Design and total synthesis of Mannich derivatives of marine natural product lamellarin D as cytotoxic agents

Li Shen; Nan Xie; Bo Yang; Yongzhou Hu; Yongmin Zhang

doi:10.1016/j.ejmech.2014.08.038

Design and total synthesis of Mannich derivatives of marine natural product lamellarin D as cytotoxic agents

Eur J Med Chem. 2014 Oct 6:85:807-17. doi: 10.1016/j.ejmech.2014.08.038. Epub 2014 Aug 12.

Authors

Li Shen¹, Nan Xie², Bo Yang², Yongzhou Hu³, Yongmin Zhang⁴

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
³ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.
⁴ ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Institut Parisien de Chimie Moléculaire, CNRS UMR 8232, Université Pierre et Marie Curie-Paris 6, 4 Place Jussieu, 75005 Paris, France.

PMID: 25189362
DOI: 10.1016/j.ejmech.2014.08.038

Abstract

Enlightened by the modification route from Camptothecin (CPT) to Topotecan and based on classical drug design theory, a series of Mannich derivatives of lamellarin D were designed and synthesized in 26-27 steps starting from vanillin and isovanilin. All synthesized compounds were then biologically evaluated for their in vitro anti-cancer activities and Topo I inhibitory activities. The results showed that most target compounds exhibited Topo I inhibitory activities in equivalent level with that of lamellarin D. Compound SL-9 exhibited better Topo I inhibitory activity than that of lamellarin D. Compounds SL-2, SL-3, SL-4, SL-5 and SL-11 exhibited better anti-proliferative activity against HT-29 cells than that of lamellarin D.

Keywords: Anti-cancer; Derivative; Lamellarin D; Mannich; Structure–activity relationships; Topo I.

MeSH terms

Alkylation
Aquatic Organisms / chemistry*
Biological Products / chemical synthesis*
Biological Products / chemistry
Biological Products / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Coumarins / chemical synthesis*
Coumarins / chemistry
Coumarins / pharmacology*
DNA Topoisomerases, Type I / metabolism
Drug Design*
Heterocyclic Compounds, 4 or More Rings / chemical synthesis*
Heterocyclic Compounds, 4 or More Rings / chemistry
Heterocyclic Compounds, 4 or More Rings / pharmacology*
Humans
Isoquinolines / chemical synthesis*
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / pharmacology

Substances

Biological Products
Coumarins
Heterocyclic Compounds, 4 or More Rings
Isoquinolines
Topoisomerase I Inhibitors
lamellarin D
DNA Topoisomerases, Type I