title: Novel Bcl-2 inhibitors: Discovery and mechanism study of small organic apoptosis-inducing agents.
abstract: Apoptosis as a novel target for cancer chemotherapy has generated an intense demand for new apoptosis-inducing agents. The newly revealed role of protein families involved in the apoptosis pathway, and resistance to cytotoxic therapies have opened new avenues for the development of novel anticancer strategies. We have established a novel strategy to rapidly obtain protein-targeted, instead of conventional DNA-targeted, apoptosis inducers as antitumor leads. First, a novel organic non-DNA intercalative compound S1 (8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile, M(W) = 331) was found with an IC50 of 10(-7)-10(-8) microM against diverse cancer cell lines. Further biological evaluation demonstrated that it was an apoptosis-inducer both in vivo and in vitro. The treatment of hydroperitoneum hepatoma cells (H22 cell line) with S1 at various concentrations (from 0.01 to 10 microM) for 24 h triggered these cells to enter the apoptosis process. The antitumor efficiency was also tested in the H22 xenotransplant models in mice. At a dosage of 0.3 mg kg(-1), S1 exhibited significant antitumor activity with a much longer survival time, a decrease in tumor size, and increased apoptosis cells in tumor tissue. More importantly, studies of the molecular mechanism of apoptosis induction by S1 revealed that S1 inactivated the Bcl-2 protein by binding to it, depolarizing the mitochondrial membrane, and then activating caspase 9, followed by caspase 3. Finally, structure-based virtual modification was performed by computer modeling. As a result, a derivative, S2 (8-oxo-3-[(thienylmethyl)amino]-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile, M(W) = 341) was identified that possessed a lower binding energy to Bcl-2, and demonstrated better antitumor potency, even on the Bcl-2-overexpressing human acute myeloid leukemia (HL-60) cells (IC50 = 1.3 microM) in vitro. S1 and S2 are the well-defined Bcl-2 inhibitors that give us a promising platform for the development of new therapeutic agents.
authors.affiliation: State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China. zczhang@dlut.edu.cn
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Liji
authors.initials: L
authors.lastname: Jin
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
authors.forename: Meijiao
authors.initials: M
authors.lastname: Wei
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.forename: Yongting
authors.initials: Y
authors.lastname: Xu
authors.forename: Fengyu
authors.initials: F
authors.lastname: Liu
mesh_terms: D000073:Acenaphthenes / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C557101:8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile; D000073:Acenaphthenes; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D004247:DNA; D020169:Caspases