Comparative molecular field analysis study of stilbene derivatives active against A549 lung carcinoma.
A series of 43 stilbene derivatives that showed cytotoxicity against human lung carcinoma (A549) was analyzed using comparative molecular field analysis (CoMFA) for defining the hypothetic pharmacophore model. The polyoxylated stilbenes were found to be active inhibitors of tubulin polymerization. Several cis-stilbenes are structurally similar to combretastatins. However, the trans-stilbenes are assumed to be close to resveratrol found in grapes and have been reported to be potential cancer chemopreventive agents by modulating the initiation, promotion, and progression of the carcinogenic process. With several synthesized compounds that were evaluated for antitumor cytotoxicity against human lung tumor cells (A549), the stilbene derivatives were subjected to CoMFA. To perform systematic molecular modeling of these compounds, a conformational search was carried out based on the precise dihedral angle analysis of the lead compound (1p). The X-ray crystallographic structure of combretastatin A-1 was also used for defining the active conformers of the compounds. After determining the energy-minimized conformers of the lead compound (1p), CoMFA was performed using five different alignments. The three dimensional (3D)-quantitative structure-activity relationship study resulted in reasonable cross-validated, conventional r(2) values equal to 0.640 and 0.958, respectively.
Kim
Sanghee
S
Natural Products Research Institute, College of Pharmacy, Seoul National University, Korea.
Min
Sun Young
SY
Lee
Sang Kook
SK
Cho
Won-Jea
WJ
D000465:Algorithms; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D013267:Stilbenes