Indole-coumarin-thiadiazole hybrids: An appraisal of their MCF-7 cell growth inhibition, apoptotic, antimetastatic and computational Bcl-2 binding potential

Pooja R. Kamath, Dhanya Sunil, Manu M. Joseph, Abdul Ajees Abdul Salam, Sreelekha T.T.

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14 Citations (Scopus)

Abstract

Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells. The circumvention of apoptosis is a prominent hallmark of cancer and hence triggering apoptosis in specific cancer cells is one of the convenient and widely used approaches for the development of anticancer chemotherapeutics. The induction of apoptosis upon treatment with IPTBC was confirmed by multiple apoptosis assays like Acridine orange-ethidium bromide, Hoechst staining, TUNEL staining, and colorimetric quantification using APOPercentage™ Apoptosis assay. The apoptosis initialisation through the active involvement of caspases was confirmed by caspase profiling tests. The wound healing assay displayed an intense impairment in the motility of MCF-7 cells suggesting the anti-metastatic potential of IPTBC. The ability of IPTBC to inhibit the antiapoptotic Bcl-2 protein by acting as a small molecule BH3 mimetic was explored through docking simulation studies. Although auxiliary investigations are warranted with this promising thiadiazole hybrid IPTBC, the perspective anticancer potential through programmed cell death, anti-metastatic and probable Bcl-2 inhibitory action will enable its further exploration in oncology.

Original languageEnglish
Pages (from-to)442-451
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume136
DOIs
Publication statusPublished - 01-01-2017

Fingerprint

Thiadiazoles
Apoptosis
Growth
Assays
Caspases
Staining and Labeling
Neoplasms
Acridine Orange
Oncology
Ethidium
MCF-7 Cells
In Situ Nick-End Labeling
Cell death
Cytotoxicity
Wound Healing
coumarin
indole
Adenocarcinoma
Breast
Cell Death

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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title = "Indole-coumarin-thiadiazole hybrids: An appraisal of their MCF-7 cell growth inhibition, apoptotic, antimetastatic and computational Bcl-2 binding potential",
abstract = "Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells. The circumvention of apoptosis is a prominent hallmark of cancer and hence triggering apoptosis in specific cancer cells is one of the convenient and widely used approaches for the development of anticancer chemotherapeutics. The induction of apoptosis upon treatment with IPTBC was confirmed by multiple apoptosis assays like Acridine orange-ethidium bromide, Hoechst staining, TUNEL staining, and colorimetric quantification using APOPercentage™ Apoptosis assay. The apoptosis initialisation through the active involvement of caspases was confirmed by caspase profiling tests. The wound healing assay displayed an intense impairment in the motility of MCF-7 cells suggesting the anti-metastatic potential of IPTBC. The ability of IPTBC to inhibit the antiapoptotic Bcl-2 protein by acting as a small molecule BH3 mimetic was explored through docking simulation studies. Although auxiliary investigations are warranted with this promising thiadiazole hybrid IPTBC, the perspective anticancer potential through programmed cell death, anti-metastatic and probable Bcl-2 inhibitory action will enable its further exploration in oncology.",
author = "Kamath, {Pooja R.} and Dhanya Sunil and Joseph, {Manu M.} and {Abdul Salam}, {Abdul Ajees} and Sreelekha T.T.",
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T2 - An appraisal of their MCF-7 cell growth inhibition, apoptotic, antimetastatic and computational Bcl-2 binding potential

AU - Kamath, Pooja R.

AU - Sunil, Dhanya

AU - Joseph, Manu M.

AU - Abdul Salam, Abdul Ajees

AU - T.T., Sreelekha

PY - 2017/1/1

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N2 - Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells. The circumvention of apoptosis is a prominent hallmark of cancer and hence triggering apoptosis in specific cancer cells is one of the convenient and widely used approaches for the development of anticancer chemotherapeutics. The induction of apoptosis upon treatment with IPTBC was confirmed by multiple apoptosis assays like Acridine orange-ethidium bromide, Hoechst staining, TUNEL staining, and colorimetric quantification using APOPercentage™ Apoptosis assay. The apoptosis initialisation through the active involvement of caspases was confirmed by caspase profiling tests. The wound healing assay displayed an intense impairment in the motility of MCF-7 cells suggesting the anti-metastatic potential of IPTBC. The ability of IPTBC to inhibit the antiapoptotic Bcl-2 protein by acting as a small molecule BH3 mimetic was explored through docking simulation studies. Although auxiliary investigations are warranted with this promising thiadiazole hybrid IPTBC, the perspective anticancer potential through programmed cell death, anti-metastatic and probable Bcl-2 inhibitory action will enable its further exploration in oncology.

AB - Cancer therapeutic potential of thiadiazole hybrids incorporating pharmacologically active indole and coumarin moieties have not been explored much. In the current investigation, three new thiadiazole hybrids with spacers of varying lengths linking indole and thiadiazole units were synthesized and their structures were well-established using various spectroscopic techniques. 3-(1-(5-(3-(1H-indol-3-yl)propyl)-1,3,4-thiadiazol-2-ylimino)ethyl)-6-bromo-2H-chromen-2-one (IPTBC) exhibited dose-dependent cytotoxicity in breast adenocarcinoma (MCF-7) cells. The circumvention of apoptosis is a prominent hallmark of cancer and hence triggering apoptosis in specific cancer cells is one of the convenient and widely used approaches for the development of anticancer chemotherapeutics. The induction of apoptosis upon treatment with IPTBC was confirmed by multiple apoptosis assays like Acridine orange-ethidium bromide, Hoechst staining, TUNEL staining, and colorimetric quantification using APOPercentage™ Apoptosis assay. The apoptosis initialisation through the active involvement of caspases was confirmed by caspase profiling tests. The wound healing assay displayed an intense impairment in the motility of MCF-7 cells suggesting the anti-metastatic potential of IPTBC. The ability of IPTBC to inhibit the antiapoptotic Bcl-2 protein by acting as a small molecule BH3 mimetic was explored through docking simulation studies. Although auxiliary investigations are warranted with this promising thiadiazole hybrid IPTBC, the perspective anticancer potential through programmed cell death, anti-metastatic and probable Bcl-2 inhibitory action will enable its further exploration in oncology.

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