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Pyrazolone-fused combretastatins and their precursors: synthesis, cytotoxicity, antitubulin activity and molecular modeling studies

Agents acting on microtubules have an important role in the treatment of diverse human cancers over the past decade. Recently reported compounds targeting the colchicine-binding domain can serve as agents that rapidly depolymerize microtubules of newly formed vasculatures and block the blood supply to tumors. Among them combretastatin (CA-4) is one of the most potent antimitotic agents. CA-4’s encouraging antivascular and anticancer activity accompanied with low water solubility and low bioavailability has stimulated the synthesis and evaluation of a large number of CA-4 analogues. CA-4 has three different moieties: A1-ring (3, 4, 5-trimethoxyphenyl ; Ar1), double bond and A2-ring (phenol ; Ar2). The isomerization from the cis to the less active trans form is the weakness of CA-4. The aim of the present study was to lock the moieties Ar1 and Ar2 of combretastatin-like compounds in the active cis position by constructing the pyrazolone ring that includes the C=C bond. In addition, we performed quantitative structure-activity relationship analysis to test the influence of the variations in the number and the position of methoxy groups on aromatic rings, an introduction of the fluorine atom into the molecule or the interchange of Ar1 functionality with Ar2. The ring-closure of the corresponding diazenes to the pyrazolone-fused combretastatins 11 resulted in drastically reduced cytotoxicity comparing to CA-4 and no inhibition of tubulin polymerization. The most promising molecules were hydrazide 9f, and pyrazolones 12a, 12b and 12c. They exhibited high cytotoxicity to various cancer cells lines. Besides, 12a and 12b were more cytotoxic to cisplatin resistant human laryngeal carcinoma CK2 cells comparing to the parental HEp-2 cells. Compounds 9f, 12a–12c and 12f possess the best antitubulin potential. Results from the cell cycle analysis of 9f supported the hypothesis that its antitubulin activity was not altered as compared to CA-4, because 9f arrested the cells in the G2/M phase of the cell cycle similar to CA-4. In addition, it strongly affected cell shape and microtubule network in a manner comparable to CA-4. The molecular modeling results showed that the studied compounds can accommo¬date into the colchicine binding site at the tubulin heterodimer, and that their specific interactions with the protein are mainly due to differences in the linker. ADME parameters (e.g. lipophilicity), may be important for the biological activity of the ligands.

CA-4 derivatives; cytotoxicity; tubulin; molecular modeling

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