Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)-2-((styrylsulfonyl)methyl)pyridine derivatives as anticancer agents: synthesis, structure-activity relationships, and biological activities

Tiangong Lu; Aik Wye Goh; Mingfeng Yu; Julian Adams; Frankie Lam; Theodosia Teo; Peng Li; Ben Noll; Longjin Zhong; Sarah Diab; Osama Chahrour; Anran Hu; Abdullahi Y Abbas; Xiangrui Liu; Shiliang Huang; Christopher J Sumby; Robert Milne; Carol Midgley; Shudong Wang

doi:10.1021/jm4019614

Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)-2-((styrylsulfonyl)methyl)pyridine derivatives as anticancer agents: synthesis, structure-activity relationships, and biological activities

J Med Chem. 2014 Mar 27;57(6):2275-91. doi: 10.1021/jm4019614. Epub 2014 Mar 10.

Affiliation

¹ Centre for Drug Discovery and Development, Sansom Institute for Health Research and School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, South Australia 5001, Australia.

PMID: 24471873
DOI: 10.1021/jm4019614

Abstract

ON01910.Na is a highly effective anticancer agent that induces mitotic arrest and apoptosis. Clinical studies with ON01910 in cancer patients have shown efficacy along with an impressive safety profile. While ON01910 is highly active against cancer cells, it has a low oral availability and requires continuous intravenous infusion or multiple gram doses to ensure sufficient drug exposure for biological activity in patients. We have identified two novel series of styrylsulfonyl-methylpyridines. Lead compounds 8, 9a, 18 and 19a are highly potent mitotic inhibitors and selectively cytotoxic to cancer cells. Impressively, these compounds possess excellent pharmaceutical properties and two lead drug candidates 9a and 18 demonstrated antitumor activities in animal models.

Publication types

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

MeSH terms

Aminopyridines / chemical synthesis*
Aminopyridines / pharmacology*
Animals
Annexin A5
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Area Under Curve
Biological Availability
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Drug Design
Drug Discovery
Glycine / analogs & derivatives*
Glycine / pharmacology
Half-Life
Indicators and Reagents
Kaplan-Meier Estimate
Magnetic Resonance Spectroscopy
Mass Spectrometry
Mice
Microsomes, Liver / metabolism
Models, Molecular
Rats
Structure-Activity Relationship
Styrenes / chemical synthesis*
Styrenes / pharmacology*
Sulfonamides / chemical synthesis*
Sulfonamides / pharmacology*
Sulfones / pharmacology*
Xenograft Model Antitumor Assays

Substances

3-methoxy-6-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-2-amine
Aminopyridines
Annexin A5
Antineoplastic Agents
Indicators and Reagents
N-(2-methoxy-5-(((2,4,6-trimethoxystyryl)sulfonyl)methyl)pyridin-3-yl)methanesulfonamide
Styrenes
Sulfonamides
Sulfones
ON 01910
Glycine