A novel small molecule inhibitor targeted at Bcl-2.
Recently, the heterocyclic compound 8-oxo-3-thiomorpholino-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) was synthesized and shown to induce apoptosis in both (H22) hematoma and (MCF-7) adenocarcinoma cells. The IC(50) values of S1 against the two cell lines were 0.17 and 0.09 micromol/L, respectively. Furthermore, the apoptosis-inducing activity of this compound was highlighted both in vivo and in vitro. Subsequent experiments identified Bcl-2 as the primary target of S1, as a significant reduction in Bcl-2 protein levels was observed in H22 cells following a two-hour treatment with 10 micromol/L S1. While rapid depolarization of mitochondrial membranes led immediately to caspase 9 activation, no changes were identified in either caspase 8 levels or levels in Bcl-2 mRNA. These data were consistent with the results of circular dichroism (CD) spectra analysis, revealing that S1 inactivated the Bcl-2 protein by destroying its critical alpha helices. Taken together, these results suggest the potential of S1 in the development of new therapeutic agents.
Jin
LiJi
L
School of Environmental & Biological Science & Technology, Dalian University of Technology, Dalian 116024, China.
Zhang
ZhiChao
Z
Wang
YuanYuan
Y
Wei
MeiJiao
M
Xu
Qin
Q
D000073:Acenaphthenes; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism; D008956:Models, Chemical; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
C557101:8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile; D000073:Acenaphthenes; D000970:Antineoplastic Agents; D009025:Morpholines; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D053181:Caspase 8