Synthesis of new heteroaryl and heteroannulated indoles from dehydrophenylalanines: Antitumor evaluation.
A 3-(dibenzothien-4-yl)indole and a phenylbenzothienoindole or a 3-(dibenzofur-4-yl)indole and a phenylbenzofuroindole were prepared by a metal-assisted C-N intramolecular cyclization of the methyl esters of N-Boc-(E) or (Z)-beta-dibenzothien-4-yl or beta-dibenzofur-4-yl dehydrophenylalanines. The latter were obtained by Suzuki cross-coupling of the methyl esters of N-Boc-(E) or (Z)-beta-bromodehydrophenylalanines with dibenzothien-4-yl or dibenzofur-4-yl boronic acids, in high yields. The intramolecular cyclization from E or Z pure Suzuki-coupling products gave the corresponding heteroaryl and heteroannulated indoles, in different ratios, by either direct cyclization or cyclization after isomerisation. Three of the cyclized compounds, the two heteroarylindoles and the phenylbenzothienoindole, were evaluated for their capacity to inhibit the in vitro growth of three human tumor cell lines, MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and SF-268 (CNS cancer). The methyl 3-(dibenzothien-4-yl)indole-2-carboxylate was the most potent compound with GI(50) values ranging from 11 to 17microM.
Queiroz
Maria-João R P
MJ
Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal. mjrpq@quimica.uminho.pt
Abreu
Ana S
AS
Carvalho
M Solange D
MS
Ferreira
Paula M T
PM
Nazareth
Nair
N
São-José Nascimento
M
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007211:Indoles; D010649:Phenylalanine; C018632:phenyldehydroalanine