New pregnene analogs of N-hydroxamic acid 6, imino-propane hydrazides 7 and 8 as well as the aryl amides 9–11, oxadiazole, pyrazole and sulfinyl analogs 13–15, via the hydrazide analog 5 of methyl ((5-pregnen-3β,17β-diol-15α-yl)thio)propanoate (4) were synthesized. The in vitro cytotoxic activities of selected synthesized steroids against two human prostate cancer cell lines (PC-3, and LNCaP-AI) were evaluated by MTT assay. Compound 10 was the most active cytotoxic agent among these steroids against PC-3 and LNCaP-AI cell lines with inhibition of 96.2%, and 93.6% at concentration levels of 10.0 μM and 91.8%, and of 79.8% at concentration of 1.0 μM, respectively. Molecular docking study of 10 showed a hydrogen bonding with the amino acid Asn705 residue of the receptor 1E3G, together with hydrophobic interactions. Therefore, compound 10 can be considered as a promising anticancer agent due to its potent cytotoxic activity.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ (2008) Cancer statistics 2008. Cancer J Clin 58:71–96. https://doi.org/10.3322/CA.2007.0010
Suzuki H, Ueda T, Ichikawa T, Ito H (2003) Androgen receptor involvement in the progression of prostate cancer. Endocr Relat Cancer 10:209–216
Harris WP, Mostaghel EA, Nelson PS, Montgomery B (2009) Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clin Pract Urol 6:76–85. https://doi.org/10.1038/ncpuro1296
Nevedomskaya E, Baumgart SJ, Haendler B (2018) Recent advances in prostate cancer treatment and drug discovery. Int J Mol Sci 19:1359–1384. https://doi.org/10.3390/ijms19051359
Edmondson RJ, Monaghan JM (2001) The epidemiology of ovarian cancer. Int J Gynecol Cancer 11:423–429. https://doi.org/10.1046/j.1525-1438.2001.01053.x
Maria J, Ghini AA, Gerardo B (2003) 6,19-Carbon-bridged steroids. Synthesis of 6,19-methano progesterone. Org Biomol Chem 1:939–943. https://doi.org/10.1039/b211974a
Leng TD, Zhang JX, Xie J, Zhou SJ, Huang YJ, Zhou YH, Zhu WB, Yan GM (2010) Synthesis and anti-glioma activity of 25(R)-spirostan-3β-5α,6β,19-tetrol. Steroids 75:224–229. https://doi.org/10.1016/j.steroids.2009.12.005
Latham KA, Zamora A, Drought H, Subramanian S, Matejuk A, Offiner H et al (2003) Estradiol treatment redirects the isotope of the autoantibody response and prevents the development of autoimmune arthritis. J Immunnol 171:5820–5827. https://doi.org/10.4049/jimmunol.171.11.5820
Dubey RK, Oparil S, Imthum B, Jackson EK (2002) Sex hormones and hypertension. Cardiovasc Res 53:688–708. https://doi.org/10.1016/s0008-6363(01)00527-2
Kostaras X, Cusano F, Kline GA, Roa W, Easaw J (2014) Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline. Curr Oncol 21:e493–e503. https://doi.org/10.3747/co.21.1769
Stanway SJ, Delavault P, Purohit A, Woo LWL, Thurieau C, Potter BVL, Reed MJ (2007) Steroid sulfatase: a new target for the endocrine therapy of breast cancer. Oncologist 12:370–374. https://doi.org/10.1634/theoncologist.12-4-370
Ndibe C, Wang CG, Sonpavde G (2015) Corticosteroids in the management of prostate cancer: a critical review. Curr Treat Options Oncol 16:6. https://doi.org/10.1007/s11864-014-0320-6
Cho H, Walker A, Williams J, Hasty KA (2015) Study of osteoarthritis treatment with anti-inflammatory drugs: cyclooxygenase-2 inhibitor and steroids. Biomed Res Int 2015:595273. https://doi.org/10.1155/2015/595273
Cushman M, Golebiewski WM, Pommier Y, Mazumder A, Reymen D, De Clercq E, Graham L, Rice WG (1995) Cosalane analogues with enhanced potencies as inhibitors of HIV-1 protease and integrase. J Med Chem 38:443–452. https://doi.org/10.1021/jm00003a007
Casimiro-Garcia A, De Clercq E, Pannecouque C, Witvrouw M (2000) Synthesis and anti-HIV activity of cosalane analogues incorporating nitrogen in the linker chain. Bioorg Med Chem 8:191–200. https://doi.org/10.1016/S0968-0896(99)00269-2
Galabov AS, Nikolaeva L, Todorovab D, Milkovab T (1998) Antiviral activity of cholesteryl esters of cinnamic acid derivatives. Z Naturforsch C 53:883–887
Vasaitis TS, Bruno RD, Njar VCO (2011) CYP17 inhibitors for prostate cancer therapy. J Steroid Biochem Mol Biol 125:23–31. https://doi.org/10.1016/j.jsbmb.2010.11.005
Njar VCO (2000) High-yield synthesis of novel imidazoles and triazoles from alcohols and phenols. Synthesis 14:2019–2028
Moreira VM, Vasaitis TS, Njar VC, Salvador JAR (2007) Synthesis and evaluation of novel 17-indazole androstane derivatives designed as CYP17 inhibitors. Steroids 72:939–948. https://doi.org/10.1016/j.steroids.2007.08.004
