Development of a novel, multifunctional, membrane-interactive pyridinium salt with potent anticancer activity

• Published in: Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (15), p.3430-3433
• Main Authors: Fahs, Sara, Rowther, Farjana B, Dennison, Sarah R, Patil-Sen, Yogita, Warr, Tracy, Snape, Timothy J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Death - drug effects; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Glioma - drug therapy; Glioma - pathology; Humans; Molecular Structure; Pyridinium Compounds - chemical synthesis; Pyridinium Compounds - chemistry; Pyridinium Compounds - pharmacology; Salts - chemical synthesis; Salts - chemistry; Salts - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.05.087

The synthesis and biological evaluation of a novel pyridinium salt is reported. Initial membrane interaction with isolated phospholipid monolayers was obtained with the pyridinium salt, and two neutral analogues for comparison, and the anticancer effects of the best compound established using a cytotoxicity screening assay against glioma cells using both an established cell line and three short-term cell cultures-one of which has been largely resistant to all chemotherapeutic drugs tested to date. The results indicate that the pyridinium salt exhibits potent anticancer activity (EC50s=9.8-312.5 μM) on all cell types, including the resistant one, for a continuous treatment of 72 h. Microscopic examination of the treated cells using a trypan blue exclusion assay showed membrane lysis had occurred. Therefore, this letter highlights the potential for a new class of pyridinium salt to be developed as a much needed alternative treatment for glioma chemotherapy.