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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

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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.

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Abbreviations

AA:

Amino acid

Ar:

Aromatic

DIPEA:

Diisopropylethylamine

DMF:

Dimethylformamide

epi-ADT:

Epi-androsterone

EtOAc:

Ethyl acetate

Fmoc:

9-Fluorenylmethoxycarbonyl

h:

Hour

HOBt:

N-hydroxybenzotriazole

HPLC:

High-performance liquid chromatography

IC50 :

Concentration inhibiting 50% of cell growth

IR:

Infrared spectroscopy

HRMS:

High resolution mass spectrometry

LRMS:

Low resolution mass spectrometry

MeOH:

Methanol

min:

Minute

NMR:

Nuclear magnetic resonance

Ph:

Phenyl

Phe:

Phenylalanine

Pro:

Proline

PS-DES:

Polystyrene diethylsilyl resin

PyBOP:

Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate

PyBrOP:

Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate

Pyr:

Pyridine

rt:

Room temperature

SAR:

Structure-activity relationship

SI:

Selective indice

TEA:

Triethylamine

THF:

Tetrahydrofuran

Tic:

1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

TLC:

Thin-layer chromatography

Ts:

Tosyl

References

  1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Fewer EJ, Thun MJ (2005) Cancer statistic 2005. Cancer J Clin 55: 10–30. doi:10.3322/canjclin.55.1.10

    Article  Google Scholar 

  2. He Q, Jiang D (1999) A novel aminosteroid is active for proliferation inhibition and differentiation induction of human acute myeloid leukemia HL-60 cells. Leuk Res 23: 369–372. doi:10.1016/S0145-2126(98)00160-X

    Article  PubMed  CAS  Google Scholar 

  3. Thibeault D, Poirier D (2003) An efficient method for the regioselective aminolysis of 2,3α-steroidal epoxide. Synlett 8: 1192–1194. doi:10.1055/s-2003-39901

    Google Scholar 

  4. Thibeault D, Roy J, DeRoy P, Poirier D (2008) Chemical synthesis of 2β-amino-5α-androstane-3α,17β-diols and biological evaluation of their antiproliferative effect on HL-60 acute myeloid leukemia cells. Bioorg Med Chem 16: 5062–5077. doi:10.1016/j.bmc.2008.03.031

    Article  PubMed  CAS  Google Scholar 

  5. Maltais R, Tremblay MR, Poirier D (2000) Solid phase synthesis of hydroxysteroids using the diethylsilyloxy linker. J Comb Chem 2: 604–614. doi:10.1021/cc0000242

    Article  PubMed  CAS  Google Scholar 

  6. Maltais R, Luu-The V, Poirier D (2001) Parallel solid-phase synthesis of 3β-peptido-3α-hydroxy-5α-androstan-17-one derivatives for inhibition of type 3 17β-hydroxysteroid dehydrogenase. Bioorg Med Chem 9: 3101–3111. doi:10.1016/S0968-0896(01)00182-1

    Article  PubMed  CAS  Google Scholar 

  7. Ciobanu LC, Poirier D (2003) Solid-phase syntesis of 17α-substitued estradiol sulfamate and phenol libraries using the multidetachable sulfamate linker. J Comb Chem 5: 429–440. doi:10.1021/cc020115u

    Article  PubMed  CAS  Google Scholar 

  8. Maltais R, Mercier C, Labrie F, Poirier D (2005) Solid-phase synthesis of model libraries of 3α,17β-dihydroxy-16α-aminoethyl-N-substitued)-5α-androstanes for the development of steroidal therapeutic agents. Mol Divers 9: 67–79. doi:10.1007/s11030-005-1312-z

    Article  PubMed  CAS  Google Scholar 

  9. Maltais R, Tremblay MR, Ciobanu LC, Poirier D (2004) Steroids and combinatorial chemistry. J Comb Chem 6: 443–456. doi:10.1021/cc030118m

    Article  PubMed  CAS  Google Scholar 

  10. Poirier D, Maltais R (2006) Solid-phase organic synthesis (SPOS) of modulators of estrogenic and androgenic action. Mini Rev Med Chem 6: 37–52. doi:10.2174/138955706775197802

    Article  PubMed  CAS  Google Scholar 

  11. Ciobanu LC, Poirier D (2006) Synthesis of libraries of 16β-aminopropyl estradiol derivatives for targeting two key steroidogenic enzymes. ChemMedChem 1: 1249–1259. doi:10.1002/cmdc.200600071

