ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Synthesis and biological evaluation of innovative thiourea derivatives as PHGDH inhibitors

Jiawei Xiang, Lei Tao, Yue Zhou, Yuping Tan, Zicheng Li, Yinglan Zhao, Qingxiang Sun, and Youfu Luo

School of Chemical Engineering, Sichuan University, Chengdu, People’s Republic of China

E-mail: sculzc@scu.edu.cn

Received: 22 October 2019  Accepted: 7 May 2020

Abstract:

In order to discover novel compounds with inhibitory activity against 3-phosphoglycerate dehydrogenase (PHGDH), a series of thiourea derivatives were designed and synthesized based on the structural modification of compound 5d. Compound 5d emerged from the visual database of ChemDiv of 200,000 small molecules by docking score ranking. Inhibition experiments on PHGDH activity of newly synthesized compounds were performed in vitro. Compounds with more than 30% inhibitory rate at 25 μM on PHGDH were screened for IC₅₀ measurement. Anti-proliferative activity of 4a, 5a, 6e, 6n against A2780, MDA-MB-468, MDA-MB-231 and HEK293T in vitro was evaluated. The results showed that the compound 4a displayed the best inhibitory activity on PHGDH among the newly synthesized compounds, and the compounds 4a, 5a, 6n had a better proliferation inhibition effect on human A2780 cell line than NCT-503 reported previously. In addition, 2D interaction diagrams revealed potential action modes of active compounds with PHGDH.

Keywords: 3-Phosphoglycerate dehydrogenase (PHGDH); Thiourea derivatives; Virtual screening; Proliferation inhibition effect; 2D interaction diagrams

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-020-01188-0

Chemical Papers 74 (11) 3873–3886 (2020)