Efficient T3P® mediated synthesis, differential cytotoxicity and apoptosis induction by indolo-triazolo-thiadiazoles in human breast adenocarcinoma cells

Pooja R. Kamath, Dhanya Sunil, Shubhankar Das, Abdul Ajees Abdul Salam, B. S.Satish Rao

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The limited efficacy of marketed anticancer agents demands the design of novel target-specific hybrid molecules incorporating multiple bioactive pharmacores to combat cancer. In the present study, a one-pot simple and efficient T3P® mediated procedure for the preparation of twelve new 3-(substituted- [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazolo)-1H-indoles with short reaction times, easy workup procedure, good yields, and purity of products is described. Cytotoxicity assay (MTT), flow-cytometric univariate cell cycle analysis, Annexin V-FITC staining and DNA fragmentation for cell death mechanism suggested that compound 3d with chloro-substituted phenyl ring induced enhanced cytotoxicity by an apoptotic pathway with high differential toxicity to breast adenocarcinoma cells (MCF-7) when compared with normal human dermal fibroblast cells. Additionally, the interaction between the BH3 domain of anti-apoptotic proteins Bcl-2 and Bcl-xL with the pharmacophore 3d was examined by molecular docking simulations to assess its potential to induce apoptosis. The docking solutions were proposed to explain the observed selectivity of 3d to Bcl-xL protein. From the present findings, the lead compound, 3d exhibited better anticancer activity when related to the other synthesized molecules with specific action on MCF-7 cells and hence can be considered as a plausible candidate chemo-therapeutic agent, although this warrants further experimentation.

Original languageEnglish
Pages (from-to)53-67
Number of pages15
JournalChemico-Biological Interactions
Volume268
DOIs
Publication statusPublished - 25-04-2017

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Thiadiazoles
Cytotoxicity
Adenocarcinoma
Breast
Molecular Docking Simulation
Cells
Apoptosis
Lead compounds
Indoles
Apoptosis Regulatory Proteins
Molecules
Fluorescein-5-isothiocyanate
Annexin A5
MCF-7 Cells
DNA Fragmentation
Cell death
Fibroblasts
Antineoplastic Agents
Toxicity
Assays

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

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abstract = "The limited efficacy of marketed anticancer agents demands the design of novel target-specific hybrid molecules incorporating multiple bioactive pharmacores to combat cancer. In the present study, a one-pot simple and efficient T3P{\circledR} mediated procedure for the preparation of twelve new 3-(substituted- [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazolo)-1H-indoles with short reaction times, easy workup procedure, good yields, and purity of products is described. Cytotoxicity assay (MTT), flow-cytometric univariate cell cycle analysis, Annexin V-FITC staining and DNA fragmentation for cell death mechanism suggested that compound 3d with chloro-substituted phenyl ring induced enhanced cytotoxicity by an apoptotic pathway with high differential toxicity to breast adenocarcinoma cells (MCF-7) when compared with normal human dermal fibroblast cells. Additionally, the interaction between the BH3 domain of anti-apoptotic proteins Bcl-2 and Bcl-xL with the pharmacophore 3d was examined by molecular docking simulations to assess its potential to induce apoptosis. The docking solutions were proposed to explain the observed selectivity of 3d to Bcl-xL protein. From the present findings, the lead compound, 3d exhibited better anticancer activity when related to the other synthesized molecules with specific action on MCF-7 cells and hence can be considered as a plausible candidate chemo-therapeutic agent, although this warrants further experimentation.",
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T1 - Efficient T3P® mediated synthesis, differential cytotoxicity and apoptosis induction by indolo-triazolo-thiadiazoles in human breast adenocarcinoma cells

AU - Kamath, Pooja R.

AU - Sunil, Dhanya

AU - Das, Shubhankar

AU - Abdul Salam, Abdul Ajees

AU - Rao, B. S.Satish

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AB - The limited efficacy of marketed anticancer agents demands the design of novel target-specific hybrid molecules incorporating multiple bioactive pharmacores to combat cancer. In the present study, a one-pot simple and efficient T3P® mediated procedure for the preparation of twelve new 3-(substituted- [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazolo)-1H-indoles with short reaction times, easy workup procedure, good yields, and purity of products is described. Cytotoxicity assay (MTT), flow-cytometric univariate cell cycle analysis, Annexin V-FITC staining and DNA fragmentation for cell death mechanism suggested that compound 3d with chloro-substituted phenyl ring induced enhanced cytotoxicity by an apoptotic pathway with high differential toxicity to breast adenocarcinoma cells (MCF-7) when compared with normal human dermal fibroblast cells. Additionally, the interaction between the BH3 domain of anti-apoptotic proteins Bcl-2 and Bcl-xL with the pharmacophore 3d was examined by molecular docking simulations to assess its potential to induce apoptosis. The docking solutions were proposed to explain the observed selectivity of 3d to Bcl-xL protein. From the present findings, the lead compound, 3d exhibited better anticancer activity when related to the other synthesized molecules with specific action on MCF-7 cells and hence can be considered as a plausible candidate chemo-therapeutic agent, although this warrants further experimentation.

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