Assessing anti‐cancer potential of newly synthesized staurosporine analogs

The discovery of staurosporine in 1977 and subsequent finding that it was a potent inhibitor of protein kinase C suggested that it might have anti‐cancer potential. Subsequently staurosporine was found to be a pan‐kinase inhibitor, making it to toxic for drug development, however, derivatives have been found with increased specificity and have been tested in clinical trials. The structure of staurosporine can be divided into three parts: a pyran ring that bridges the indole nitrogen atoms, an indolocarbazole central core, and a fused pyrrol‐2‐one. We focus on the synthesis and biological activity of the pyrrolinone group and bis‐indole motifs. Using a cytotoxicity assays we have analyzed structure‐function activity of our derivatives and endeavor to synthetic new targets with increased potency. We recently reported on the synthesis and biological activity of a 1st generation of analogs with low micromolar potency. Our findings suggested that biologically effective compounds require: a) an indole cis to the carbonyl oxygen atom on the 3‐pyrrolin‐2‐one central core ring, b) a flexible, rather than a planar, fused analog, c) aryl/heteroaryl groups at both the C3 and C4 position of the 3‐pyrrolin‐2‐one core, and d) multiple methoxy groups on the C4 ring. Building upon this work, we now report on a 2nd generation of compounds with nanomolar cytotoxic activity. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .