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

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 molec...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-01, Vol.59 (2), p.763-769
Main Authors: Karki, Subhas S, Das, Umashankar, Umemura, Naoki, Sakagami, Hiroshi, Iwamoto, Shoko, Kawase, Masami, Balzarini, Jan, De Clercq, Erik, Dimmock, Stephen G, Dimmock, Jonathan R
Format: Article
Language:English
Subjects:
Animals
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Antineoplastic Agents, Alkylating - pharmacology
Apoptosis - drug effects
Benzylidene Compounds - chemical synthesis
Benzylidene Compounds - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Cytotoxins - chemical synthesis
Cytotoxins - pharmacology
DNA Fragmentation - drug effects
Drug Screening Assays, Antitumor
Fluorouracil - pharmacology
Humans
Melphalan - pharmacology
Mice
Piperidones - chemical synthesis
Piperidones - pharmacology
Poly(ADP-ribose) Polymerases - drug effects
Structure-Activity Relationship
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01706