Imidazolone-amide bridges and their effects on tubulin polymerization in cis-locked vinylogous combretastatin-A4 analogues: synthesis and biological evaluation.

A series of novel combretastatin-A4 analogues in which the cis-olefinic bridge is replaced by an imidazolone-amide were synthesized, and their cytotoxicity and tubulin-polymerization inhibitory activities were evaluated. These compounds appear to be potential tubulin-polymerization inhibitors. Compounds 10, 9b and 9c, bearing 3'-NH2-4'-OCH3, 4'-CH3 and 3'-CH3-substituted 1-phenyl B-ring, confer optimal bioactivity. The binding modes of these compounds to tubulin were obtained by molecular docking, which can explain the compounds' structure-activity relationship. The studies presented here provide a new structural type for the development of novel antitumor agents.

Construction of a three-dimensional pharmacophore for Bcl-2 inhibitors by flexible docking and the multiple copy simultaneous search method.

B-Cell lymphoma-2 (Bcl-2) protein is a new promising target for anticancer drugs. A number of anticancer Bcl-2 inhibitors with diverse chemical structures have been discovered in recent years. In this paper, the flexible docking was performed to determine the binding modes of the representative inhibitors from different structural types. Subsequently, the binding modes of inhibitor were used to construct a primary three- dimensional (3D) pharmacophore model. It proved that this model can effectively disrupt the binding of the BH3 domain of proapoptotic Bcl-2 family members to Bcl-2, and match the structural requirement of a new type of Bcl-2 inhibitors. However, these distances between pharmacophoric points are not optimal due to the fact that not all of individual functional groups are located in the ideal position when inhibitors bind to its receptor. In this paper, we proposed a new idea to improve the quality of the pharmacophore model: the multiple copy simultaneous search (MCSS) method was performed to determine the energetically favorable distribution of functional groups with similar features to these pharmacophoric points in the active site of Bcl-2 first. Then their most energetically favorable minima in the positions near the pharmacophoric points were used to optimize the distances between pharmacophoric points. By examining the binding modes of several inhibitors from the same structural type, it was found that the more potent the inhibitor was, the closer it was to the optimized distances between pharmacophoric points. The optimized 3D pharmacophore model obtained in this paper may provide a good starting point for further rational design of Bcl-2 inhibitors.

Design, synthesis, and antifungal activities of novel 1H-triazole derivatives based on the structure of the active site of fungal lanosterol 14 alpha-demethylase (CYP51).

A series of fluconazole (1) analogues, compounds 3a-k, were prepared as potential antifungal agents. They were designed by computational docking experiments to the active site of the cytochrome P450 14alpha-sterol demethylase (CYP51), whose crystal structure is known. Preliminary biological tests showed that most of the target compounds exhibit significant activities against the eight most-common pathogenic fungi. Thereby, the most potent congener, 1-[(4-tert-butylbenzyl)(cyclopropyl)amino]-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (3j), was found to exhibit a broad antifungal spectrum, being more active against Candida albicans, Candida tropicalis, Cryptococcus neoformans, Microsporum canis, and Trichophyton rubrum (MIC80 < 0.125 microg/ml) than the standard clinical drug itraconazole (2). The observed affinities of the lead molecules towards CYP51 indicate that a cyclopropyl residue enhances binding to the target enzyme. Our results may provide some guidance for the development of novel triazole-based antifungal lead structures.