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Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer

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Abstract

Human DNA ligase I (hLigI) plays an important role in the process of DNA replication and repair mechanisms, making it an important target for cancer. This article reports the design, synthesis, and biological activity of a series of 59 curcumin-monocarbonyl-dithiocarbamate hybrid molecules. Many of the synthetic compounds tested in this study showed a significant inhibitory effect on hLig1 activity (>90% inhibition) and demonstrated significant antiproliferative activity against colon cancer cells (DLD-1) at the 10 µM concentrations, with certain compounds showing selective activity against DLD-1 as compared to the normal HEK-293 and VERO cell line. The activity of curcuminoids were compared against Doxorubicin and Bleomycin which were used as positive control compounds with activity towards hLigI. Further, we checked the cytotoxicity of two compounds (27 and 49) along with positive control Doxorubicin in a concentration-dependent manner against DLD-1, HEK293, and VERO cell lines. Overall, our studies demonstrated that compounds 27 and 49 have significantly better hLigI inhibition and targeted cytotoxic activities than the previously reported monocarbonyl-curcumin hybrid compound 23*. This study brings us a step closer towards our quest to explore the molecular space for novel hLig1 inhibitors that will be suitable for clinical trials in cancer patients.

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Acknowledgements

We acknowledge CSIR-CDRI, Govt. of India, for financial and infrastructure support. Financial support from the SERB grant (EMR/2017/002080) and CSIR-CDRI(HCP0040) is also acknowledged. Authors also acknowledge CSIR (DM, DKS), DBT (PM), ICMR (SK), and UGC (SK) for research fellowships. We acknowledge Mrs. Tara Rawat (Senior Technical Officer) for technical assistance and SAIF Division for acquiring NMR spectral data. This manuscript bears the CDRI Manuscript No.10501.

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  1. These authors contributed equally: Deependra K. Singh, Dhanaraju Mandalapu, Sushil Kumar

Authors and Affiliations

  1. Cancer Biology Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow, 226031, India

    Deependra K. Singh, Sushil Kumar, Pooja Maurya, Vishnu L. Sharma & Dibyendu Banerjee

  2. Academy of Scientific and Innovative Research (AcSIR), Gaziabad, 201002, India

    Deependra K. Singh, Dhanaraju Mandalapu, Sushil Kumar, Pooja Maurya, Shagun Krishna, Mohammad Imran Siddiqi & Dibyendu Banerjee

  3. Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow, 226031, India

    Dhanaraju Mandalapu

  4. Molecular and Structural Biology Division, CSIR-CDRI, Lucknow, India

    Shagun Krishna, Mohammad Imran Siddiqi & Vishnu L. Sharma

  5. Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, 229010, India

    Subhadra Thakur & Suyash Pant

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  1. Deependra K. Singh
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Singh, D.K., Mandalapu, D., Kumar, S. et al. Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer. Med Chem Res 32, 57–75 (2023). https://doi.org/10.1007/s00044-022-02983-y

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