title: Design, synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids.
abstract: 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.
authors.forename: Nagula
authors.initials: N
authors.lastname: Shankaraiah
authors.forename: Shalini
authors.initials: S
authors.lastname: Nekkanti
authors.forename: Karmarajsinh J
authors.initials: KJ
authors.lastname: Chudasama
authors.forename: Kishna Ram
authors.initials: KR
authors.lastname: Senwar
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: Manish Kumar
authors.initials: MK
authors.lastname: Jeengar
authors.forename: V G M
authors.initials: VG
authors.lastname: Naidu
authors.forename: Vunnam
authors.initials: V
authors.lastname: Srinivasulu
authors.forename: Gannoju
authors.initials: G
authors.lastname: Srinivasulu
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; D006827:Hydantoins