2. Academic Validation
  3. Synthesis and biological evaluation of 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4

Synthesis and biological evaluation of 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4

  • Eur J Med Chem. 2018 Feb 25:146:185-193. doi: 10.1016/j.ejmech.2018.01.052.
Yajing Liu 1,  Di Yang 1,  Zexin Hong 1,  Su Guo 1,  Moyi Liu 1,  Daiying Zuo 2,  Dandan Ge 1,  Mingze Qin 3,  Deyu Sun 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: qinmingze001@126.com.
  • 4 Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Dadong District, PR China. Electronic address: 91111@126.com.
PMID: 29407949 DOI: 10.1016/j.ejmech.2018.01.052
Abstract

A series of novel 4,6-diphenyl-2-(1H-pyrrol-1-yl)nicotinonitrile analogues of crolibulin and combretastatin A-4 (CA-4) were discovered using a 2-(1H-pyrrol-1-yl)pyridine ring as link-bridge to retain the cis-orientations of A-ring and B-ring. All the target compounds were synthesized and evaluated for their antiproliferative activity against five human Cancer cell lines. Compounds 6a-d exhibited superior potency, with IC50 values at nanomolar levels. In particular, compound 6a exhibited antitumor activity similar to or higher than crolibulin and CA-4. Moreover, the inhibition of microtubule assembly by compound 6a was comparable to that by CA-4. A molecular modeling study of compound 6a was performed to elucidate its binding mode at the colchicine binding site in the tubulin dimer, which also provided a basis for further structure-guided design of novel colchicine binding site inhibitors.

Keywords

Antiproliferative activity; Colchicine binding site inhibitors; Combretastatin A-4; Crolibulin; Synthesis.

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