    Article  PubMed  CAS  Google Scholar 

  12. Roy J, DeRoy P, Poirier D (2007) Development of aminosteroids with cytotoxic effect against leukemia using parallel solid-phase approach. J Comb Chem 9: 347–358. doi:10.1021/cc060098z

    Article  PubMed  CAS  Google Scholar 

  13. Roy J (2006) Synthèse chimique et activité biologique d’agents stéroïdiens pour le traitement du cancer de la prostate et de la leucémie. PhD thesis, Laval University (Québec, Canada), Chap. 4, pp194-216. http://ariane.ulaval.ca/cgi-bin/recherche.cgi?qu=a1595498

  14. Robak T, Wierzbowska A (2009) Current and emerging therapies for acute myeloid leukemia. Clin Ther 31: 2349–2370. doi:10.1016/j.clinthera.2009.11.017

    Article  PubMed  CAS  Google Scholar 

  15. Anderson A, Boyd AC, Byford A, Campbell AC, Gemmell DK, Hamilton NM, Hill DR, Hill-Venning C, Lambert JJ, Maidment MS, May V, Marshall RJ, Peters JA, Rees DC, Stevenson D, Sundaram H (1997) Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA A receptors. J Med Chem 40: 1668–1681. doi:10.1021/jm960733n

    Article  PubMed  CAS  Google Scholar 

  16. Hudlicky M (1988) Fluorination with diethylaminosulfur trifluoride and related aminofluorosulfuranes. Org React 35: 513–641. doi:10.1002/0471264180.or035.03

    CAS  Google Scholar 

  17. Decreau RA, Marson CM (2004) Synth Commun 34: 4369–4385. doi:10.1081/SCC-200039449

    Article  CAS  Google Scholar 

  18. Bird TG, Fredericks PM, Jones ERH, Meakins GD (1979) Convenient general preparation of oxy-generated monofluoro-5α-androstanes using diethylaminosulfur trifluoride. J Chem Soc Chem Commun, 65–66. doi:10.1039/C39790000065

  19. Druker BJ, Lydon NB (2000) Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105: 3–7. doi:10.1172/JCI9083

    Article  PubMed  CAS  Google Scholar 

  20. Fausel C (2007) Targeted chronic myeloid leukemia therapy: Seeking a cure. Am J Health Syst Pharm 64: S9–S15. doi:10.2146/ajhp070482

    Article  PubMed  CAS  Google Scholar 

  21. Iriarte J, Rosenkranz G, Sondheimer F (1955) A synthesis of androsterone. J Org Chem 20: 542–545. doi:10.1021/jo01122a018

    Article  CAS  Google Scholar 

  22. Kagialis-Girard S, Mialou V, Chebel A, Chien WW, Tigaud I, Mokdad F, Badiou C, French MF (2007) Inhibition of normal lymphocyte proliferation by Indirubin-3’-monoxime: a multifactorial process. Leuk Lymphoma 48: 605–615. doi:10.1080/10428190601059696

    Article  PubMed  CAS  Google Scholar 

  23. Rocha DD, Gadelha Militao GC, Veras ML, Pessoa ODL, Rocha Silveira E, NegreirasNumes Alves AP, Odericode Moraes M, Pessoa C, Veras Costa-Lotufo L (2006) Selective cytotoxicity of withaphysalins in myeloid leukemia cell lines versus peripheral blood mononuclear cells. Life Sci 79: 1692–1701. doi:10.1016/j.lfs.2006.05.026

    Article  PubMed  CAS  Google Scholar 

  24. Cwynarski K, Laylor R, Macchiarulo E, Goldman J, Lombardi G, Melo JV, Dazzi F (2004) Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 18: 1332–1339. doi:10.1038/sj.leu.2403401

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Medicinal Chemistry, Endocrinology and Genomic Unit, CHUQ-(CHUL) Research Center, 2705 Laurier Boulevard, Quebec, QC, G1V 4G2, Canada

    Jenny Roy, René Maltais, Hajer Jegham & Donald Poirier

  2. Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec, QC, Canada

    Jenny Roy, René Maltais, Hajer Jegham & Donald Poirier

Authors
  1. Jenny Roy
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  2. René Maltais
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  3. Hajer Jegham
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  4. Donald Poirier
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Corresponding author

Correspondence to Donald Poirier.

Additional information

Jenny Roy and René Maltais contributed equally.

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Roy, J., Maltais, R., Jegham, H. et al. 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. Mol Divers 15, 317–339 (2011). https://doi.org/10.1007/s11030-010-9273-2

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