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Solid-phase synthesis of model libraries of 3 α17β-dihydroxy-16α-(aminoethyl-N-substituted)-5α-androstanes for the development of steroidal therapeutic agents

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Abstract

The solid-phase synthesis of 16α-derivatives of 5α-androstane-3α,17β-diol with one, two or three levels of molecular diversity was accomplished using the diethylsilyloxy linker. Libraries with one level of diversity (10 members) and two levels of diversity (40 members) were synthesized in a parallel fashion in good yields and acceptable HPLC purities for the majority of library members. Compounds with three levels of diversity (15 pools) were realized in a split and pool fashion to allow further deconvolution by the positional scanning method. The screening of the generated model libraries revealed interesting preliminary structure–activity relationships related to their antiproliferative activities on androgen-sensitive Shionogi cells. In the case of the two-level library, the presence of a hydrophobic amino acid at R1 (isoleucine (Ile) or phenylalanine (Phe)) and a six-membered ring (aromatic or not) at R2 seems an important requirement for activity. In the three-level library, the amino acid residues isoleucine and phenylalanine clearly provided a better antiproliferative activity than glycine (Gly) and proline (Pro). These model libraries will serve as basis for the generation of larger libraries of peptidosteroids toward the development of therapeutic agents.

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Abbreviations

ADT:

androsterone

AR:

androgen receptor

DHP:

dihydropyran

DHT:

dihydrotestosterone

3α-diol:

5α-androstane-3α,17β-diol

DIPEA:

diisopropylethylamine

DMF:

dimethylformamide

DMSO:

dimethylsulfoxide

EtOAc:

ethyl acetate

Fmoc:

9-fluorenylmethoxycarbonyl

Gly:

glycine

h:

hour

HMPA:

hexamethylphosphoramide

HOBt:

N-hydroxybenzotriazole

HPLC:

high-performance liquid chromatography

HSD:

hydroxysteroid dehydrogenase

IR:

infrared spectroscopy

Ile:

isoleucine

LCMS:

liquid chromatography mass spectrometry

LDA:

lithium diisopropylamide

LRMS:

low resolution mass spectrometry

MS:

mass spectrometry

MeOH:

methanol

min:

minute

NMR:

nuclear magnetic resonance

Ph:

phenyl

Phe:

phenylalanine

Pro:

proline

PS-DES:

polystyrene diethylsilyl resin

p-TSA:

p-toluenesulfonic acid

PyBOP:

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

rt:

room temperature

TBAF:

tetrabutylammonium fluoride

TBDMS:

tert-butyldimethylsilyl

THF:

tetrahydrofuran

THP:

tetrahydropyran

TLC:

thin-layer chromatography.

References

  1. Hanson, J.R., Steroids: Reactions and partial synthesis, Nat. Prod. Rep., 19 (2002) 381–389, and references therein.

    Google Scholar 

  2. Maltais, R., Tremblay, M.R., Ciobanu, L. and Poirier, D., Steroids and combinatorial chemistry, J. Comb. Chem., 6 (2004), 443–456.

    Google Scholar 

  3. Poirier, D., Inhibitors of 17β-hydroxysteroid dehydrogenases, Curr. Med. Chem., 10 (2003) 453–477.

    Google Scholar 

  4. Singh, S.M., Gauthier, S. and Labrie, F., Androgen receptor antagonist (antiandrogens): Structure–activity relationships, Curr. Med. Chem., 7 (2000) 211–247.

    Google Scholar 

  5. Newman, D.J., Cragg, G.M. and Snader, K.M., The influence of natural products upon drug discovery, Nat. Prod. Rep., 17 (2000) 215–234.

    Google Scholar 

  6. Bratoeff, E., Ramirez, E., Murillo, E., Flores, G. and Cabeza, M., Steroidal antiandrogens and 5α -reductase inhibitors, Curr. Med. Chem., 6 (1999) 1107–1123.

    Google Scholar 

  7. Poirier, D., Ciobanu, L.C. and Maltais, R., Steroid sulfatase inhibitors, Exp. Opin. Ther. Patents., 9 (1999) 1083–1099.

    Google Scholar 

  8. Hamada, H., Newmann, F. and Junkman, K., Intrauterine antimaskuline beeinflussing von rattenfetendurch ein stark gestagen wirksames steroid, Steroid Acta Endocrinol., 44 (1963) 330.

    Google Scholar 

  9. Labrie, F., Cusan, L., Dupont, A., Gomez, J.L., Simard, J., Luu-The, V., Pelletier, G., Labrie, C. and Bélanger, A., In Reproductive Endocrinology, Surgery and Technology. Lippincott-Raven, Philadelphia, 1996.

    Google Scholar 

  10. Brooks, J.R., Berman, C., Primka, R.L., Reynolds, G.F. and Rasmusson, G.H., 5 Alpha-reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat, Steroids, 47 (1986) 1–19.

    Google Scholar 

  11. Tchédam-Ngatcha, B., Luu-The, V. and Poirier, D., Androsterone 3β -substituted derivatives as inhibitors of type 3 17β -hydroxysteroid dehydrogenase, Bioorg. Med. Chem. Lett., 10 (2000) 2533–2536.

    Google Scholar 

  12. Tchédam-Ngatcha, B., Luu-The, V. and Poirier, D., Androsterone derivatives substituted at position 16: Chemical synthesis, inhibition of type 3 17β -hydroxysteroid dehydrogenase, binding affinity for steroid receptors and proliferative/antiproliferative activity on Shionogi (AR+) cells, J. Enz. Inh. Med. Chem., 17 (2002) 155–165.

