The Efficacy of Synthetic Steroids to Inhibit Hormonal Receptors Malik D. Lewis Howard University...
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Transcript of The Efficacy of Synthetic Steroids to Inhibit Hormonal Receptors Malik D. Lewis Howard University...
The Efficacy of Synthetic Steroids to Inhibit Hormonal
Receptors
Malik D. LewisHoward University
Department of Chemistry07-26-07
Outline
Introduction to SteroidsPurposes of Hormonal ResearchSpecific Synthetic SteroidsStructure and ActivityResearch Focus
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)
Steroids
Configuration of Steroids
A B
C D1
23
4 5 678
910
11
12
13
14 15
16
1718
19
2021
β- denotes the substituents above the plane
R
R
α- denotes the substituents below the plane
Lednicer, D. Strategies for Organic Drug Synthesis and Design. New York: John Wiley & Sons, 1998, (84-145)
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)
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.
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.
Androgenic Hormones and Receptors Main Androgens
Testosterone
5α-dihydrotestosterone
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.
Androgen Receptor Antagonists Ligand-binding domain is the site at which the
antagonist inhibits the helix 12 folding.
Flutamide and Bicalutimide Finasteride
Mifepristone
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.
Muddana, S. S.; Price, A. M.; MacBride, M. M.; Peterson, B. R.; J. Med. Chem. 2004, 47, 4985.
Synthetic Steroids
Primary Focus:
7α- methylnortestosterone substituted dihydrotestosterone
11β- methyl substituent alkyl-Δ9-19-nortestosterone
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.
Muddana, S. S.; Price, A. M.; MacBride, M. M.; Peterson, B. R.; J. Med. Chem. 2004, 47, 4985.
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.
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.
Structure and Activity
7α- substituents hypothesized to have great Antagonistic activity based on study of ERβ LBD. Optimal Length reported was 16-18 atoms.
Study tested 7α-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.
Structure and Activity
11β – 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.
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.
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.
Research Focus
HO1. PCC, CH2Cl2
2. oxalic acid, ethanol
O
1
2
Research Focus
O
Ac2O, CH3COCl,pyridine, reflux,N2, 3 h
O
O
2
3
Research Focus
O
O DMF, NBS, N2
0oC, 1 h
O
O
Br
3
4
Research Focus
O
O
O
Li2CO3, LiBr,
N2, 95oC, 3 h
Br4
5
Research Focus
O R MgBr
CuCl, THF
O R
5
6
Research Focus
Characterization of compound: FTIR GC/MS 1H NMR
HO1. PCC, CH2Cl2
2. oxalic acid, ethanol
O
1
2
Acknowledgements
NIH-NCI Howard-Hopkins Partnership Grant AGEP Program
Special Thanks to
Dr. Oladapo Bakare, PhD
and the students of his lab