65010-93-7Relevant articles and documents
An Inhibitor of the Interaction of Survivin with Smac in Mitochondria Promotes Apoptosis
Park, Seong-Hyun,Shin, Insu,Park, Sang-Hyun,Kim, Nam Doo,Shin, Injae
supporting information, p. 4035 - 4041 (2019/08/02)
Herein we report the first small molecule that disrupts the survivin-Smac interaction taking place in mitochondria. The inhibitor, PZ-6-QN, was identified by initially screening a phenothiazine library using a fluorescence anisotropy assay and then conducting a structure–activity relationship study. Mutagenesis and molecular docking studies suggest that PZ-6-QN binds to survivin similarly to the known Smac peptide, AVPI. The results of the effort also show that PZ-6-QN exhibits good anticancer activity against various cancer cells. Moreover, cell-based mechanistic studies provide evidence for the proposal that PZ-6-QN enters mitochondria to inhibit the survivin-Smac interaction and promotes release of Smac and cytochrome c from mitochondria into the cytosol, a process that induces apoptosis in cancer cells. Overall, the present study suggests that PZ-6-QN can serve as a novel chemical probe for study of processes associated with the mitochondrial survivin-Smac interaction and it will aid the discovery of novel anticancer agents.
Synthesis and pharmacology of new dithiocarbamic acid esters derived from phenothiazine and diphenylamine
Karali, Nilguen,Apak, Idil,Oezkirimli, Sumru,Guersoy, Aysel,Dogan, Soenmez Uydes,Eraslan, Aylin,Oezdemir, Osman
, p. 422 - 426 (2007/10/03)
2-Methylthio-10-[N,N-disubstituted-thiocarbamoylthio)acetyl]- phenothiazines (4a-g) and N-(3-methylthiophenyl)-N-[(N,N-disubstituted- thiocarbamoylthio)acetyl]phenylamines (5a-g) were synthesized by subsequent treatment of 2-methylthio-10-chloroacetylphenothiazines (1) and N-(3- methylthiophenyl)-N-chloroacetylphenylamine (2) with potassium salts of N,N- disubstituted dithiocarbamic acid derivatives (3a-i). The structures of the compounds were determined by analytical and spectral (IR, 1H NMR, 13C NMR, EIMS) methods. The antihistaminic and anticholinergic activities of 4a, 4c, 4e-g, 5a-c 5e, and 5g were evaluated in comparison with H1-receptor antagonist mepyramine and nonselective cholinergic antagonist atropine. In the first series of experiments, the cumulative concentration-response curves to histamine (10-8-10-4 M) and acetylcholine (10-8-10-4 M) were constructed in separate fundus strips. The test compounds exhibited marked antihistaminic activity at 10-6 M concentration but compounds did not influence acetylcholine induced contractions. Concentration-related experiments carried out on 4g and 5g revealed that a moderate antihistaminic activity was present at 10-7 M concentration of the compounds and became strong at higher concentrations. In the second series of experiments, the cumulative concentration-response curve to histamine (10-9-10-4 M) was constructed in guinea-pig ileum segments. Maximal responses were obtained by 10-6-3 x 10-6 M concentrations of histamine in ileum segments. Similar inhibitions of histamine contractions were also obtained with the test compounds. Their inhibitory effectiveness was evaluated by comparing the pA2 values.
