2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition

被引：21

作者：

Romagnoli, Romeo ^{[1
]}

Kimatrai Salvador, Maria ^{[2
]}

Schiaffino Ortega, Santiago ^{[2
]}

Baraldi, Pier Giovanni ^{[1
]}

Oliva, Paola ^{[1
]}

Baraldi, Stefania ^{[1
]}

Carlota Lopez-Cara, Luisa ^{[2
]}

Brancale, Andrea ^{[3
]}

Ferla, Salvatore ^{[3
]}

Hamel, Ernest ^{[4
]}

Balzarini, Jan ^{[5
]}

Liekens, Sandra ^{[5
]}

Mattiuzzo, Elena ^{[6
]}

Basso, Giuseppe ^{[6
]}

Viola, Giampietro ^{[6
]}

机构：

[1] Univ Ferrara, Dipartimento Sci Chim & Farmaceut, I-44121 Ferrara, Italy

[2] Fac Farm, Dept Quim Farmaceut & Organ, Campus Cartuja S-N, Granada 18071, Spain

[3] Cardiff Univ, Sch Pharm & Pharmaceut Sci, King Edward VII Ave, Cardiff CF10 3NB, S Glam, Wales

[4] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA

[5] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Leuven, Belgium

[6] Univ Padua, Lab Oncoematol Pediat, Dipartimento Salute Donna & Bambino, I-35131 Padua, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 143卷

关键词：

Microtubule; Tubulin polymerization inhibitors; Antiproliferative agents; Colchicine site; Structure-activity relationship; COLCHICINE BINDING-SITE; BIOLOGICAL EVALUATION; IN-VITRO; POTENT; ANTICANCER; DERIVATIVES; GENERATION; APOPTOSIS; CANCER; LIFE;

D O I：

10.1016/j.ejmech.2017.11.096

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC50 values ranging from 0.13 to 0.84 mu M against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IO50 value of 140 nM, inhibited tubulin polymerization with an IO50 value of 1.2 mu M, similar to that of CA-4 (IC50: 1.1 mu M), and induced apoptosis in HeLa cells. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：683 / 698

页数：16

共 38 条

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