    Google Scholar 

  13. Fevig, T.L. and Katzenellenbogen, J.A., A short, stereoselective route to 16α-(substituted-alkyl)-estradiol derivatives, J. Org. Chem., 52 (1987) 247–251.

    Google Scholar 

  14. Tremblay, M.R., Auger, S. and Poirier, D., Synthesis of 16-(bromoalkyl)-estradiols having inhibitory effect on human placental estradiol 17β -hydroxysteroid dehydrogenase (17β -HSD type 1), Bioorg. Med. Chem., 3 (1995) 505–523.

    Google Scholar 

  15. Tremblay, M.R. and Poirier, D., Overview of a rational approach to design type I 17β -hydroxysteroid dehydrogenase inhibitors without estrogenic activity: Chemical synthesis and biological evaluation, J. Steroid Biochem. Mol. Biol., 66 (1998) 179–191.

    Google Scholar 

  16. Maltais, R., Tremblay, M.R. and Poirier, D., Solid phase synthesis of hydroxysteroids using the diethylsilyloxy linker, J. Comb. Chem., 2 (2000) 604–614.

    Google Scholar 

  17. Tremblay, M.R and Poirier, D., Solid-phase of phenolic steroids: From optimization studies to a convenient procedure for combinatorial synthesis of biologically relevant estradiol derivatives, J. Comb. Chem., 2 (2000) 48–65.

    Google Scholar 

  18. Hu, Y., Porco, J.A., Labadie, J.W. and Gooding, O.W., Novel polymer-supported trialkylsilanes and their use in solid-phase organic synthesis, J. Org. Chem., 63 (1998) 4518–4521.

    Google Scholar 

  19. Bartra, M., Romea, P., Urpi, F. and Vilarrasa, J., A fast procedure for the reduction of azides and nitro compounds based on the reducing ability of Sn(SR)3-species. Tetrahedron, 46 (1990) 587–594.

    Google Scholar 

  20. Furka, A., Sebestyn, F. and Asgedom, M., General method for rapid synthesis of multicomponent peptide mixtures, Int. J. Pept. Protein Res., 37 (1991) 487–493.

    Google Scholar 

  21. Smith, P.W., Lai, J.Y.Q., Whittington, A.R., Cox, B., Houston, J.G., Stylli, C.H., Banks, M.N. and Tiller, P.R., Synthesis and biological evaluation of a library containing potentially 1600 amides/esters. A strategy for rapid compound generation and screening, Bioorg. Med. Chem. Lett., 4 (1994) 2821–2824.

    Google Scholar 

  22. Pirrung, M.C. and Chen, J., Preparation and screening against acetylcholinesterase of a non-peptide ‘indexed’ combinatorial library, J. Am. Chem. Soc., 117 (1995) 1240–1245.

    Google Scholar 

  23. Sack, J.S., Kish, K.F., Wang, C., Attar, R.M., Kiefer, S.E., An, Y., Wu, G.Y., Scheffler, J.E., Salvati, M.E., Krystek, S.R. Jr., Weinmann, R. and Einspahr, H.M., Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone, Proc. Natl. Acad. Sci. U.S.A., 98 (2001) 4904–4909.

    Google Scholar 

  24. Matias, P.M., Donner, P., Coelho, R., Thomaz, M., Peixoto, C., Macedo, S., Otto, N., Joschko, S., Scholz, P., Wegg, A., Bäsler, S., Schäfer, M., Egner, U. and Carrondo, M.A., Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations, J. Biol. Chem., 275 (2000) 26164–26171.

    Google Scholar 

  25. Luthy, I., Begin, D. and Labrie, F., Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture, J. Steroid Biochem., 31 (1988) 845–852.

    Google Scholar 

  26. Plante, M., Lapointe, S. and Labrie, F., Stimulatory effect of synthetic progestins currently used for the treatment of prostate cancer on growth of the androgen-sensitive Shionogi tumor in mice, J. Steroid Biochem., 31 (1988) 61–64.

    Google Scholar 

  27. Simard, J., Dauvois, S., Haagensen, D.E., Lévesque, C., Mérand, Y. and Labrie, F., Regulation of progesterone binding breast cyst protein GCDFP-24 secretion by estrogens and androgens in human breast cancer cell: a new marker of steroid action in breast cancer, Endocrinology, 126 (1990) 3223–3231.

    Google Scholar 

  28. Fiszer-Szafarz, B., Szafarz, D. and Guevara de Murillo, A., A general, fast and sensitive micromethod for DNA determination: Application to rat and mouse liver, rat hepatoma, human leukocytes, chicken fibroblasts and yeast cells, Anal. Biochem., 110 (1981) 165–170.

    Google Scholar 

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Authors and Affiliations

  1. Oncology and Molecular Endocrinology Research Center (Medicinal Chemistry Division, Université Laval, Centre Hospitalier Universitaire de Québec (CHUQ)-Pavillon CHUL, 2705 Laurier Blvd, Québec, Canada G1V 4G2

    René Maltais, Caroline Mercier, Fernand Labrie & Donald Poirier

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  1. René Maltais
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  2. Caroline Mercier
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  3. Fernand Labrie
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  4. Donald Poirier
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Correspondence to Donald Poirier.

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Maltais, R., Mercier, C., Labrie, F. et al. Solid-phase synthesis of model libraries of 3 α17β-dihydroxy-16α-(aminoethyl-N-substituted)-5α-androstanes for the development of steroidal therapeutic agents. Mol Divers 9, 67–79 (2005). https://doi.org/10.1007/s11030-005-1312-z

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