Synthesis of ACT-007 and Its Analogues with Antiproliferative Activity

Abstract

By investigating the highly efficient synthesis conditions for ACT-007 (2), we developed a simple, highly productive, and mild gram-scale synthesis method for ACT-007 (2). ACT-007 (2) and six novel analogues (3–9) were obtained via a one-pot synthesis from staurosporine (1) using bis(trichloromethyl)carbonate (BTC) or thiophosgene (CSCl2) and silica gel under reduced pressure on a rotary evaporator, achieving yields ranging from 25% to 99%. Additionally, new analogues 10–13, as well as 14 and 15, were synthesized from staurosporine (1) through three and five-step sequences, resulting in overall yields of 53–60%, 52%, and 48%, respectively. Compounds 5, 13, and 15 demonstrated significant antiproliferative activity against the human acute myeloid leukemia cell line MV4–11, with IC50 values of 73.2, 51.9, and 5.1 nM, respectively. Furthermore, among compounds 2–15, only compound 15 showed activity against the human colorectal cancer cell line HCT-116 and the bladder carcinoma cell line 5637, with IC50 values of 580.6 and 375.9 nM, respectively. These results suggest that compounds 5, 13, and 15 hold promise as potential leads for the development of new antiacute myeloid leukemia drugs, while compound 15, in particular, emerges as a novel candidate for treating colorectal cancer and bladder carcinoma.