2β-(N-Substituted Piperazino)-5α-Androstane-3α,17β-Diols: Parallel Solid-Phase Synthesis and Antiproliferative Activity on Human Leukemia HL-60 Cells

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Abstract
Leukemia is the most common cancer affecting children. A steroid possessing a methylpiperazine nucleus was recently reported to inhibit the proliferation of HL-60 leukemia cells. To speed up the development of this promising potential new drug, we generated libraries of analogues using parallel solid-phase organic synthesis (SPOS). A 6-step sequence of reactions, starting from dihydrotestosterone, afforded a steroidal 2,3α-epoxide, which was selectively opened to give, after N-Fmoc protection, a diol with suitable stereochemistry. The difference of reactivity between 3α-OH and 17β-OH was then used to allow the regioselective coupling of 17β-OH to chloro-activated butyldiethylsilane polystyrene. We next generated three libraries of 2β-piperazinyl-5α-androstane-3α,17β-diol N-derivatives with 1, 2, or 3 levels of molecular diversity in acceptable yields and purities for our biological screening assay. Several members of these libraries were more potent than the lead compound, especially five members with a proline as the first level of diversity and a cyclohexylcarbonyl, methylbutyryl, cyclohexylacetyl, cyclopentylpropionyl, or hexanoyl as the second level of diversity. They efficiently inhibited HL-60 cell proliferation with IC50 values of 0.58, 0.66, 1.78, 1.98, and 2.57 μM, respectively. The present work demonstrates the potential of our SPOS approach for the optimization of a new class of cytotoxic agents.

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