Discovery of Novel N‑Heterocyclic-Fused Deoxypodophyllotoxin Analogues as Tubulin Polymerization Inhibitors Targeting the Colchicine-Binding Site for Cancer Treatment

Natural products are a major source of anticancer agents and play critical roles in anticancer drug development. Inspired by the complexity-to-diversity strategy, novel deoxypodophyllotoxin (DPT) analogues were designed and synthesized. Among them, compound C3 exhibited the potent antiproliferative...

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Published inJournal of medicinal chemistry Vol. 65; no. 24; pp. 16774 - 16800
Main Authors Leng, Jiafu, Zhao, Yongjun, Sheng, Ping, Xia, Yuanzheng, Chen, Tingting, Zhao, Shifang, Xie, Shanshan, Yan, Xiangyu, Wang, Xiaobing, Yin, Yong, Kong, Lingyi
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 22.12.2022
Subjects
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Binding Sites
Cell Line, Tumor
Cell Proliferation
Colchicine - metabolism
Drug Screening Assays, Antitumor
Endothelial Cells - metabolism
Humans
MCF-7 Cells
Neoplasms - drug therapy
Polymerization
Structure-Activity Relationship
Tubulin - metabolism
Tubulin Modulators - chemistry
Tubulin Modulators - pharmacology
Tubulin Modulators - therapeutic use
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Abstract Natural products are a major source of anticancer agents and play critical roles in anticancer drug development. Inspired by the complexity-to-diversity strategy, novel deoxypodophyllotoxin (DPT) analogues were designed and synthesized. Among them, compound C3 exhibited the potent antiproliferative activity against four human cancer cell lines with IC50 values in the low nanomolar range. Additionally, it showed marked activity against paclitaxel-resistant MCF-7 cells and A549 cells. Moreover, compound C3 can inhibit tubulin polymerization by targeting the colchicine-binding site of tubulin. Further study revealed that compound C3 could arrest cancer cells in the G2/M phase and disrupt the angiogenesis in human umbilical vein endothelial cells. Meanwhile, C3 remarkably inhibited cancer cell motility and migration, as well as considerably inhibited tumor growth in MCF-7 and MCF-7/TxR xenograft model without obvious toxicity. Collectively, these results indicated that compound C3 may be a promising tubulin polymerization inhibitor development for cancer treatment.
AbstractList Natural products are a major source of anticancer agents and play critical roles in anticancer drug development. Inspired by the complexity-to-diversity strategy, novel deoxypodophyllotoxin (DPT) analogues were designed and synthesized. Among them, compound C3 exhibited the potent antiproliferative activity against four human cancer cell lines with IC50 values in the low nanomolar range. Additionally, it showed marked activity against paclitaxel-resistant MCF-7 cells and A549 cells. Moreover, compound C3 can inhibit tubulin polymerization by targeting the colchicine-binding site of tubulin. Further study revealed that compound C3 could arrest cancer cells in the G2/M phase and disrupt the angiogenesis in human umbilical vein endothelial cells. Meanwhile, C3 remarkably inhibited cancer cell motility and migration, as well as considerably inhibited tumor growth in MCF-7 and MCF-7/TxR xenograft model without obvious toxicity. Collectively, these results indicated that compound C3 may be a promising tubulin polymerization inhibitor development for cancer treatment.Natural products are a major source of anticancer agents and play critical roles in anticancer drug development. Inspired by the complexity-to-diversity strategy, novel deoxypodophyllotoxin (DPT) analogues were designed and synthesized. Among them, compound C3 exhibited the potent antiproliferative activity against four human cancer cell lines with IC50 values in the low nanomolar range. Additionally, it showed marked activity against paclitaxel-resistant MCF-7 cells and A549 cells. Moreover, compound C3 can inhibit tubulin polymerization by targeting the colchicine-binding site of tubulin. Further study revealed that compound C3 could arrest cancer cells in the G2/M phase and disrupt the angiogenesis in human umbilical vein endothelial cells. Meanwhile, C3 remarkably inhibited cancer cell motility and migration, as well as considerably inhibited tumor growth in MCF-7 and MCF-7/TxR xenograft model without obvious toxicity. Collectively, these results indicated that compound C3 may be a promising tubulin polymerization inhibitor development for cancer treatment.
Natural products are a major source of anticancer agents and play critical roles in anticancer drug development. Inspired by the complexity-to-diversity strategy, novel deoxypodophyllotoxin (DPT) analogues were designed and synthesized. Among them, compound C3 exhibited the potent antiproliferative activity against four human cancer cell lines with IC50 values in the low nanomolar range. Additionally, it showed marked activity against paclitaxel-resistant MCF-7 cells and A549 cells. Moreover, compound C3 can inhibit tubulin polymerization by targeting the colchicine-binding site of tubulin. Further study revealed that compound C3 could arrest cancer cells in the G2/M phase and disrupt the angiogenesis in human umbilical vein endothelial cells. Meanwhile, C3 remarkably inhibited cancer cell motility and migration, as well as considerably inhibited tumor growth in MCF-7 and MCF-7/TxR xenograft model without obvious toxicity. Collectively, these results indicated that compound C3 may be a promising tubulin polymerization inhibitor development for cancer treatment.
Natural products are a major source of anticancer agents and play critical roles in anticancer drug development. Inspired by the complexity-to-diversity strategy, novel deoxypodophyllotoxin (DPT) analogues were designed and synthesized. Among them, compound exhibited the potent antiproliferative activity against four human cancer cell lines with IC values in the low nanomolar range. Additionally, it showed marked activity against paclitaxel-resistant MCF-7 cells and A549 cells. Moreover, compound can inhibit tubulin polymerization by targeting the colchicine-binding site of tubulin. Further study revealed that compound could arrest cancer cells in the G /M phase and disrupt the angiogenesis in human umbilical vein endothelial cells. Meanwhile, remarkably inhibited cancer cell motility and migration, as well as considerably inhibited tumor growth in MCF-7 and MCF-7/TxR xenograft model without obvious toxicity. Collectively, these results indicated that compound may be a promising tubulin polymerization inhibitor development for cancer treatment.
Author Zhao, Shifang
Zhao, Yongjun
Sheng, Ping
Yin, Yong
Kong, Lingyi
Xia, Yuanzheng
Yan, Xiangyu
Wang, Xiaobing
Chen, Tingting
Leng, Jiafu
Xie, Shanshan
AuthorAffiliation Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy
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Snippet Natural products are a major source of anticancer agents and play critical roles in anticancer drug development. Inspired by the complexity-to-diversity...
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SubjectTerms Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Binding Sites
Cell Line, Tumor
Cell Proliferation
Colchicine - metabolism
Drug Screening Assays, Antitumor
Endothelial Cells - metabolism
Humans
MCF-7 Cells
Neoplasms - drug therapy
Polymerization
Structure-Activity Relationship
Tubulin - metabolism
Tubulin Modulators - chemistry
Tubulin Modulators - pharmacology
Tubulin Modulators - therapeutic use
Title Discovery of Novel N‑Heterocyclic-Fused Deoxypodophyllotoxin Analogues as Tubulin Polymerization Inhibitors Targeting the Colchicine-Binding Site for Cancer Treatment
URI http://dx.doi.org/10.1021/acs.jmedchem.2c01595
https://www.ncbi.nlm.nih.gov/pubmed/36471625
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Volume 65
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