Huang, P; Le, X; Huang, F; Yang, J; Yang, H; Ma, J; Hu, G; Li, Q; Chen, Z; ,
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.
2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[1 (6 amino 2 chloro 9h purin 9 yl) 2,2,2 trichloroethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[1 (6 benzamido 9h purin 9 yl) 2,2,2 trichloroethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[1 [(2 amino 4,6 dichloropyrimidin 5 yl)amino] 2,2,2 trichloroethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[1 [(4 aminopyrimidin 2 yl)amino] 2,2,2 trichloroethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[1 [(5 amino 4,6 dichloropyrimidin 2 yl)amino] 2,2,2 trichloroethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[1 [6 (benzylamino) 9h purin 9 yl] 2,2,2 trichloroethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 (2,6 diamino 9h purin 9 yl)ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 (6 chloro 9h purin 9 yl)ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 (isoquinolin 1 ylamino)ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 (isoquinolin 3 ylamino)ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 (pyrimidin 4 ylamino)ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 (quinolin 2 ylamino)ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 [(4 chloropyrimidin 2 yl)amino]ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 [(4 methoxypyrimidin 2 yl)amino]ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 [(4 methylpyrimidin 2 yl)amino]ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 [(4,6 dichloro 5 methylpyrimidin 2 yl)amino]ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 [(4,6 dichloropyrimidin 2 yl)amino]ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 [(6 oxo 1,6 dihydropyrimidin 2 yl)amino]ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1 yl)ethyl[2,2,2 trichloro 1 [6 (dimethylamino) 9h purin 9 yl]ethyl]carbamate; 2 (2 methyl 5 nitro 1h imidazol 1yl)ethyl[1 (1h benzo[d]imidazol 1 yl) 2,2,2 trichloroethyl]carbamate; 2 morpholinoethyl[1 (6 amino 2 fluoro 9h purin 9 yl) 2,2,2 trichloroethyl]carbamate; antimitotic agent; apcin derivative; carbamic acid derivative; caspase 3; cell cycle protein 20; paclitaxel; protein inhibitor; tubulin; unclassified drug; unindexed drug; antineoplastic agent; apcin; carbamic acid derivative; CDC20 protein, human; cell cycle protein 20; diamine; protein binding; tubulin modulator; A-375 cell line; A-549 cell line; antineoplastic activity; antiproliferative activity; apoptosis; Article; binding affinity; cancer inhibition; Caov-3 cell line; cell cycle M phase; comparative study; concentration response; controlled study; drug design; drug mechanism; drug potency; drug protein binding; drug synthesis; enzyme activation; female; HeLa cell line; Hep-G2 cell line; human; human cell; in vitro study; MCF-7 cell line; microtubule assembly; migration inhibition; mitosis inhibition; mitosis spindle; molecular model; OVCAR-3 cell line; protein expression level; structure activity relation; tumor invasion; cell motion; cell proliferation; chemical structure; drug development; drug effect; drug screening; metabolism; microtubule; mitosis; surface plasmon resonance; synthesis; Antineoplastic Agents; Apoptosis; Carbamates; Cdc20 Proteins; Cell Movement; Cell Proliferation; Diamines; Drug Discovery; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Microtubules; Mitosis; Molecular Structure; Protein Binding; Structure-Activity Relationship; Surface Plasmon Resonance; Tubulin Modulators