Structure-activity relationships study of neolamellarin A and its analogues as hypoxia inducible factor-1 (HIF-1) inhibitors

Guangzhe Li; Huijuan Dong; Yao Ma; Kun Shao; Yueqing Li; Xiaodan Wu; Shisheng Wang; Yujie Shao; Weijie Zhao

doi:10.1016/j.bmcl.2019.06.017

Structure-activity relationships study of neolamellarin A and its analogues as hypoxia inducible factor-1 (HIF-1) inhibitors

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2327-2331. doi: 10.1016/j.bmcl.2019.06.017. Epub 2019 Jun 15.

Authors

Guangzhe Li¹, Huijuan Dong², Yao Ma³, Kun Shao⁴, Yueqing Li¹, Xiaodan Wu², Shisheng Wang⁵, Yujie Shao², Weijie Zhao¹

Affiliations

¹ Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology, Dalian 116023, China; State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China.
² Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology, Dalian 116023, China.
³ Dalian Hospital of Obstetrics and Gynaecology, Dalian 116083, China.
⁴ State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China.
⁵ Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology, Dalian 116023, China; State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China. Electronic address: wangss@dlut.edu.cn.

PMID: 31281016
DOI: 10.1016/j.bmcl.2019.06.017

Abstract

The novel marine pyrrole alkaloid neolamellarin A derived from sponge has been shown to inhibit hypoxia-induced HIF-1 activity. In this work, we designed and synthesized neolamellarin A and its series of derivatives by a convergent synthetic strategy. The HIF-1 inhibitory activity and cytotoxicity of these compounds were evaluated in Hela cells by dual-luciferase reporter gene assay and MTT assay, respectively. The results showed that neolamellarin A 1 (IC₅₀ = 10.8 ± 1.0 μM) and derivative 2b (IC₅₀ = 11.9 ± 3.6 μM) had the best HIF-1 inhibitory activity and low cytotoxicity. Our SAR research focused on the effects of key regions aliphatic carbon chain length, aromatic ring substituents and C-7 substituent on biological activity, providing a basis for the subsequent research on the development of novel pyrrole alkaloids as HIF-1 inhibitors and design of small molecule probes for target protein identification.

Keywords: Anti-tumor; Hypoxia inducible factor (HIF)-1; Marine alkaloids; Neolamellarin A; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HeLa Cells
Humans
Hypoxia-Inducible Factor 1 / antagonists & inhibitors*
Hypoxia-Inducible Factor 1 / metabolism
Molecular Structure
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Hypoxia-Inducible Factor 1
Pyrroles
neolamellarin A