Computational Design and Synthesis of Novel Fluoro-Analogs of Combretastatins A-4 and A-1.

Combretastatin A-1 (CA-1) and combretastatin A-4 (CA-4) isolated from the African bush willow Combretum caffrum are highly potent tubulin polymerization inhibitors, possessing strong antitumor activities because of their vascular disrupting properties. Extensive SAR studies have been done for CA-4 analogs. Because of poor solubility, water-soluble prodrugs of CA-4 and CA-1 have been developed, which are currently in human clinical trials. Fluorine plays an important role in the current drug discovery and development due to its unique properties. Thus, several fluorine-containing analogs of CA-4/CA-1 have been studied. However, no analogs, which have a CF3 O-, CF2 HO- or CF3 - group instead of the 4'-methoxy group in the B ring, have been investigated. Therefore, we set out to design and synthesize those novel fluoro-analogs of CA-4/CA-1. For the design of the new analogs, we took a structure-based design approach based on the X-ray crystal structure of colchicine-tubulin complex (PDB: 4O2B) and computational docking analysis using the AutoDock Vina program. A library of novel fluoro-analogs of CA-4/CA-1 was generated and their docking energy scores obtained. It was found that those novel fluoro-analogs exhibited better docking energy scores than CA-4/CA-1. Also, docking poses of all of these fluoro-analogs were virtually superimposable and very good fit to the colchine binding site. Among 15 compounds designed and analyzed, we have synthesized 5 compounds and evaluated their cytotoxicity against drug-sensitive and multidrug-resistant cancer cell lines. All fluoro-analogs exhibited strong cytotoxicity even against multidrug-resistant cell line. However, the critical activity of this class of compounds is its vascular disrupting activity. Thus, further biological evaluations are warranted for those novel fluoro-analogs of CA-4/CA-1.