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Effect of methionine and glucosamine conjugation on the anticancer activity of aromatic dinitrobenzamide mustards

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Abstract

Certain nutrients viz., glucose and methionine are consumed more by cancer cells. Hence, an anticancer agent conjugated to them may render more toxicity in cancer cells due to higher uptake. To probe this effect, methionine and glucosamine were conjugated to a series of well-known aromatic dinitrobenzamide mustards. The in vitro cytotoxicity studies performed to probe the effect of such conjugation showed that the conjugation of methionine and glucosamine to one of the dinitrobenzamide mustard led to more toxicity selectively in human breast adenocarcinoma (MCF-7) cell lines. However, effect of functionalization cannot be generalized. Hypoxia based studies showed that IC50 value did not show much change from normoxic condition which is encouraging as many drugs deactivate in hypoxia. Among the glucosamine and methionine conjugated dinitrobenzamide mustards, the methionine conjugated aromatic dinitrobenzamide mustard of 2-chlorobenzoic acid is the most effective one. It acts by inducing apoptosis through G2/M phase arrest and encouragingly, is much less toxic to nontumorigenic human embryonic kidney (HEK-293T) and mouse embryonic fibroblast (NIH 3T3) cell lines in vitro.

In vitro studies show that conjugation of methionine and glucosamine to certain dinitrobenzamide mustards may enhance selectivity and increase toxicity against breast adenocarcinoma as compared to nontumorigenic HEK-293T and mouse fibroblast NIH 3T3.

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Acknowledgements

We want to thank DST-India for funding (vide Project Grant no. SR/S1/IC-36/2010). We are also thankful to IISER Kolkata for financial and infrastructural support. We also want to acknowledge Dr. Jayasri Das Sarma and Dr. Tapas K Sengupta for providing us the human cancer cell lines. SK wants to thank UGC-India for providing a fellowship. SB sincerely thanks CSIR-India for a research fellowship.

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Authors and Affiliations

  1. Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741 246, India

    SUBHENDU KARMAKAR, SUDIPTA BHATTACHARYYA & ARINDAM MUKHERJEE

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  1. SUBHENDU KARMAKAR
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  2. SUDIPTA BHATTACHARYYA
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  3. ARINDAM MUKHERJEE
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Correspondence to ARINDAM MUKHERJEE.

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Supplementary Information (SI)

The supplementary material includes synthetic schemes, NMR data of synthesized compounds, NMR and HRMS of stability studies and plots of MTT assay. The supplementary data associated with this article can be found in the online version at www.ias.ac.in/chemsci.

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KARMAKAR, S., BHATTACHARYYA, S. & MUKHERJEE, A. Effect of methionine and glucosamine conjugation on the anticancer activity of aromatic dinitrobenzamide mustards. J Chem Sci 128, 401–413 (2016). https://doi.org/10.1007/s12039-015-1019-3

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  • DOI: https://doi.org/10.1007/s12039-015-1019-3

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