An alkaloid with antibacterial activity
Marinopyrrole A is a selective inhibitor of Mcl-1 with IC50 value of 10.1μM [1].
Marinopyrrole A is a natural product froma species of marine-derived streptomycetes and is reported to be an antagonist of Mcl-1. Mcl-1 is a member of the anti-apoptotic Bcl-2 family, which is a well-validated drug target for cancer treatment. NMR titration experiments show that Marinopyrrole A can directly interact with Mcl-1. It can prevent Bim-BH3 peptides from binding to Mcl-1 but not Bcl-XL. The cell based assay shows a high selectivity of Marinopyrrole A. Treatment with Marinopyrrole A inhibit the viability of K562 cells transfected with Mcl-1 gene with EC50 value of 1.6μM. The selectivity is more than 40-fold greater over the cells transfected with Bcl-XL gene. Moreover, Marinopyrrole A can decreases Mcl-1 expression by increasing the cleavage of caspase-3 and PARP. Marinopyrrole A is also reported to completely restore the sensitivity of multidrug resistant leukemia cells to ABT-737 [1].
参考文献:
[1] Doi K, Li R, Sung SS, et al. Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem. 2012 Mar, 287(13): 10224-35.
Cell experiment: | Maritoclax (Marinopyrrole A) cytotoxicity is assessed by seeding 2×104 HeLa or L929 cells per well in sterile 96-well tissue culture-treated plates. After 24 h, the medium is replaced with fresh medium containing increasing concentrations of marinopyrrole A, and the plates are incubated at 37°C in 5% CO2 for 24 h. Cytotoxicity is assayed at 24 h by measuring the reduction of MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] using the CellTiter 96 Aqueous nonradioactive cell proliferation assay according to the manufacturer's instructions. |
参考文献: [1]. Doi K, et al. Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem. 2012 Mar 23;287(13):10224-35. | |
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