Solid-phase chemical synthesis and in vitro biological evaluation of novel 2β-piperazino-(20R)-5α-pregnane-3α,20-diol N-derivatives as anti-leukemic agents.

The steroid nucleus is an interesting scaffold for the development of new therapeutic agents. Within the goal of identifying anticancer agents, new pregnane derivatives were prepared by using a sequence of liquid and solid-phase reactions. After we dehydrated epi-allopregnanolone in one step with diethylaminosulfur trifluoride and generated a 2,3α-epoxide, the regio- and stereo-selective aminolysis of this epoxide enabled us to obtain a 2β-piperazino-pregnane, whose secondary amine was protected as N-Fmoc-derivative.

Biological evaluation of a new family of aminosteroids that display a selective toxicity for various malignant cell lines.

This study investigated the antineoplasic potential of a new family of aminosteroids. The antiproliferative activity of seven 5α-androstane-3α,17β-diol derivatives selected from a screening study was measured on nine cancerous cell lines (HL-60, K-562, LNCaP, PC-3, Shionogi, MCF-7, MDA-MB-231, BT-20, and OVCAR-3) and two normal cell lines (peripheral blood lymphocytes and WI-38). The aminosteroids efficiently inhibited the cell growth of seven cancer cell lines [inhibitory concentration (IC(50)) values=0.

A novel aminosteroid of the 5α-androstane-3α,17β-diol family induces cell cycle arrest and apoptosis in human promyelocytic leukemia HL-60 cells.

RM, a novel aminosteroid synthesized by our research group, shows a broad spectrum of antitumor activity against nine cancer cell lines and limited toxicity against two normal cell lines. However, its related mechanism of action has not yet been elucidated. In this study, we investigated the cellular and molecular events underlying the cytotoxicity of RM in human acute promyelocytic leukemia HL-60 cells.

Libraries of 2β-(N-substituted piperazino)-5α-androstane-3α, 17β-diols: chemical synthesis and cytotoxic effects on human leukemia HL-60 cells and on normal lymphocytes.

Libraries of steroid derivatives with two levels of molecular diversity were prepared to optimize the antiproliferative activity on leukemia HL-60 cells by first varying the amino acid (AA) at R(1) (libraries A, B, C, and D: with 45, 45, 20, and 20 members, respectively) and, subsequently, the capping group at R(2) (library E: 168 members). The screening of these aminosteroids revealed interesting structure-activity relationships. In library A, the compounds bearing a tetrahydroisoquinolone residue as the first element of diversity showed potent cytotoxicity, principally when isovaleric or cyclohexyl acetic acid was used as a capping group (>40% of cell growth inhibition at 1 μM).