65010-93-7Relevant academic research and scientific papers
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 SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis
Scalacci, Nicolò,Brown, Alistair K.,Pavan, Fernando R.,Ribeiro, Camila M.,Manetti, Fabrizio,Bhakta, Sanjib,Maitra, Arundhati,Smith, Darren L.,Petricci, Elena,Castagnolo, Daniele
, p. 147 - 158 (2016/12/30)
The neuroleptic drug thioridazine has been recently repositioned as possible anti-tubercular drug. Thioridazine showed anti-tubercular activity against drug resistant mycobacteria but it is endowed with adverse side effects. A small library of thioridazine derivatives has been designed through the replacement of the piperidine and phenothiazine moieties, with the aim to improve the anti-tubercular activity and to reduce the cytotoxic effects. Among the resulting compounds, the indole derivative 12e showed an antimycobacterial activity significantly better than thioridazine and a cytotoxicity 15-fold lower.
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.
