Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products.
The Red Sea sponge Hemimycale arabica afforded the known (Z)-5-(4-hydroxybenzylidene)-hydantoin (1), (R)-5-(4-hydroxybenzyl)hydantoin (2), and (Z)-5-((6-bromo-1H-indol-3-yl)methylene)-hydantoin (3). The natural phenylmethylene hydantoin (PMH) 1 and the synthetic (Z)-5-(4-(ethylthio)benzylidene)-hydantoin (4) showed potent in vitro anti-growth and anti-invasive properties against PC-3M prostate cancer cells in MTT and spheroid disaggregation assays. PMHs 1 and 4 also showed significant anti-invasive activities in orthotopic xenograft and transgenic mice models. To study the effect of electronic and lipophilic parameters on the activity, a wide array of several substituted aldehydes possessing electron-withdrawing (+sigma), lipophilic (+pi), electron-donating (-sigma), and less lipophilic substituents (-pi) were used to synthesize several PMHs. Few des-phenylmethylenehydantoins and 2-thiohydanoins were also synthesized and the anti-invasive activities of all compounds were evaluated. Comparative molecular field analysis (CoMFA) was then used to study the 3D QSAR. Predictive 3D QSAR model with conventional r(2) and cross validated coefficient (q(2)) values up to 0.910 and 0.651 were established. In conclusion, PMH is a novel antimetastatic lead class with potential to control metastatic prostate cancer.
Mudit
Mudit
M
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
Khanfar
Mohammad
M
Muralidharan
Anbalagan
A
Thomas
Shibu
S
Shah
Girish V
GV
van Soest
Rob W M
RW
El Sayed
Khalid A
KA
D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009362:Neoplasm Metastasis; D019906:Nuclear Magnetic Resonance, Biomolecular; D011161:Porifera / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D006827:Hydantoins