Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products

Abstract

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. a b s t r a c tThe 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 (+r), lipophilic (+p), electron-donating (Àr), and less lipophilic substituents (Àp) 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.

Subereamolline A as a Potent Breast Cancer Migration, Invasion and Proliferation Inhibitor and Bioactive Dibrominated Alkaloids from the Red Sea Sponge Pseudoceratina arabica

“…The antimigratory activity of compounds 1 – 3 , 5 , and 7 – 11 against the highly metastatic MDA-MB-231 human breast cancer cell line was evaluated using the wound-healing assay (WHA, Figure 4) [21,22]. The wound-healing assay is a simple tool to investigate the in vitro directional cell migration [21,22,23].…”

“…The wound-healing assay is a simple tool to investigate the in vitro directional cell migration [21,22,23]. The scratched tumor cell monolayer heals the wound in a specific fashion.…”

Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity

“…Therefore, this assay provides a more robust knowledge of the efficacy of the inhibitor in the presence of a multitude of proteins. Compound 15 showed considerable inhibition of HTop1 activity in the ex vivo relaxation assays, both under the conditions when the lysates were pre-incubated with the compound 15 ( Figure 3, panel B, lanes [5][6][7][8][9] or added simultaneously ( Figure 3, panel B, lanes [14][15][16][17]. Quantification ( Figure 3, panel C) of the data suggests that compound 15 is potent in inhibiting its target (HTop1) in the midst of a plethora of proteins, corroborating well with the in vitro plasmid relaxation assays (see Figure 1) and is in keeping with the possibility that compound 15 may be a suitable anticancer agent.…”

“…Hydantoin derivatives are reported to have anti-cancer [16][17][18], anti-bacterial [19], anti-viral [18] and anti-parasitic [20] activities. A series of 3,5-disubstituted hydantoin (1,3-imidazolidinedione) derivatives showed selective inhibitory effect against cervical, breast, pancreatic, lung and colon carcinoma cell lines [18].…”

Sintesis Senyawa 5-(4'-klorobenzilidena)imidazolina-2,4-dion

“…Senyawa 5-benzalhidantoin dan turunannya dari Laxosubrites sp. dan Hemimycale arabica beberapa senyawa turunan hidantoin yang lainnya, seperti (R)-5-(4'-hidroksibenzil)hidantoin (5) dan (Z)-5-((6'-bromo-1'H-indol-3'-yl)metilena)hidantoin-(6) (Mudit et al, 2009). Beberapa bioaktivitas seperti antikonvulsan (Thenmozhiyal et al 2004), antiproliferasi (Zuliani et al 2009), antijamur dan antimikroba (Hidayat et al 2016) telah dilaporkan pada senyawa-senyawa turunan 5-benzalhidantoin.…”