caa a22 4500 44587905X CHVBK 20180317145536.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s11030-010-9273-2 doi (NATIONALLICENCE)springer-10.1007/s11030-010-9273-2 Libraries of 2 β -( N -substituted piperazino)-5 α -androstane-3 α , 17 β -diols: chemical synthesis and cytotoxic effects on human leukemia HL-60 cells and on normal lymphocytes [Elektronische Daten] [Jenny Roy, René Maltais, Hajer Jegham, Donald Poirier] 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 1μM). 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. Springer Science+Business Media B.V., 2010 Aminosteroid nationallicence Androstane nationallicence Solid-phase synthesis nationallicence Cancer nationallicence HL-60 cells nationallicence AA : Amino acid nationallicence Ar : Aromatic nationallicence DIPEA : Diisopropylethylamine nationallicence DMF : Dimethylformamide nationallicence epi-ADT : Epi-androsterone nationallicence EtOAc : Ethyl acetate nationallicence Fmoc : 9-Fluorenylmethoxycarbonyl nationallicence h : Hour nationallicence HOBt : N-hydroxybenzotriazole nationallicence HPLC : High-performance liquid chromatography nationallicence IC50 : Concentration inhibiting 50% of cell growth nationallicence IR : Infrared spectroscopy nationallicence HRMS : High resolution mass spectrometry nationallicence LRMS : Low resolution mass spectrometry nationallicence MeOH : Methanol nationallicence min : Minute nationallicence NMR : Nuclear magnetic resonance nationallicence Ph : Phenyl nationallicence Phe : Phenylalanine nationallicence Pro : Proline nationallicence PS-DES : Polystyrene diethylsilyl resin nationallicence PyBOP : Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate nationallicence PyBrOP : Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate nationallicence Pyr : Pyridine nationallicence rt : Room temperature nationallicence SAR : Structure-activity relationship nationallicence SI : Selective indice nationallicence TEA : Triethylamine nationallicence THF : Tetrahydrofuran nationallicence Tic : 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid nationallicence TLC : Thin-layer chromatography nationallicence Ts : Tosyl nationallicence Roy Jenny Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut Maltais René Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut Jegham Hajer Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut Poirier Donald Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut Molecular Diversity Springer Netherlands 15/2(2011-05-01), 317-339 1381-1991 15:2<317 2011 15 11030 https://doi.org/10.1007/s11030-010-9273-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11030-010-9273-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Roy Jenny Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut NATIONALLICENCE 700 1- Maltais René Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut NATIONALLICENCE 700 1- Jegham Hajer Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut NATIONALLICENCE 700 1- Poirier Donald Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, G1V 4G2, Quebec, QC, Canada aut NATIONALLICENCE 773 0- Molecular Diversity Springer Netherlands 15/2(2011-05-01), 317-339 1381-1991 15:2<317 2011 15 11030 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer