Synthesis, Nmr Characterization, And Antileukemic Activity Of N-Nonanoylpiperazinyl-5 Alpha-Androstane-3 Alpha,17 Beta-Diol A-Ring Derivatives

The combination of an androstane-3,17-diol nucleus and a 2 beta-N-alkylamidopiperazino sidechain is important for the anticancer activity of a new family of steroid derivatives. As the structure-activity relationship studies have so far been limited to the beta orientation of the substituent at position 2 of the steroid nucleus, a series of analogs (compounds 1-4) were synthesized to investigate the impact on biological activity of A-ring substitution. Nuclear magnetic resonance (NMR) analysis, especially using a series of 2D experiments, such as correlation spectroscopy (COSY), homonuclear Overhauser effect spectroscopy (NOESY), heteronuclear single-quantum correlation (HSQC), and heteronuclear multiple-bond correlation (HMBC) provided crucial information that was found essential in confirming the sidechain position and orientation of compounds 1-4. Assessment of their antiproliferative activity on leukemia HL-60 cells confirmed the best efficiency of the 2 beta-sidechain/3 alpha-OH orientation (compound 1) compared to the other configurations tested (compounds 2-4).