title: Design, synthesis, and biological evaluation of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs in MCF-7 and MDA-MB-468 breast cancer cell lines.
abstract: A series of novel 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs were designed and synthesized for developing pyrazinoindolone scaffolds as anti-breast cancer agents. Compounds 1h and 1i, having a furan-2-yl-methylamide and benzylamide group, respectively, exhibited more potent cytotoxicity in MDA-MB-468 triple-negative breast cancer (TNBC) cells than compounds possessing aliphatic groups. Compounds 2a and 2b, as (R)-enantiomers of 1h and 1i, also had inhibitory activity against MDA-MB-468 cells. Moreover, analogs (3a-b and 3d-e) bearing a benzyl group at the N-2 position showed more potent activity than gefitinib, as a potent EFGR-TK inhibitor. Especially, compound 3a exhibited selective cytotoxic activity against MDA-MB-468 cells; it also had a synergistic effect in combination with gefitinib against MDA-MB-468 cells. In addition, we confirmed that compounds 3a and 3d inhibit phosphorylation of Akt in MDA-MB-468 cells using western blot analysis. Therefore, these 1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-3-carboxamide analogs may be helpful for investigating new anti-TNBC agents.
authors.affiliation: College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea.
authors.forename: Ye Jin
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea.
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Pyo
authors.affiliation: College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea. Electronic address: youngjung@pusan.ac.kr.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Kyungsung University, Busan 48434, Republic of Korea. Electronic address: jhkwak@ks.ac.kr.
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kwak
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D007211:Indoles; D011799:Quinazolines; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib
keywords: Anti-breast cancer activity; Gefitinib-resistant TNBC; Inhibition of p-Akt; Pyrazinoindolone scaffold