3,5-Bis(3-alkylaminomethyl-4-hydroxybenzylidene)-4-piperidones: A Novel Class of Potent Tumor-Selective Cytotoxins

  • J Med Chem. 2016 Jan 28;59(2):763-9. doi: 10.1021/acs.jmedchem.5b01706.
Subhas S Karki  1 ,  Umashankar Das  1 ,  Naoki Umemura  2 ,  Hiroshi Sakagami  2 ,  Shoko Iwamoto  2 ,  Masami Kawase  3 ,  Jan Balzarini  4 ,  Erik De Clercq  4 ,  Stephen G Dimmock  5 ,  Jonathan R Dimmock  1
Affiliations
  • 1. Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan , Saskatoon, Saskatchewan S7H 5C9, Canada.
  • 2. Department of Diagnostic and Therapeutic Sciences, Division of Pharmacology, Meikai University School of Dentistry , 1-1 Keyakidai, Sakado, Saitama 350-0238, Japan.
  • 3. Faculty of Pharmaceutical Sciences, Matsuyama University , 4-2 Bunkyo-Chu, Matsuyama, Ehime 790-8578, Japan.
  • 4. Rega Institute for Medical Research, Katholieke Universiteit Leuven , B-3000 Leuven, Belgium.
  • 5. Department of Finance, Nanyang Technological University , Singapore 639798, Singapore.
PMID: 26727215 DOI: 10.1021/acs.jmedchem.5b01706
Abstract

Novel 4-piperidone derivatives 2a-f are disclosed as potent cytotoxins. Many of these compounds are more potent than the reference drug melphalan. The compounds in series 2, 4-7 display selective toxicities toward various neoplasms compared to some normal cells. 2a is one of the promising lead molecules that display >11-fold higher growth inhibiting potency than 5-fluorouracil against human colon Cancer cells. 2a induces Apoptosis, DNA fragmentation, and cleavage of poly ADP-ribose polymerase.