Discovery and preclinical evaluation of a novel class of cytotoxic propynoic acid carbamoyl methyl amides (PACMAs).

Abstract

Herein, we discovered a series of propynoic acid carbamoyl methyl-amides (PACMAs) with potent cytotoxicity against a panel of cancer cell lines. These compounds interrupted cell cycle progression at low micromolar concentrations and induced early and late stage apoptosis. A representative compound suppressed tumor growth without apparent toxicity in an MDA-MB-435 mouse xenograft model. We used a Kinexus 628-antibody microarray and the Ingenuity Pathway Analysis (IPA) bioinformatics tools to better understand their mechanisms. The IPA analysis revealed the initiation of Nrf2-mediated oxidative stress through modulating the expression of SOD1 and STIP1 by compound 1. The involvement of the oxidative stress pathway was further validated by measuring the levels of the PACMA-induced mitochondrial superoxide species. To our knowledge, this is the first report on the discovery and biological evaluations of PACMAs as anticancer agents. Their broad-spectrum in vitro cytotoxicity, possibly through an oxidative stress-mediated pathway, and in vivo efficacy warrant further preclinical investigations.

• Authors: Roppei Yamada, Xuefei Cao, Alexey N Butkevich, Melissa Millard, Srinivas Odde, Nick Mordwinkin, Rambabu Gundla, Ebrahim Zandi, Stan G Louie, Nicos A Petasis, Nouri Neamati
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 8 Pg. 2902-14 (Apr 28 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21443194 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• Alkynes
• Amides
• Antineoplastic Agents
• Propionates
• Tumor Suppressor Protein p53
• Caspase 9
• propiolic acid

Topics

• Alkynes (chemistry, pharmacokinetics, pharmacology)
• Amides (chemistry)
• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Caspase 9 (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• Drug Discovery
• Drug Evaluation, Preclinical
• Humans
• Magnetic Resonance Spectroscopy
• Mice
• Oxidative Stress
• Propionates (chemistry, pharmacokinetics, pharmacology)
• Tumor Suppressor Protein p53 (drug effects)
• Xenograft Model Antitumor Assays