Temozolomide analogs with improved brain/plasma ratios – Exploring the possibility of enhancing the therapeutic index of temozolomide

Roopa Rai, Monali Banerjee, Darren H. Wong, Emma McCullagh, Ashu Gupta, Shailendra Tripathi, Eduardo Riquelme, Ramnivas Jangir, Shyamraj Yadav, Mohd Raja, Pankaj Melkani, Vikas Dixit, Umesh Patil, Ritesh Shrivastava, Sandip Middya, Felipe Olivares, Javier Guerrero, Arjun Surya, Son M. Pham, Sebastián Bernales & 3 others Andrew A. Protter, David T. Hung, Sarvajit Chakravarty

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    Abstract

    Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.

    Original languageEnglish
    Pages (from-to)5103-5109
    Number of pages7
    JournalBioorganic and Medicinal Chemistry Letters
    Volume26
    Issue number20
    DOIs
    Publication statusPublished - 01-01-2016

    Fingerprint

    temozolomide
    Brain
    Alkylation
    Glioblastoma
    Plasmas
    DNA
    Methyltransferases
    Glioma
    Toxicity
    Rats
    Up-Regulation
    Therapeutics
    Genes
    Research

    All Science Journal Classification (ASJC) codes

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry

    Cite this

    Rai, Roopa ; Banerjee, Monali ; Wong, Darren H. ; McCullagh, Emma ; Gupta, Ashu ; Tripathi, Shailendra ; Riquelme, Eduardo ; Jangir, Ramnivas ; Yadav, Shyamraj ; Raja, Mohd ; Melkani, Pankaj ; Dixit, Vikas ; Patil, Umesh ; Shrivastava, Ritesh ; Middya, Sandip ; Olivares, Felipe ; Guerrero, Javier ; Surya, Arjun ; Pham, Son M. ; Bernales, Sebastián ; Protter, Andrew A. ; Hung, David T. ; Chakravarty, Sarvajit. / Temozolomide analogs with improved brain/plasma ratios – Exploring the possibility of enhancing the therapeutic index of temozolomide. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 20. pp. 5103-5109.
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    abstract = "Temozolomide is a chemotherapeutic agent that is used in the treatment of glioblastoma and other malignant gliomas. It acts through DNA alkylation, but treatment is limited by its systemic toxicity and neutralization of DNA alkylation by upregulation of the O6-methylguanine-DNA methyltransferase gene. Both of these limiting factors can be addressed by achieving higher concentrations of TMZ in the brain. Our research has led to the discovery of new analogs of temozolomide with improved brain:plasma ratios when dosed in vivo in rats. These compounds are imidazotetrazine analogs, expected to act through the same mechanism as temozolomide. With reduced systemic exposure, these new agents have the potential to improve efficacy and therapeutic index in the treatment of glioblastoma.",
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    Rai, R, Banerjee, M, Wong, DH, McCullagh, E, Gupta, A, Tripathi, S, Riquelme, E, Jangir, R, Yadav, S, Raja, M, Melkani, P, Dixit, V, Patil, U, Shrivastava, R, Middya, S, Olivares, F, Guerrero, J, Surya, A, Pham, SM, Bernales, S, Protter, AA, Hung, DT & Chakravarty, S 2016, 'Temozolomide analogs with improved brain/plasma ratios – Exploring the possibility of enhancing the therapeutic index of temozolomide', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 20, pp. 5103-5109. https://doi.org/10.1016/j.bmcl.2016.08.064

    Temozolomide analogs with improved brain/plasma ratios – Exploring the possibility of enhancing the therapeutic index of temozolomide. / Rai, Roopa; Banerjee, Monali; Wong, Darren H.; McCullagh, Emma; Gupta, Ashu; Tripathi, Shailendra; Riquelme, Eduardo; Jangir, Ramnivas; Yadav, Shyamraj; Raja, Mohd; Melkani, Pankaj; Dixit, Vikas; Patil, Umesh; Shrivastava, Ritesh; Middya, Sandip; Olivares, Felipe; Guerrero, Javier; Surya, Arjun; Pham, Son M.; Bernales, Sebastián; Protter, Andrew A.; Hung, David T.; Chakravarty, Sarvajit.

    In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 20, 01.01.2016, p. 5103-5109.

    Research output: Contribution to journalArticle

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    AU - Rai, Roopa

    AU - Banerjee, Monali

    AU - Wong, Darren H.

    AU - McCullagh, Emma

    AU - Gupta, Ashu

    AU - Tripathi, Shailendra

    AU - Riquelme, Eduardo

    AU - Jangir, Ramnivas

    AU - Yadav, Shyamraj

    AU - Raja, Mohd

    AU - Melkani, Pankaj

    AU - Dixit, Vikas

    AU - Patil, Umesh

    AU - Shrivastava, Ritesh

    AU - Middya, Sandip

    AU - Olivares, Felipe

    AU - Guerrero, Javier

    AU - Surya, Arjun

    AU - Pham, Son M.

    AU - Bernales, Sebastián

    AU - Protter, Andrew A.

    AU - Hung, David T.

    AU - Chakravarty, Sarvajit

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