Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors.

Abstract

A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.

• Authors: Gianluca Sbardella, Antonello Mai, Sara Bartolini, Sabrina Castellano, Roberto Cirilli, Dante Rotili, Ciro Milite, Marisabella Santoriello, Serena Orlando, Ilaria Sciamanna, Annalucia Serafino, Patrizia Lavia, Corrado Spadafora
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 16 Pg. 5927-36 (Aug 25 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21755950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 American Chemical Society

Chemical References

• 2-(sec-butylthio)-6-(1-(2,6-difluorophenyl)propyl)-5-methylpyrimidin-4(3H)-one
• Pyrimidinones
• Reverse Transcriptase Inhibitors

Topics

• Animals
• Apoptosis (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Fluorescent Antibody Technique, Indirect
• Humans
• Melanoma (pathology, prevention & control)
• Mice
• Mice, Nude
• Microscopy, Confocal
• Molecular Structure
• Pyrimidinones (chemistry, pharmacology)
• Reverse Transcriptase Inhibitors (chemistry, pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays