Journal of Enzyme Inhibition and Medicinal Chemistry p. 1225 - 1238 (2018)
Update date:2022-08-26
Topics:
Preti, Delia
Romagnoli, Romeo
Rondanin, Riccardo
Cacciari, Barbara
Hamel, Ernest
Balzarini, Jan
Liekens, Sandra
Schols, Dominique
Estévez-Sarmiento, Francisco
Quintana, José
Estévez, Francisco
Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ~1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.
View MoreWeifang Arylchem Chemical Co., LTD
Contact:86-536-5217866
Address:Development Zone, Shouguang, Shandong Province
Henan PURUI Pharmaceutical Co., Ltd.
website:http://www.puruipharm.com
Contact:17739583555
Address:Yezhuangqiao,Xihua town, Henan province
Contact:+86-(0)21-3770 9035
Address:Room 301, Building 2, Meijiabang Road 1508, Shanghai China
Wuxi Innopal International Trade CO.,LTD
Contact:+86-510-80711901-8003
Address:Room 402,Building 5,Longze Garden,No.17,South huanjiu Road,Yixing City, Jiangsu,China
Shanghai Yongyi Biotechnology Co., Ltd
Contact:+86-0512-69561955
Address:Suite 3005, City Gateway, No.398 North CaoXi Road, XuHui District, Shanghai 200030, China.
Doi:10.1021/ja01196a054
(1947)Doi:10.1080/00397911.2017.1412465
(2018)Doi:10.1039/b924121c
(2010)Doi:10.1021/jo00940a036
(1974)Doi:10.1016/S0040-4039(00)92642-X
(1991)Doi:10.1016/0040-4039(95)01510-O
(1995)