Abstract
We have exploited the reaction of 1,1'-carbonylbis(2-methylimidazole) (CBMI) with several 17beta-hydroxy androstanes to synthesize a series of novel C17 steroidal carbamates. Structural elucidation features have been provided for the final compounds based on 1D and 2D NMR techniques, IR spectroscopy, and related literature. The new compounds were tested for inhibition of human cytochrome 17alpha-hydroxylase-C17,20-lyase (CYP17) and androgen receptor (AR) binding and function effects. Their inhibitory potential against PC-3 cell proliferation was also evaluated. Compounds 11 and 23 were found to inhibit CYP17 with IC50 values of 17.1 and 11.5 microM, respectively. The carbamate moiety at C17 allowed tight binding of the synthesized compounds to both wild-type (wt-) and mutated AR. When bound to the mutated AR, the compounds were found to have a dual effect, stimulating transcription at low concentrations while almost fully blocking it at the higher concentrations tested, in the presence of the natural androgen dihydrotestosterone (DHT). Compounds 8 and 12 were the most active against PC-3 cell proliferation with EC50 values of 2.2 and 0.2 microM, respectively.
| Original language | English |
|---|---|
| Pages (from-to) | 1217-1227 |
| Number of pages | 11 |
| Journal | Steroids |
| Volume | 73 |
| Issue number | 12 |
| Early online date | 6 Jun 2008 |
| DOIs | |
| Publication status | Published - 30 Nov 2008 |
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Keywords
- carbamates
- cell division
- cell line, tumor
- magnetic resonance spectroscopy
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Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth. / Moreira, Vânia M.A.; Vasaitis, Tadas S.; Guo, Zhiyong; Njar, Vincent C.O.; Salvador, Jorge A.R.
In: Steroids, Vol. 73, No. 12, 30.11.2008, p. 1217-1227.Research output: Contribution to journal › Article
TY - JOUR
T1 - Synthesis of novel C17 steroidal carbamates. Studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth
AU - Moreira, Vânia M.A.
AU - Vasaitis, Tadas S.
AU - Guo, Zhiyong
AU - Njar, Vincent C.O.
AU - Salvador, Jorge A.R.
PY - 2008/11/30
Y1 - 2008/11/30
N2 - We have exploited the reaction of 1,1'-carbonylbis(2-methylimidazole) (CBMI) with several 17beta-hydroxy androstanes to synthesize a series of novel C17 steroidal carbamates. Structural elucidation features have been provided for the final compounds based on 1D and 2D NMR techniques, IR spectroscopy, and related literature. The new compounds were tested for inhibition of human cytochrome 17alpha-hydroxylase-C17,20-lyase (CYP17) and androgen receptor (AR) binding and function effects. Their inhibitory potential against PC-3 cell proliferation was also evaluated. Compounds 11 and 23 were found to inhibit CYP17 with IC50 values of 17.1 and 11.5 microM, respectively. The carbamate moiety at C17 allowed tight binding of the synthesized compounds to both wild-type (wt-) and mutated AR. When bound to the mutated AR, the compounds were found to have a dual effect, stimulating transcription at low concentrations while almost fully blocking it at the higher concentrations tested, in the presence of the natural androgen dihydrotestosterone (DHT). Compounds 8 and 12 were the most active against PC-3 cell proliferation with EC50 values of 2.2 and 0.2 microM, respectively.
AB - We have exploited the reaction of 1,1'-carbonylbis(2-methylimidazole) (CBMI) with several 17beta-hydroxy androstanes to synthesize a series of novel C17 steroidal carbamates. Structural elucidation features have been provided for the final compounds based on 1D and 2D NMR techniques, IR spectroscopy, and related literature. The new compounds were tested for inhibition of human cytochrome 17alpha-hydroxylase-C17,20-lyase (CYP17) and androgen receptor (AR) binding and function effects. Their inhibitory potential against PC-3 cell proliferation was also evaluated. Compounds 11 and 23 were found to inhibit CYP17 with IC50 values of 17.1 and 11.5 microM, respectively. The carbamate moiety at C17 allowed tight binding of the synthesized compounds to both wild-type (wt-) and mutated AR. When bound to the mutated AR, the compounds were found to have a dual effect, stimulating transcription at low concentrations while almost fully blocking it at the higher concentrations tested, in the presence of the natural androgen dihydrotestosterone (DHT). Compounds 8 and 12 were the most active against PC-3 cell proliferation with EC50 values of 2.2 and 0.2 microM, respectively.
KW - carbamates
KW - cell division
KW - cell line, tumor
KW - magnetic resonance spectroscopy
UR - http://www.sciencedirect.com/science/article/pii/S0039128X08001785
U2 - 10.1016/j.steroids.2008.05.010
DO - 10.1016/j.steroids.2008.05.010
M3 - Article
C2 - 18582482
VL - 73
SP - 1217
EP - 1227
JO - Steroids
JF - Steroids
SN - 1878-5867
IS - 12
ER -