2. Academic Validation
  3. Discovery of 9H-purins as potential tubulin polymerization inhibitors: Synthesis, biological evaluation and structure-activity relationships

Discovery of 9H-purins as potential tubulin polymerization inhibitors: Synthesis, biological evaluation and structure-activity relationships

  • Eur J Med Chem. 2017 Sep 29:138:1126-1134. doi: 10.1016/j.ejmech.2017.07.054.
Zhong-Zhen Zhou 1,  Xiu-Dong Shi 2,  Hong-Fang Feng 2,  Yu-Fang Cheng 2,  Hai-Tao Wang 2,  Jiang-Ping Xu 3
Affiliations

Affiliations

  • 1 Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: zhouzz@smu.edu.cn.
  • 2 Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: jpx@smu.edu.cn.
PMID: 28763647 DOI: 10.1016/j.ejmech.2017.07.054
Abstract

Two series of N-(4-methoxyphenyl)-N-methyl-9H-purin-6-amines (9a-d and 10a-h) and 9-substituted benzyl-6-chloro-9H-purines (11a-h) were designed and synthesized. Their antiproliferative activities against human myelogenous leukemia (K562), human neuroblastoma (SH-SY5Y) and gastric Cancer (AGS) cell lines were evaluated using the MTT assay. The preliminary results indicated that compounds 9d and 11e-h displayed low-micromole GI50 values against all tested cell lines. In addition, compounds 10b and 10d showed wonderful antiproliferative activities towards SH-SY5Y cells with selectivity of >230-fold over K562 and AGS cells. Among them, compounds 9d, 10b, 10d and 11g with good antitumor activities exhibited high selectivity for tumor cell lines over immortalized mouse hippocampal (HT22) cell line. Moreover, compound 9d with sub-micromole GI50 values toward AGS cells exhibited moderate tubulin polymerization inhibitory activity, and induced Apoptosis at G2/M phase arrest with a dose-dependent manner in the human AGS cells.

Keywords

9H-purins; Antiproliferative activity; Apoptosis; Cell cycle arrest; Tubulin-polymerization inhibitors.

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