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 |
| |
Authors: | Jenny Roy René Maltais Hajer Jegham and Donald Poirier |
| |
Institution: | (1) Japan Grassland Agriculture and Forage Seed Association, Forage Crop Research Institute, 388-5 Higashiakada, Nasushiobara Tochigi, 329-2742, Japan |
| |
Abstract: | 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 R1 (libraries A, B, C, and D: with 45, 45, 20, and 20 members, respectively) and, subsequently, the capping group at R2 (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).
In library B, the phenylalanine (Phe) derivatives bearing a cyano group induced a higher growth inhibition than the other
Phe derivatives. The screening of library C indicated the increase of hydrophobicity of proline (Pro) seems to preserve the
cytotoxic effect achieved by the lead compound. However, the synthesis of structural Pro variants (library D) clearly shows
weaker activities when compared to L-Pro building blocks. Finally, by incorporating some of the most active AA of libraries A–D in library E, we observed that
the amide coupling functionality gave stronger cytotoxic activity compared to the corresponding sulfonamides or benzylamines.
Six of the most active amide derivatives (E-37P, E-41P, E-42P, E-46P, E-48F, and E-12T) were selected and IC50 determined on HL-60 cells as well as on normal human lymphocytes. Among this series of new anticancer agents, good to high
selectivity indices (SI = IC50 (lymphocytes)/IC50 (HL-60 cells) = 5 - 55) were obtained. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|