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Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons

BACKGROUND: The development of 3, 3′-diindolyl methane (DIM) resistant parasite Leishmania donovani (LdDR50) by adaptation with increasing concentrations of the drug generates random mutations in the large and small subunits of heterodimeric DNA topoisomerase I of Leishmania (LdTOP1LS). Mutation of...

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Autores principales: Roy, Amit, Chowdhury, Sayan, Sengupta, Souvik, Mandal, Madhumita, Jaisankar, Parasuraman, D'Annessa, Ilda, Desideri, Alessandro, Majumder, Hemanta K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236199/
https://www.ncbi.nlm.nih.gov/pubmed/22174820
http://dx.doi.org/10.1371/journal.pone.0028493
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author Roy, Amit
Chowdhury, Sayan
Sengupta, Souvik
Mandal, Madhumita
Jaisankar, Parasuraman
D'Annessa, Ilda
Desideri, Alessandro
Majumder, Hemanta K.
author_facet Roy, Amit
Chowdhury, Sayan
Sengupta, Souvik
Mandal, Madhumita
Jaisankar, Parasuraman
D'Annessa, Ilda
Desideri, Alessandro
Majumder, Hemanta K.
author_sort Roy, Amit
collection PubMed
description BACKGROUND: The development of 3, 3′-diindolyl methane (DIM) resistant parasite Leishmania donovani (LdDR50) by adaptation with increasing concentrations of the drug generates random mutations in the large and small subunits of heterodimeric DNA topoisomerase I of Leishmania (LdTOP1LS). Mutation of large subunit of LdTOP1LS at F270L is responsible for resistance to DIM up to 50 µM concentration. METHODOLOGY/PRINCIPAL FINDINGS: In search of compounds that inhibit the growth of the DIM resistant parasite and inhibit the catalytic activity of mutated topoisomerase I (F270L), we have prepared three derivatives of DIM namely DPDIM (2,2′-diphenyl 3,3′-diindolyl methane), DMDIM (2,2′-dimethyl 3,3′-diindolyl methane) and DMODIM (5,5′-dimethoxy 3,3′-diindolyl methane) from parent compound DIM. All the compounds inhibit the growth of DIM resistant parasites, induce DNA fragmentation and stabilize topo1-DNA cleavable complex with the wild type and mutant enzyme. CONCLUSION: The results suggest that the three derivatives of DIM can act as promising lead molecules for the generation of new anti-leishmanial agents.
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spelling pubmed-32361992011-12-15 Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons Roy, Amit Chowdhury, Sayan Sengupta, Souvik Mandal, Madhumita Jaisankar, Parasuraman D'Annessa, Ilda Desideri, Alessandro Majumder, Hemanta K. PLoS One Research Article BACKGROUND: The development of 3, 3′-diindolyl methane (DIM) resistant parasite Leishmania donovani (LdDR50) by adaptation with increasing concentrations of the drug generates random mutations in the large and small subunits of heterodimeric DNA topoisomerase I of Leishmania (LdTOP1LS). Mutation of large subunit of LdTOP1LS at F270L is responsible for resistance to DIM up to 50 µM concentration. METHODOLOGY/PRINCIPAL FINDINGS: In search of compounds that inhibit the growth of the DIM resistant parasite and inhibit the catalytic activity of mutated topoisomerase I (F270L), we have prepared three derivatives of DIM namely DPDIM (2,2′-diphenyl 3,3′-diindolyl methane), DMDIM (2,2′-dimethyl 3,3′-diindolyl methane) and DMODIM (5,5′-dimethoxy 3,3′-diindolyl methane) from parent compound DIM. All the compounds inhibit the growth of DIM resistant parasites, induce DNA fragmentation and stabilize topo1-DNA cleavable complex with the wild type and mutant enzyme. CONCLUSION: The results suggest that the three derivatives of DIM can act as promising lead molecules for the generation of new anti-leishmanial agents. Public Library of Science 2011-12-12 /pmc/articles/PMC3236199/ /pubmed/22174820 http://dx.doi.org/10.1371/journal.pone.0028493 Text en Roy et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Roy, Amit
Chowdhury, Sayan
Sengupta, Souvik
Mandal, Madhumita
Jaisankar, Parasuraman
D'Annessa, Ilda
Desideri, Alessandro
Majumder, Hemanta K.
Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons
title Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons
title_full Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons
title_fullStr Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons
title_full_unstemmed Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons
title_short Development of Derivatives of 3, 3′-Diindolylmethane as Potent Leishmania donovani Bi-Subunit Topoisomerase IB Poisons
title_sort development of derivatives of 3, 3′-diindolylmethane as potent leishmania donovani bi-subunit topoisomerase ib poisons
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236199/
https://www.ncbi.nlm.nih.gov/pubmed/22174820
http://dx.doi.org/10.1371/journal.pone.0028493
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