Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Pharmacological Evaluation
Compound No. | IC50 (µM) |
---|---|
Bicalutamide | 0.89 |
1 | Inactive |
2 | 0.031 |
3 | 0.037 |
4 | 0.034 |
5 | 0.041 |
6 | 0.044 |
7 | 0.057 |
8 | 0.077 |
9 | 0.075 |
10 | 0.023 |
11 | 0.039 |
12 | 0.091 |
13 | 0.029 |
Compound No. | % (Inhibition) | ED50 (mg/kg) |
---|---|---|
Bicalutamide | 75 | 1.6 |
1 | Inactive | Inactive |
2 | 95.49 | 0.049 |
3 | 91 | 0.063 |
4 | 93.98 | 0.051 |
5 | 89.09 | 0.089 |
6 | 88.76 | 0.092 |
7 | 87.56 | 0.094 |
8 | 85.43 | 0.097 |
9 | 86.56 | 0.095 |
10 | 98.87 | 0.071 |
11 | 90.01 | 0.045 |
12 | 84.65 | 0.098 |
13 | 97.56 | 0.047 |
Compound No. | IC50 (nM) PC-3 | IC50 (nM) LNCaP |
---|---|---|
Bicalutamide | 822 | 619.00 |
1 | Inactive | Inactive |
2 | 156.78 | 51.47 |
3 | 177.45 | 58.58 |
4 | 178.6 | 56.59 |
5 | 190.1 | 64.28 |
6 | 201.23 | 72.39 |
7 | 256.78 | 74.56 |
8 | 278.67 | 78.54 |
9 | 268.77 | 76.65 |
10 | 109.29 | 43.54 |
11 | 180.01 | 61.58 |
12 | 288.78 | 79.98 |
13 | 145.67 | 49.65 |
2.3. Determination of Acute Toxicity (Lethal Dose 50 (LD50))
Compound No. | LD50 (mg/kg) |
---|---|
1 | 1164.45 |
2 | 163.46 |
3 | 174.56 |
4 | 265.67 |
5 | 266.58 |
6 | 257.79 |
7 | 146.80 |
8 | 235.99 |
9 | 124.89 |
10 | 315.78 |
11 | 324.57 |
12 | 234.46 |
13 | 443.35 |
3. Experimental Section
3.1. General Experimental Procedures
3.2. Synthetic Procedures
3.2.1. Synthesis of 2-[3-Amino-4-cyanopyrazol-2-yl]naphthalino[1,2-d]thiazole (2)
3.2.2. Synthesis of 2-[6-Aminopyrimidino[4,5-c]pyrazol-2-yl]naphthalino[1,2-d]thiazole (3)
3.2.3. Synthesis of 2-[5-Amino-3H-pyrazolo[3,4-c]pyrazol-2-yl]naphthalino[1,2-d]thiazole (4)
3.2.4. Synthesis of 2-[6-Amino-3H-4-thiopyrimidino[4,5-c]pyrazol-2-yl]naphthalino[1,2-d]thiazole (5)
3.2.5. Synthesis of 2-[6-Imino-3H-4-thiothiazino[4,5-c]pyrazol-2-yl]naphthalino[1,2-d]thiazole (6)
3.2.6. Synthesis of 2-[6-Amino-5-ethoxycarbonyl-4-methylpyridino[2,3-c]pyrazol-2-yl]naphthalino-[1,2-d]thiazole (7)
3.2.7. Synthesis of 2-[3-Ethylimidoformat-4-cyanopyrazol-2-yl]naphthalino[1,2-d]thiazole (8)
3.2.8. Synthesis of 2-[3-Imidoformic hydrazido-4-cyanopyrazol-2-yl]naphthalino[1,2-d]thiazole (9)
3.2.9. Synthesis of 2-[6-Methyl[1,2,4]triazolo[2,3-c]pyrimidino[6,5-c]pyrazol-2-yl]naphthalino[1,2-d]thiazole (10)
3.2.10. Synthesis of 2-[7-Benzamido-6-iminopyrimidino[4,5-c]pyrazol-2-yl]naphthalino[1,2-d]thiazole (11)
3.2.11. Synthesis of 2-[3-(2-Ethoxy-4-oxo-5-dihydro-1,3-thiazol-3-yl)-4-cyanopyrazol-2-yl]-naphthalino[1,2-d]thiazole (12)
3.2.12. Synthesis of 2-[3-Ethoxy-5-dihydro-6H-7-oxo-[1,3]thiazolo[3,4-b]pyrimidino[4,5-c]pyrazol-2-yl]naphthalino[1,2-d]thiazole (13)
3.3. Pharmacological Evaluation
3.3.1. Animals
3.3.2. Evaluation of Transcriptional Activity for Human Androgen Receptor
Establishment of Chinese Hamster Cell Model
Activities of the Tested Compounds to Inhibit Androgen Receptor Mediated Transcription Induced by Dihydrotestosterone (DHT) (AR Antagonistic Activity)
3.3.3. In Vivo Evaluation of Anti-Androgenic Activities in Castrated Immature Rats
3.3.4. Anti-Prostate Cancer Screening Anti-Androgenic Bioassay in Human Prostate Cancer Cells
4. Structure Activity Relationship (SAR)
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Bahashwan, S.A.; Fayed, A.A.; Ramadan, M.A.; Amr, A.E.-G.E.; Al-Harbi, N.O. Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives. Int. J. Mol. Sci. 2014, 15, 21587-21602. https://doi.org/10.3390/ijms151121587
Bahashwan SA, Fayed AA, Ramadan MA, Amr AE-GE, Al-Harbi NO. Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives. International Journal of Molecular Sciences. 2014; 15(11):21587-21602. https://doi.org/10.3390/ijms151121587
Chicago/Turabian StyleBahashwan, Saleh A., Ahmed A. Fayed, Mohamed A. Ramadan, Abd El-Galil E. Amr, and Naif O. Al-Harbi. 2014. "Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives" International Journal of Molecular Sciences 15, no. 11: 21587-21602. https://doi.org/10.3390/ijms151121587