Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer
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...
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| Veröffentlicht in: | Medicinal chemistry research 2023, Vol.32 (1), p.57-75 |
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| creator | Singh, Deependra K. Mandalapu, Dhanaraju Kumar, Sushil Maurya, Pooja Krishna, Shagun Thakur, Subhadra Pant, Suyash Siddiqi, Mohammad Imran Sharma, Vishnu L. Banerjee, Dibyendu |
| description | 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.
Graphical abstract |
| doi_str_mv | 10.1007/s00044-022-02983-y |
| format | Article |
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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.
Graphical abstract</description><identifier>ISSN: 1054-2523</identifier><identifier>EISSN: 1554-8120</identifier><identifier>DOI: 10.1007/s00044-022-02983-y</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Biochemistry ; Biological activity ; Biomedical and Life Sciences ; Biomedicine ; Bioorganic Chemistry ; Bleomycin ; Clinical trials ; Colon cancer ; Colorectal cancer ; Curcumin ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA ligase (ATP) ; DNA repair ; Doxorubicin ; Inorganic Chemistry ; Medicinal Chemistry ; Original Research ; Pharmacology/Toxicology ; Toxicity</subject><ispartof>Medicinal chemistry research, 2023, Vol.32 (1), p.57-75</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022. corrected publication 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c319t-dbaf750b729368ad3dc0f40e85a31a4ba0ba0ba907a3fa9be21cbeb75bbbb3453</citedby><cites>FETCH-LOGICAL-c319t-dbaf750b729368ad3dc0f40e85a31a4ba0ba0ba907a3fa9be21cbeb75bbbb3453</cites><orcidid>0000-0003-4244-9714</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00044-022-02983-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00044-022-02983-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27922,27923,41486,42555,51317</link.rule.ids></links><search><creatorcontrib>Singh, Deependra K.</creatorcontrib><creatorcontrib>Mandalapu, Dhanaraju</creatorcontrib><creatorcontrib>Kumar, Sushil</creatorcontrib><creatorcontrib>Maurya, Pooja</creatorcontrib><creatorcontrib>Krishna, Shagun</creatorcontrib><creatorcontrib>Thakur, Subhadra</creatorcontrib><creatorcontrib>Pant, Suyash</creatorcontrib><creatorcontrib>Siddiqi, Mohammad Imran</creatorcontrib><creatorcontrib>Sharma, Vishnu L.</creatorcontrib><creatorcontrib>Banerjee, Dibyendu</creatorcontrib><title>Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer</title><title>Medicinal chemistry research</title><addtitle>Med Chem Res</addtitle><description>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.
Graphical abstract</description><subject>Biochemistry</subject><subject>Biological activity</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bioorganic Chemistry</subject><subject>Bleomycin</subject><subject>Clinical trials</subject><subject>Colon cancer</subject><subject>Colorectal cancer</subject><subject>Curcumin</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA ligase (ATP)</subject><subject>DNA repair</subject><subject>Doxorubicin</subject><subject>Inorganic Chemistry</subject><subject>Medicinal Chemistry</subject><subject>Original Research</subject><subject>Pharmacology/Toxicology</subject><subject>Toxicity</subject><issn>1054-2523</issn><issn>1554-8120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9UE1P3DAQjapWggJ_gNNIPacd2wlJjquFUiSgl3K2xo6TNUpssB2q_Ar-cs0uUm-MZjSj0Xvz8YrinOF3htj8iIhYVSVynqNrRbl-Ko5ZXVdlyzh-zjXmmtdcHBVfY3xEFA1W9XHxeu9fzATbJehltg7uvPOagvJunWDjaPLjYspLm3Z236eZkoHdqoLtYfaT0ctkIiQKo0mwW2ZycHm_gcmOFA3cALke4s7_BTs_hbyrB9LJvti0Ao1kXUyg_eQdaHLahNPiy0BTNGfv-aR4-Hn1Z_urvP19fbPd3JZasC6VvaKhqVE1vBMXLfWi1zhUaNqaBKNKEe69w4bEQJ0ynGllVFOrbKKqxUnx7TA3H_W8mJjko19C_jdK3lwwzrAVmFH8gNLBxxjMIJ-CnSmskqF8E14ehJdZeLkXXq6ZJA6kmMFuNOH_6A9Y_wDPMIqG</recordid><startdate>2023</startdate><enddate>2023</enddate><creator>Singh, Deependra K.