Modulation of Cell Differentiation, Proliferation, and Tumor Growth by Dihydrobenzyloxopyrimidine Non-Nucleoside Reverse Transcriptase Inhibitors

详细信息    查看全文

• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5927-5936
• 全文大小：1042K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a鈥?b>h) belonging to the F₂-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.