Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors

LUO Chuan; YU Zhiliang; ZHANG Wannian; MIAO Zhenyuan

doi:10.3969/j.issn.1006-0111.201901012

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Objective To develop novel NAE inhibitors with non-nucleoside scaffold by a scaffold hopping strategy and study the in vitro antitumor activities. Methods Disulfonamideindazole 14 was synthesized through 23 steps with a good yield. Its chemical structure was confirmed by ¹H NMR and MS. MTT method was used to determine the in vitro antitumor activities. Results Compound 14 exhibited moderate antitumor activities against various cancer cells and promoted significant UBC12 accumulation in a dose-dependent manner. Conclusion Compound 14 is a potent NAE inhibitor with remarkable apoptosis induction and cell cycle arrest in prostate cancer PANC-1 cells. Our work provides a valuable leading compound for the further design and development of NAE inhibitors.

Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors

1. Anhui Huarun Golden Frog Pharmaceutical Co., Ltd., Huaibei 235000, China

2. Department of Medicinal Chemistry, School of Pharmacy, Naval Medical University, Shanghai 200433, China

Received Date: 2019-01-10

Rev Recd Date: 2019-04-17

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Abstract: Objective To develop novel NAE inhibitors with non-nucleoside scaffold by a scaffold hopping strategy and study the in vitro antitumor activities. Methods Disulfonamideindazole 14 was synthesized through 23 steps with a good yield. Its chemical structure was confirmed by ¹H NMR and MS. MTT method was used to determine the in vitro antitumor activities. Results Compound 14 exhibited moderate antitumor activities against various cancer cells and promoted significant UBC12 accumulation in a dose-dependent manner. Conclusion Compound 14 is a potent NAE inhibitor with remarkable apoptosis induction and cell cycle arrest in prostate cancer PANC-1 cells. Our work provides a valuable leading compound for the further design and development of NAE inhibitors.

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Reference (11)

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Design, synthesis and biological activity of non-nucleoside NEDD8-activating enzyme inhibitors

doi: 10.3969/j.issn.1006-0111.201901012

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通讯作者: 陈斌, [email protected]

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