Design, Synthesis And Evaluation Of Biological Activity Of Novel Maleimides And Analogues

Staurosporine, a broad-spectrum kinase inhibitor, possesses various biological activities, such as anti-cancer, anti-diabetes, antifungal activity, and hypotensive activity. Staurosporine may inhibit PKC, Topo I and CDKs to achieve antineoplastic activity; on the other hand, it also inhibits GSK3βto treat other diseases such as anti-diabetes.When synthesizing a series of bisindolylmaleimide derivatives as PKC inhibitors, the intermediates, 1-methyl-3-chloro-4-(indol-3-yl) maleimides, were found to bear even better cytotoxic activities by our group. Accordingly,25 novel 3-chloro-4-(indol-3-yl) maleimide derivatives were designed, synthesized, and confirmed by 1H NMR and MS. All compounds were tested for their in vitro cytotoxic activities against five human tumor cell lines, and most compounds exhibited potent cytotoxic activities with IC50 values in the low micromolar range. It was noteworthy that the cytotoxic effects of most tested compounds against ECA-109 cells were equal to or greater than that of taxol. The chlorine atom at the 3-position of the maleimide ring was proved to be crucial for the activity. These results suggest that these compounds have excellent antitumor activities, and further pharmacological tests are in progress.GSK3βplays crucial roles in multiple signaling pathways, and GSK3βinhibitors have been researched extensively in the treatment of diabetes, neurological diseases, cancer, and inflammation. Based on sufficient analysis of the crystal structures of staurosporine-GSK3(3 complex and maleimide 1-6-GSK3βcomplex as well as detailed study on the structure-activity relationships of maleimdes, maleimide ring was replaced by 1,2-dihydropyrazol-3-one to retain the hydrogen bonds on the carbonyl and NH groups with Val135 and Asp133 of GSK3βaccording to bioisostere and ring substitution principle; indolyl was introduced to 4-position while phenyl or indolyl was introduced to 5-position on the pyrazolone ring to retain the hydrophobic interaction between the aromatic groups and GSK3β. Accordingly,20 novel 1,2-dihydropyrazol-3-ones were synthesized, confirmed by 1H NMR and MS. They were tested in vitro for their GSK3P inhibitory activity, the result showed that:some compounds exhibited potent inhibitory activity; the most potent compoundsⅡ-54 andⅡ-65 exhibited IC50 values of 9.28 and 8.98μM respectively. These compounds have little cytotoxic activity, demonstrating the potential for the treatment of diabetes and Alzheimer's disease.