The Efficacy of Synthetic Steroids to Inhibit Hormonal Receptors

1
The Efficacy of Synthetic Steroids to Inhibit
Hormonal Receptors

• Malik D. Lewis
• Howard University
• Department of Chemistry
• 07-26-07

2
Outline

• Introduction to Steroids
• Purposes of Hormonal Research
• Specific Synthetic Steroids
• Structure and Activity
• Research Focus

3
Steroids

• Steroid Nucleus- Tetracyclic structure
• Four Groups of Mammalian Hormones
• Estrogen
• Androgen
• Progestin
• Corticosteroid

Lednicer, D. Strategies for Organic Drug
Synthesis and Design. New York John Wiley
Sons, 1998, (84-145)
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Steroids

• Configuration of Steroids

• ß- denotes the substituents above the plane

• a- denotes the substituents below the plane

Lednicer, D. Strategies for Organic Drug
Synthesis and Design. New York John Wiley
Sons, 1998, (84-145)
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Steroids

• Cholesterol is the metabolic starting point for
  endogenous synthesis of all other steroids.
• Stereochemical and Structural complexities
  prohibit total exogenous syntheses.

Lednicer, D. Strategies for Organic Drug
Synthesis and Design. New York John Wiley
Sons, 1998, (84-145)
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Estrogen and Androgen

• Mutations of the DNA sites
• Recruitment of components of transcriptional
  machinery
• Activate expression in specific genes
• Producing translocation of hormone receptor into
  nucleus

Muddana, S. S. Price, A. M. MacBride, M. M.
Peterson, B. R. J. Med. Chem. 2004, 47, 4985.
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Prostate Cancer

• -has the greatest incidence of death among men in
  the United States.
• - growth is incumbent on androgenic hormones
  which are also used in hormone replacement
  therapy.

Tachibana, K. Imaoka, I. Yoshino, H. Emura,
T. Kodama, H. Furuta, Y. Kato, N. Nakamura,
M. Ohta, M. Taniguchi, K. Ishikura, N.
Nagamuta, M. Onuma, E. Sato, H. Bioorg. Med.
Chem. 2007, 15, 174.
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Androgenic Hormones and Receptors

• Main Androgens
• Testosterone
• 5a-dihydrotestosterone

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Cancer treatment

• Antiestrogens and antiandrogens are utilized to
  treat breast cancer and prostate cancer,
  respectively.
• Antagonists act by disrupting the transcription
  factor proteins that contribute to
  ligand-regulated gene expression.

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Androgen Receptor Antagonists

• Ligand-binding domain is the site at which the
  antagonist inhibits the helix 12 folding.
• Flutamide and Bicalutimide
• Finasteride
• Mifepristone

Muddana, S. S. Price, A. M. MacBride, M. M.
Peterson, B. R. J. Med. Chem. 2004, 47, 4985.
Tachibana, K. Imaoka, I. Yoshino, H. Emura,
T. Kodama, H. Furuta, Y. Kato, N. Nakamura,
M. Ohta, M. Taniguchi, K. Ishikura, N.
Nagamuta, M. Onuma, E. Sato, H. Bioorg. Med.
Chem. 2007, 15, 174.
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Synthetic Steroids

• Primary Focus
• 7a-
• methylnortestosterone
• substituted dihydrotestosterone
• 11ß-
• methyl substituent
• alkyl-?9-19-nortestosterone

Muddana, S. S. Price, A. M. MacBride, M. M.
Peterson, B. R. J. Med. Chem. 2004, 47, 4985.
Tachibana, K. Imaoka, I. Yoshino, H. Emura,
T. Kodama, H. Furuta, Y. Kato, N. Nakamura,
M. Ohta, M. Taniguchi, K. Ishikura, N.
Nagamuta, M. Onuma, E. Sato, H. Bioorg. Med.
Chem. 2007, 15, 174.
12
Activity

• Relative binding affinity with receptor.
• Reporter gene assays performed with
  hAR-transfected HeLa cells.

Tachibana, K. Imaoka, I. Yoshino, H. Emura,
T. Kodama, H. Furuta, Y. Kato, N. Nakamura,
M. Ohta, M. Taniguchi, K. Ishikura, N.
Nagamuta, M. Onuma, E. Sato, H. Bioorg. Med.
Chem. 2007, 15, 174.
13
Activity

• Agonistic Activity
• FI5 concentration of compound-treated group in
  which the transcriptional activity is five times
  the transcriptional activity of the case without
  the compound.
• Antagonistic Activity
• IC50 concentration of compound to inhibit the
  transcriptional activity of 0.1 nM of DHT by 50

Tachibana, K. Imaoka, I. Yoshino, H. Emura,
T. Kodama, H. Furuta, Y. Kato, N. Nakamura,
M. Ohta, M. Taniguchi, K. Ishikura, N.
Nagamuta, M. Onuma, E. Sato, H. Bioorg. Med.
Chem. 2007, 15, 174.
14
Structure and Activity

• 7a- substituents hypothesized to have great
  Antagonistic activity based on study of ERß LBD.
  
• Optimal Length reported was 16-18 atoms.
• Study tested 7a-dihydrotestosterones within a
  range of 11-19 atoms.

• Sulfoxide Derivatives
• Nitrogen Derivatives
• Cyclic groups

• Substituents bearing

Tachibana, K. Imaoka, I. Yoshino, H. Emura,
T. Kodama, H. Furuta, Y. Kato, N. Nakamura,
M. Ohta, M. Taniguchi, K. Ishikura, N.
Nagamuta, M. Onuma, E. Sato, H. Bioorg. Med.
Chem. 2007, 15, 174.
15
Structure and Activity

• 11ß utilized competition flourescence
  polarization assays compare affinities of
  19-nortestosterone derivatives.
• Greater the side chain length greater affinity
  to Androgen receptor.

Muddana, S. S. Price, A. M. MacBride, M. M.
Peterson, B. R. J. Med. Chem. 2004, 47, 4985.
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Structure and Activity

• Antiandrogens show partial agonist activity.
• Receptors maintain the ability to modify their
  conformations in response to ligands.
• Current therapeutic antiandrogens exhibit low
  relative binding affinities, low selectivity
  across the nuclear hormone receptor superfamily,
  or agonist activity toward androgen receptor
  mutants that can emerge in advanced prostate
  cancer.

Cook, C. E. Kepler, J. A. Bioorg. Med. Chem.
Lett. 2005, 15, 1213.
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Cholesterol Derivatives

• Cholesterol derivatives allow for an abundant
  plasma-membrane-associated steroid that controls
  membrane fluidity to be covalently bonded to
  proteins in cellular signaling.

Hussey,S. L. He, E. Peterson, B. Org. Lett.,
Vol. 4, No. 3, 2002, 416.
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Research Focus
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Research Focus
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Research Focus
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Research Focus
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Research Focus
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Research Focus

• Characterization of compound
• FTIR
• GC/MS
• 1H NMR

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Acknowledgements

• NIH-NCI Howard-Hopkins Partnership Grant
• AGEP Program
• Special Thanks to
• Dr. Oladapo Bakare, PhD
• and the students of his lab