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| Main Authors: | , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
European journal of medicinal chemistry
2026
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41166764/ |
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| _version_ | 1868266132952055809 |
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| author | Wang, Lijun Wang, Yinghan Guo, Shuju Jiang, Bo Guo, Chuanlong Wang, Guangce |
| author_facet | Wang, Lijun Wang, Yinghan Guo, Shuju Jiang, Bo Guo, Chuanlong Wang, Guangce Wang, Lijun Wang, Yinghan Guo, Shuju Jiang, Bo Guo, Chuanlong Wang, Guangce |
| collection | PubMed - marine biology |
| contents | Discovery of novel thiosemicarbazone dimers as effective inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) for use in cancer therapy. Wang, Lijun Wang, Yinghan Guo, Shuju Jiang, Bo Guo, Chuanlong Wang, Guangce Humans Thiosemicarbazones Poly (ADP-Ribose) Polymerase-1 Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors Animals Cell Proliferation Structure-Activity Relationship Drug Screening Assays, Antitumor Mice Molecular Structure Dose-Response Relationship, Drug Drug Discovery Female Cell Line, Tumor Dimerization Apoptosis Mice, Nude For the development of anticancer drugs, poly(ADP-ribose) polymerase-1 (PARP-1) has become an attractive target. With superior binding affinity and cytotoxic effects, dimeric molecules exhibit greater anti-tumor efficacy than monomers, positioning them as promising candidates for next-generation anticancer drugs. In this investigation, the pharmacological skeleton of active molecules as PARP-1 inhibitors served as the basis for the design and synthesis of a series of thiosemicarbazone dimers, and their anticancer properties were assessed. Compound 13, one of the dimers, exhibited nanomolar activity against PARP-1 (IC = 64.98 ± 2.46 nM) and inhibited the growth of BRCA mutant cells, especially the BRCA1 mutant breast cancer HCC-1937 cell line (IC = 0.88 ± 0.21 μM). The mechanism study demonstrated that compound 13 inhibited PAR formation, induced PARP-1-DNA trapping, and DSBs on HCC-1937 cells. The flow cytometry analysis's findings showed that compound 13 caused HCC-1937 cells to enter a G2/M phase arrest. It has also been shown that compound 13 triggers apoptosis via the mitochondrial apoptotic pathway. In vivo studies showed a reduction in the growth of HCC-1937 xenografts following treatment with compound 13, with an acceptable safety profile. In conclusion, compound 13 demonstrated favorable preliminary activity, especially those that have BRCA mutations. |
| format | Artículo científico |
| id | pubmed_41166764 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | European journal of medicinal chemistry |
| record_format | pubmed |
| spellingShingle | Discovery of novel thiosemicarbazone dimers as effective inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) for use in cancer therapy. Wang, Lijun Wang, Yinghan Guo, Shuju Jiang, Bo Guo, Chuanlong Wang, Guangce Humans Thiosemicarbazones Poly (ADP-Ribose) Polymerase-1 Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors Animals Cell Proliferation Structure-Activity Relationship Drug Screening Assays, Antitumor Mice Molecular Structure Dose-Response Relationship, Drug Drug Discovery Female Cell Line, Tumor Dimerization Apoptosis Mice, Nude Discovery of novel thiosemicarbazone dimers as effective inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) for use in cancer therapy. Wang, Lijun Wang, Yinghan Guo, Shuju Jiang, Bo Guo, Chuanlong Wang, Guangce Humans Thiosemicarbazones Poly (ADP-Ribose) Polymerase-1 Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors Animals Cell Proliferation Structure-Activity Relationship Drug Screening Assays, Antitumor Mice Molecular Structure Dose-Response Relationship, Drug Drug Discovery Female Cell Line, Tumor Dimerization Apoptosis Mice, Nude For the development of anticancer drugs, poly(ADP-ribose) polymerase-1 (PARP-1) has become an attractive target. With superior binding affinity and cytotoxic effects, dimeric molecules exhibit greater anti-tumor efficacy than monomers, positioning them as promising candidates for next-generation anticancer drugs. In this investigation, the pharmacological skeleton of active molecules as PARP-1 inhibitors served as the basis for the design and synthesis of a series of thiosemicarbazone dimers, and their anticancer properties were assessed. Compound 13, one of the dimers, exhibited nanomolar activity against PARP-1 (IC = 64.98 ± 2.46 nM) and inhibited the growth of BRCA mutant cells, especially the BRCA1 mutant breast cancer HCC-1937 cell line (IC = 0.88 ± 0.21 μM). The mechanism study demonstrated that compound 13 inhibited PAR formation, induced PARP-1-DNA trapping, and DSBs on HCC-1937 cells. The flow cytometry analysis's findings showed that compound 13 caused HCC-1937 cells to enter a G2/M phase arrest. It has also been shown that compound 13 triggers apoptosis via the mitochondrial apoptotic pathway. In vivo studies showed a reduction in the growth of HCC-1937 xenografts following treatment with compound 13, with an acceptable safety profile. In conclusion, compound 13 demonstrated favorable preliminary activity, especially those that have BRCA mutations. |
| title | Discovery of novel thiosemicarbazone dimers as effective inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) for use in cancer therapy. |
| topic | Humans Thiosemicarbazones Poly (ADP-Ribose) Polymerase-1 Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors Animals Cell Proliferation Structure-Activity Relationship Drug Screening Assays, Antitumor Mice Molecular Structure Dose-Response Relationship, Drug Drug Discovery Female Cell Line, Tumor Dimerization Apoptosis Mice, Nude |
| url | https://pubmed.ncbi.nlm.nih.gov/41166764/ |