesis. O-Demethylation and aromatic hydroxylation are the two major phase I biotransformation pathways, the latter being regioselective for phenyl ring B of 1. Indeed, incubation with rat and human microsomal fractions led to the formation of a number of metabolites, eight of which were identified. The regioselectivity of microsomal oxidation was also demonstrated by the lack of metabolites arising from stilbenic double bond epoxidation. Alongside the oxidative metabolism, Z-E isomerization during in vitro study was also observed, contributing to the complexity of the metabolite pattern. Moreover, when 1 was incubated with a cytosolic fraction, metabolites were not observed. Aromatic hydroxylation at the C-6 of phenyl ring B and isomerization led to the formation of M1 and M2 metabolites, which were further oxidized to the corresponding paraquinone (M7 and M8) species whose role in pharmacodynamic activity is unknown. Metabolites M4 and M5, arising from O-demethylation of phenyl ring B, did not form the ortho-quinones. O-Demethylation of phenyl ring A formed the metabolite M3 with a complete isomerization of the stilbenic double bond.

Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins embodying a furazan ring (combretafurazans). To achieve this, we have developed a new strategy that exploits the dehydration of vicinal dioximes using the Mitsunobu reaction. Among the advantages of following such a strategy are the mild conditions used for the construction of the diarylfurazan derivatives, allowing for the presence of highly functionalized substrates and deactivated aromatic rings. Combretafurazans are more potent in vitro cytotoxic compounds compared to combretastatins in neuroblastoma cells, yet maintaining similar structure-activity relationship and pharmacodynamic profiles.