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Relevant academic research and scientific papers

Anti-cancer hydantoin compounds and methods

The present invention relates to methods of either treating or preventing cancer and novel compositions relevant to that treatment and prevention. More particularly, this invention relates to compounds which share features with (Z)-5-(4-hydroxybenzylidene)imidazolidine-2,4-dione and (Z)-5-(4-S-ethylbenzylidene)imidazolidine-2,4-dione and anti-cancer uses for those compounds. Embodiments of the present invention include methods that have anti-cancer effects including anti-metastatic, anti-growth, and anti-invasive activities.

Optimization of (phenylmethylidene)-hydantoins as prostate cancer migration inhibitors: SAR-directed design, synthesis, and pharmacophore modeling

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

Phenylmethylene hydantoins as prostate cancer invasion and migration inhibitors. CoMFA approach and QSAR analysis

Prostrate cancer constitutes the second leading cause of cancer deaths in men in United States. In the process of discovery of new antiproliferative and anti-metastatic agents against prostate cancer, marine-derived phenylmethylene hydantoin (PMH) derivatives were identified with activity level range between 50 and 200 μM. 3D-QSAR CoMFA model was used in virtual screening of commercially available derivatives of PMH. PMH derivatives with manifold increase in anti-migratory and anti-invasive activities were discovered using wound-healing and Cultrex invasion assays. Benzene ring replacement with other heterocyclic rings did not significantly improve the methylene hydantoins activities. Multivariate analysis performed on the whole series of methylene hydantoins, which further supported the findings of CoMFA model. Predictive QSAR model with conventional r2 and cross-validated coefficient (q 2) values up to 0.982 and 0.803 were established. The molecular volume (MV) and the log P were identified as critical parameters for methylene hydatoins migration inhibitory activity. PMH is a novel anti-metastatic lead class with potential therapeutic activity against prostate cancer.