</creator><creator>Mandalapu, Dhanaraju</creator><creator>Kumar, Sushil</creator><creator>Maurya, Pooja</creator><creator>Krishna, Shagun</creator><creator>Thakur, Subhadra</creator><creator>Pant, Suyash</creator><creator>Siddiqi, Mohammad Imran</creator><creator>Sharma, Vishnu L.</creator><creator>Banerjee, Dibyendu</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>FR3</scope><scope>M7Z</scope><scope>P64</scope><orcidid>https://orcid.org/0000-0003-4244-9714</orcidid></search><sort><creationdate>2023</creationdate><title>Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer</title><author>Singh, Deependra K. ; Mandalapu, Dhanaraju ; Kumar, Sushil ; Maurya, Pooja ; Krishna, Shagun ; Thakur, Subhadra ; Pant, Suyash ; Siddiqi, Mohammad Imran ; Sharma, Vishnu L. ; Banerjee, Dibyendu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c319t-dbaf750b729368ad3dc0f40e85a31a4ba0ba0ba907a3fa9be21cbeb75bbbb3453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Biochemistry</topic><topic>Biological activity</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bioorganic Chemistry</topic><topic>Bleomycin</topic><topic>Clinical trials</topic><topic>Colon cancer</topic><topic>Colorectal cancer</topic><topic>Curcumin</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA biosynthesis</topic><topic>DNA ligase (ATP)</topic><topic>DNA repair</topic><topic>Doxorubicin</topic><topic>Inorganic Chemistry</topic><topic>Medicinal Chemistry</topic><topic>Original Research</topic><topic>Pharmacology/Toxicology</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Deependra K.</creatorcontrib><creatorcontrib>Mandalapu, Dhanaraju</creatorcontrib><creatorcontrib>Kumar, Sushil</creatorcontrib><creatorcontrib>Maurya, Pooja</creatorcontrib><creatorcontrib>Krishna, Shagun</creatorcontrib><creatorcontrib>Thakur, Subhadra</creatorcontrib><creatorcontrib>Pant, Suyash</creatorcontrib><creatorcontrib>Siddiqi, Mohammad Imran</creatorcontrib><creatorcontrib>Sharma, Vishnu L.</creatorcontrib><creatorcontrib>Banerjee, Dibyendu</creatorcontrib><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Medicinal chemistry research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Deependra K.</au><au>Mandalapu, Dhanaraju</au><au>Kumar, Sushil</au><au>Maurya, Pooja</au><au>Krishna, Shagun</au><au>Thakur, Subhadra</au><au>Pant, Suyash</au><au>Siddiqi, Mohammad Imran</au><au>Sharma, Vishnu L.</au><au>Banerjee, Dibyendu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer</atitle><jtitle>Medicinal chemistry research</jtitle><stitle>Med Chem Res</stitle><date>2023</date><risdate>2023</risdate><volume>32</volume><issue>1</issue><spage>57</spage><epage>75</epage><pages>57-75</pages><issn>1054-2523</issn><eissn>1554-8120</eissn><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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| source | Springer Journals |
| subjects | Biochemistry Biological activity Biomedical and Life Sciences Biomedicine Bioorganic Chemistry Bleomycin Clinical trials Colon cancer Colorectal cancer Curcumin Cytotoxicity Deoxyribonucleic acid DNA DNA biosynthesis DNA ligase (ATP) DNA repair Doxorubicin Inorganic Chemistry Medicinal Chemistry Original Research Pharmacology/Toxicology Toxicity |
| title | Novel Curcumin Monocarbonyl Analogue-Dithiocarbamate hybrid molecules target human DNA ligase I and show improved activity against colon cancer |
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