Synthesis, biological evaluation and structure-activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity

Yilin Chen; Shelley L Cass; Samuel K Kutty; Eugene M H Yee; Daniel S H Chan; Christopher R Gardner; Orazio Vittorio; Eddy Pasquier; David StC Black; Naresh Kumar

doi:10.1016/j.bmcl.2015.09.027

Synthesis, biological evaluation and structure-activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity

Bioorg Med Chem Lett. 2015 Nov 15;25(22):5377-83. doi: 10.1016/j.bmcl.2015.09.027. Epub 2015 Sep 11.

Authors

Affiliations

¹ School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
² School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia.
³ Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia; Australian Centre for NanoMedicine, University of New South Wales, Sydney, NSW 2052, Australia.
⁴ Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia; Metronomics Global Health Initiative, Marseille, France.
⁵ School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia; Australian Centre for NanoMedicine, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: n.kumar@unsw.edu.au.

PMID: 26432036
DOI: 10.1016/j.bmcl.2015.09.027

Abstract

Phenoxodiol, an analogue of the isoflavone natural product daidzein, is a potent anti-cancer agent that has been investigated for the treatment of hormone dependent cancers. This molecular scaffold was reacted with different primary amines and secondary amines under different Mannich conditions to yield either benzoxazine or aminomethyl substituted analogues. These processes enabled the generation of a diverse range of analogues that were required for structure-activity relationship (SAR) studies. The resulting Mannich bases exhibited prominent anti-proliferative effects against SHEP neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines. Further cytotoxicity studies against MRC-5 normal lung fibroblast cells showed that the isoflavene analogues were selective towards cancer cells.

Keywords: Anti-cancer; Benzoxazine; Isoflavene; Mannich base; Phenoxodiol.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / toxicity
Breast Neoplasms / drug therapy
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Female
Fibroblasts / cytology
Fibroblasts / drug effects
Humans
Inhibitory Concentration 50
Isoflavones* / chemical synthesis
Isoflavones* / chemistry
Isoflavones* / toxicity
Mannich Bases / chemical synthesis*
Mannich Bases / chemistry
Mannich Bases / pharmacology*
Mannich Bases / toxicity
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Isoflavones
Mannich Bases
isoflavanone