Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin.

Abstract

Apcin is one of the few compounds that have been previously reported as a Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assays. It is possible that another mechanism of action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the microtubule network, and blocked the cell cycle at the M phase with changes in the expression of cyclins. Thus, it induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results provide guidance for developing the current series as potential new anticancer therapeutics.

• Authors: Pan Huang, Xiangyang Le, Fei Huang, Jie Yang, Haofeng Yang, Junlong Ma, Gaoyun Hu, Qianbin Li, Zhuo Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 9 Pg. 4685-4700 (05 14 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 32290657 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Carbamates
• Cdc20 Proteins
• Diamines
• Tubulin Modulators
• apcin
• CDC20 protein, human

Topics

• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Apoptosis (drug effects)
• Carbamates (chemical synthesis, metabolism, pharmacology)
• Cdc20 Proteins (antagonists & inhibitors, metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Diamines (chemical synthesis, metabolism, pharmacology)
• Drug Discovery
• Drug Screening Assays, Antitumor
• Hep G2 Cells
• Humans
• Microtubules (drug effects)
• Mitosis (drug effects)
• Molecular Structure
• Protein Binding
• Structure-Activity Relationship
• Surface Plasmon Resonance
• Tubulin Modulators (chemical synthesis, metabolism, pharmacology)