4-hydroxyphenylmethylene-hydantoin and Prostatic-Neoplasms

Sarcophine (1) is a bioactive cembranoid diterpene isolated from the Red Sea soft coral Sarcophyton glaucum. Previous semisynthesis attempts resulted in decreased or complete loss of 1's anticancer activity. Sarcophine and analogues showed antimigratory activity against breast and prostate cancer cell lines. This encouraged further semisynthestic optimizations to improve its activity and establish a preliminary structure-activity relationship. Eight new and five known semisynthetic analogues were generated. These compounds were evaluated for their ability to inhibit growth, proliferation, and migration of the prostate and breast metastatic cancer cell lines PC-3 and MDA-MB-231, respectively. Most analogues exhibited enhanced antimigratory activity.

Topics: 4-Butyrolactone; Animals; Anthozoa; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Migration Assays; Cell Migration Inhibition; Cell Proliferation; Diterpenes; Drug Screening Assays, Antitumor; Female; Humans; Indian Ocean; Male; Prostatic Neoplasms; Structure-Activity Relationship

Alcyonaria species are among the important marine invertebrate classes that produce a wealth of chemically diverse bioactive diterpenes. Examples of these are the potent microtubule disruptor sarcodictyins and eleutherobin. The genus Cladiella has proven to be a rich source of cytotoxic eunicellin-based diterpenoids. Five new eunicellin diterpenes, pachycladins A-E (1-5), were isolated from the Red Sea soft coral Cladiella pachyclados. The known sclerophytin A Cladiellisin, 3-acetylcladiellisin, 3,6-diacetylcladiellisin, (+)-polyanthelin A, klysimplexin G, klysimplexin E, sclerophytin F methyl ether, (6Z)-cladiellin (cladiella-6Z,11(17)-dien-3-ol), sclerophytin B, and patagonicol were also identified. The structures of the isolated compounds were elucidated by extensive interpretation of their spectroscopic data. These compounds were evaluated for their ability to inhibit growth, proliferation, invasion, and migration of the prostate cancer cells PC-3. Some of the new metabolites exhibited significant anti-invasive activity.

Topics: Animals; Anthozoa; Antineoplastic Agents; Bridged-Ring Compounds; Cell Movement; Cell Proliferation; Diterpenes; Drug Screening Assays, Antitumor; Furans; Humans; Indian Ocean; Male; Marine Biology; Molecular Structure; Prostatic Neoplasms; Stereoisomerism; Structure-Activity Relationship; Wound Healing

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 r(2) and cross-validated coefficient (q(2)) values up to 0.982 and 0.803 were established. The molecular volume (MV) and the logP 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.

Topics: Cell Line, Tumor; Chromatography, Liquid; Dose-Response Relationship, Drug; Humans; Hydantoins; Magnetic Resonance Spectroscopy; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Principal Component Analysis; Prostatic Neoplasms; Quantitative Structure-Activity Relationship; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet

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.

Topics: Animals; Animals, Genetically Modified; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Drug Design; Humans; Hydantoins; Male; Mice; Models, Molecular; Neoplasm Metastasis; Nuclear Magnetic Resonance, Biomolecular; Porifera; Prostatic Neoplasms; Quantitative Structure-Activity Relationship; Xenograft Model Antitumor Assays