Synthesis of the analogs of plocabulin and their preliminary structure-activity relationship study

Leiming Wang; Xin Li; Hong Cui; Xinsheng Lei; Hongchun Liu; Quanrui Wang; Yingxia Li

doi:10.1016/j.bmcl.2021.128355

Synthesis of the analogs of plocabulin and their preliminary structure-activity relationship study

Bioorg Med Chem Lett. 2021 Nov 1:51:128355. doi: 10.1016/j.bmcl.2021.128355. Epub 2021 Sep 8.

Authors

Leiming Wang¹, Xin Li², Hong Cui³, Xinsheng Lei³, Hongchun Liu⁴, Quanrui Wang⁵, Yingxia Li⁶

Affiliations

¹ Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, China; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
² Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
³ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
⁴ Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: hchliu@simm.ac.cn.
⁵ Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 200438, China. Electronic address: qrwang@fudan.edu.cn.
⁶ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: liyx417@fudan.edu.cn.

PMID: 34508844
DOI: 10.1016/j.bmcl.2021.128355

Abstract

Plocabulin, a marine natural polyketide isolated from the sponge Lithoplocamia lithistoides, is a novel and potent microtubule-destabilizing agent. Guided by the reported binding mode, several new analogs of plocabulin have been designed through removing the right aliphatic chain and further modifying on the carbamate group and the enamide unit. The preliminary results indicate that the right aliphatic chain in plocabulin is allowed to remove with a little loss of activity, the carbamate group plays a role in the activity, and particularly, the enamide unit has an important effect on the activity. This new finding will aid the design of novel potent tubulin-binding agents based on plocabulin.

Keywords: Antiproliferation; Marine nature products; PM060184; Plocabulin; Synthesis.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Polyketides / chemical synthesis
Polyketides / chemistry
Polyketides / pharmacology*
Pyrones / chemical synthesis
Pyrones / chemistry
Pyrones / pharmacology*
Structure-Activity Relationship
Tubulin / metabolism*
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*

Substances

Antineoplastic Agents
Polyketides
Pyrones
Tubulin
Tubulin Modulators
plocabulin