Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 23; pp. 5413 - 5417
• Main Authors: Shankaraiah, Nagula, Nekkanti, Shalini, Chudasama, Karmarajsinh J., Senwar, Kishna Ram, Sharma, Pankaj, Jeengar, Manish Kumar, Naidu, V.G.M., Srinivasulu, Vunnam, Srinivasulu, Gannoju, Kamal, Ahmed
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.12.2014; Elsevier
• Subjects: Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - pharmacology; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Screening Assays, Antitumor; Eg5 inhibitor; HR22C16; Humans; Hydantoins - chemical synthesis; Hydantoins - chemistry; Hydantoins - pharmacology; Kinesin spindle protein; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Structure-Activity Relationship; Tetrahydro-β-carboline; Tetrahydro-β-carboline-hydantoin hybrids; Tetrahydro-β-carboline; HR22C16; Eg5 inhibitor; Anticancer; Kinesin spindle protein; Tetrahydro-β-carboline-hydantoin hybrids; MICROTUBULES; Tetrahydro-beta-carboline-hydantoin hybrids; SPINDLE; Tetrahydro-beta-carboline; KINESIN; DNA; INHIBITORS; MOTORS; DERIVATIVES
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.10.038

A series of new tetrahydro-β-carboline-hydantoin hybrids were synthesized and evaluated for their in vitro cytotoxic potency on selected cancer cell lines and an attempt was made to rationalize their mechanism of action through cell cycle analysis that indicates a G2/M cell cycle arrest. [Display omitted] A series of new tetrahydro-β-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08±0.2, IC50 μM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction.