Overman rearrangement and Pomeranz-Fritsch reaction for the synthesis of benzoazepinoisoquinolones to discover novel antitumor agents.
The B-ring of Benzoazepinoisoquinolones 1a-b was successfully constructed by Pomeranz-Fritsch reaction. The key intermediates 5a-b could be transformed from 9a-b via Overman rearrangement. The bioassay showed that 11 compounds are more active than sorafenib (IC₅₀ = 7.56 μM) against A375 melanoma cell line, among which 1a, 5a, 8a and 10c with IC₅₀ values of 0.59, 0.20, 0.17 and 0.11 μM, respectively, showed potent cytotoxicity close to or even stronger than the anti-melanoma drug vemurafenib (IC₅₀ = 0.18 μM). In addition, 5a, 8a and 10c are more active than both vemurafenib and sorafenib on HCT116 colon cell line (IC₅₀ values: 0.86, 0.65, 0.42, >30 and 5.65 μM for 5a, 8a, 10c, vemurafenib and sorafenib). Therefore, these compounds are promising candidates for further drug development.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: boli@simm.ac.cn.
Bo
B
Li
Gaihong
G
Wang
Mu
M
Yang
Zhijian
Z
Xu
Bubing
B
Zeng
Heyao
H
Wang
Jingshan
J
Shen
Kaixian
K
Chen
Weiliang
W
Zhu
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020014:K562 Cells; D008545:Melanoma / Q000188:drug therapy*; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D000077484:Vemurafenib
D000970:Antineoplastic Agents; D001552:Benzazepines; D007211:Indoles; D010671:Phenylurea Compounds; D015363:Quinolones; D013449:Sulfonamides; D000077484:Vemurafenib; D009536:Niacinamide; D000077157:Sorafenib
Antitumor; Benzoazepinoisoquinolone; N-Allylated 3-arylisoquinolone; Overman rearrangement; Pomeranz–Fritsch reaction