Chemical synthesis of 2β-amino-5α-androstane-3α,17β-diol N-derivatives and their antiproliferative effect on HL-60 human leukemia cells Original Research Article

Even though few steroids are used for the treatment of leukemia, 2β-(4-methylpiperazinyl)-5α-androstane-3α,17β-diol (1) was recently reported for its ability to inhibit the proliferation of human leukemia HL-60 cells. With an efficient procedure that we had developed for the aminolysis of hindered steroidal epoxides, we synthesized a series of 2β-amino-5α-androstane-3α,17β-diol N-derivatives structurally similar to 1. Hence, the opening of 2,3α-epoxy-5α-androstan-17β-diol with primary and secondary amines allowed the synthesis of aminosteroids with diverse length, ramification, and functionalization of the 2β-side chain. Sixty-four steroid derivatives were tested for their capacity to inhibit the proliferation of HL-60 cells; thus obtaining first structure–activity relationship results. Ten aminosteroids with long alkyl chains (7–16 carbons) or bulky groups (diphenyl or adamantyl) have shown antiproliferative activity over 78% at 10 μM and superior to that of the lead compound. The 3,3-diphenylpropylamino, 4-nonylpiperazinyl and octylamino derivatives of 5α-androstane-3α,17β-diol inhibited the HL-60 cell growth with IC50 of 3.1, 4.2 and 6.4 μM, respectively. They were also found to induce the HL-60 cell differentiation.