2. Academic Validation
  3. Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3- b] Pyridazines as Antitubulin Agents

Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3- b] Pyridazines as Antitubulin Agents

  • ACS Med Chem Lett. 2016 Oct 17;7(12):1202-1206. doi: 10.1021/acsmedchemlett.6b00252.
Qile Xu 1,  Yueting Wang 1,  Jingwen Xu 2,  Maolin Sun 1,  Haiqiu Tian 1,  Daiying Zuo 2,  Qi Guan 1,  Kai Bao 3,  Yingliang Wu 2,  Weige Zhang 1
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02214, United States.
PMID: 27994764 DOI: 10.1021/acsmedchemlett.6b00252
Abstract

A series of 3,6-diaryl-[1,2,4]triazolo[4,3-b]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo[4,3-b]pyridazine scaffold. Twenty-one target compounds were synthesized and exhibited moderate to potent antiproliferative activity. The compound 4q with a 3-amino-4-methoxyphenyl moiety as the B-ring, comparable to CA-4 (IC50 = 0.009-0.012 μM), displayed the highly active antiproliferative activity against SGC-7901, A549, and HT-1080 cell lines with IC50 values of 0.014, 0.008, and 0.012 μM, respectively. Tubulin polymerization experiments indicated that 4q effectively inhibited tubulin polymerization, and immunostaining assay revealed that 4q significantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound 4q dramatically arrested cell cycle progression at G2/M phase in A549 cells. Molecular modeling studies showed that 4q could bind to the colchicine binding site on microtubules.

Keywords

[1,2,4]Triazolo[4,3-b]pyridazine; colchicine binding site; combretastatin A-4; molecular modeling; tubulin.

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