462626-00-2Relevant articles and documents
Optimization of (phenylmethylidene)-hydantoins as prostate cancer migration inhibitors: SAR-directed design, synthesis, and pharmacophore modeling
Mudit, Mudit,El Sayed, Khalid A.
experimental part, p. 1470 - 1485 (2011/11/06)
Prostate cancer is one of the most common cancer forms among males of Western countries. Natural products proved to be an unparalleled source of molecular diversity. The 4-(hydroxyphenylmethylidene)hydantoin (PMH; 1), (5Z)-5-(4-hydroxybenzylidene)imidazolidine-2,4-dione, was isolated from the Red Sea sponge Hemimycale arabica, and recently showed junctional complexes stabilization, anti-invasive, and antimetastatic activities in vitro and in vivo. The related synthetic analogue, (5Z)-5-[4-(ethylsulfanyl)benzylidene] imidazolidine-2,4-dione (2), showed several-fold-improved in vivo antimetastatic properties against the highly invasive prostate cancer. To further optimize the activity of PMHs, various ligand-based strategies were used including the extension of the structure, structural simplification, linker extension, and computer-assisted CoMFA (Comparative Molecular Field Analysis) results. These strategies yielded thirty 2nd-generation PMHs, designed based on the 1st-generation PMHs, such as 1 and 2. Wound-healing assay was selected to evaluate the in vitro anti-migratory potential of these new PMHs against the PC-3 cell line. Several active PMHs, including 10, 13, 24, 29, with nearly twelvefold enhancement of activity vs. 2, were identified. Active compounds were then used to build a pharmacophore model using the SYBYL's DIStance COmparison technique (DISCOtech). Active PMHs were also screened for fragment-based drug likeness using the OSIRIS program, and an overall drug score was also calculated. Interestingly, the overall drug scores of 24 and 29 along with their anti-migratory activity were significantly greater than those of 1 and 2. In conclusion, PMHs can be the appropriate scaffolds for the urgently needed drug candidates for the control of androgen independent prostate cancer. Copyright