Moreira VMA, Salvador JAR, Vasaitis TS, Njar VCO (2008) Synthesis inhibitors for prostate cancer treatment—an update. Curr Med Chem 15:868–899. https://doi.org/10.2174/092986708783955428
Moreira VMA, Vasaitis TS, Guo Z, Njar VCO, Salvador JAR (2008) Synthesis of novel C17 steroidal carbamates, studies on CYP17 action, androgen receptor binding and function, and prostate cancer cell growth. Steroids 73:1217–1227. https://doi.org/10.1016/j.steroids.2008.05.010
Owen CP (2009) 17α-hydroxylase/17,20-lyase (p450(17α)) inhibitors in the treatment of prostate cancer: a review. Anticancer Agents Med Chem 9:613–626. https://doi.org/10.2174/187152009788680046
Hartmann RW, Ehmer RW, Haidar S, Hector M, Jose J, Klein CD, Seidel SB, Sergejew TF, Wachall BG, Wächter GA, Zhuang Y (2002) Review: inhibition of CYP 17, a new strategy for the treatment of prostate cancer. Arch Pharm Pharm Med Chem 335:119–128. https://doi.org/10.1002/1521-4184(200204)335:4%3c119:AID-ARDP119%3e3.0.CO;2
Hu Q, Negri M, Olgen S, Hartmann RW (2010) The role of fluorine Substitution in biphenyl methylene imidazole type CYP17 inhibitors for the treatment of prostate carcinoma. ChemMedChem 5:899–910. https://doi.org/10.1002/cmdc.201000065
Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW (2003) Effects of novel 17 α-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J Steroid Biochem Mol Biol 84:555–562. https://doi.org/10.1016/s0960-0760(03)00070-0
Al-Masoudi NA, Abdul-Rida NA, Kadhim RA, Krugs SJ, Engels M, Saeed BA (2016) Synthesis and CYP17a hydroxylase inhibition activity of new 3α- and 3β-ester derivatives of pregnenolone and related ether analogues. Med Chem Res 25:310–321. https://doi.org/10.1007/s00044-015-1480-z
Al-Masoudi NA, Kadhim RA, Abdul-Rida NA, Saeed BA, Engel M (2015) New biaryl-chalcone derivatives of pregnenolone via Suzuki–Miyaura cross-coupling reaction. Synthesis, CYP17 hydroxylase inhibition activity, QSAR, and molecular docking study. Steroids 101:43–50. https://doi.org/10.1016/j.steroids.2015.05.011
Njar VC, Brodie AM (1999) Inhibitors of 17alpha-hydroxylase/17,20-lyase (CYP17): potential agents for the treatment of prostate cancer. Curr Pharm Des 5:163–180
Banday AH, Shameem SA, Gupta BD, Kumar HMS (2010) D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: synthesis and biological evaluation. Steroids 75:801–804. https://doi.org/10.1016/j.steroids.2010.02.015
Al-Masoudi NA, Mahdi KM, Abdul-Rida NA, Saeed BA, Engel M (2015) A new pregnenolone analogues as privileged scaffolds in inhibition of CYP17 hydroxylase enzyme. Synthesis and in silico molecular docking study. Steroids 100:52–59. https://doi.org/10.1016/j.steroids.2015.05.002
Al-Masoudi NA, Ali DS, Saeed B, Hartmann RW, Engel M, Rashid S, Saeed A (2014) New CYP17 hydroxylase inhibitors: synthesis, biological evaluation, QSAR, and molecular docking study of new pregnenolone analogs. Arch Pharm Chem Life Sci 347:896–907. https://doi.org/10.1002/ardp.201400255
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al (2011) Abiraterone and increased survival in metastatic prostate cancer. Engl J Med 364:1995–2005. https://doi.org/10.1056/NEJMoa1014618
Bryce A, Ryan CJ (2012) Development and clinical utility of abiraterone acetate as an androgen synthesis inhibitor. Clin Pharmacol Ther 91:101–108. https://doi.org/10.1038/clpt.2011.275
Handratta VD, Jelovac D, Long BJ, Kataria R, Nnane IP, Njar VC, Brodie AM (2004) Potent CYP17 inhibitors: Improved syntheses, pharmacokinetics and antitumor activity in the LNCaP human prostate cancer model. J Steroid Biochem Mol Biol 92:155–165. https://doi.org/10.1016/j.jsbmb.2004.07.006
Handratta VD, Vasaitis TS, Njar VC, Gediya LK, Kataria R, Chopra P et al (2005) Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem 48:2972–2984. https://doi.org/10.1021/jm040202w
Brodie A, Njar VC (2006). Novel C-17-heteroaryl steroidal CYP17 inhibitors/antian-drogens: synthesis, in vitro biological activities, pharmacokinetics and antitumor activity. WO Patent 093993
Ligr M, Li Y, Logan SK, Taneja S, Melamed J, Lepor H, Garabedian MJ, Lee P (2012) Mifepristone inhibits GRβ-coupled prostate cancer cell proliferation. J Urol 188:981–988. https://doi.org/10.1016/j.juro.2012.04.102
Wilt TJ, Macdonald R, Hagerty K, Schellhammer P, Tacklind J, Somerfield MR, Kramer BS (2010) 5-α-Reductase inhibitors for prostate cancer chemoprevention: an updated Cochrane systematic review. BJU Int 106:1444–1451
Bologna M, Muzi P, Biordi L, Festuccia C, Vicentini C (1995) Finasteride dose-dependently reduces the proliferation rate of the LNCaP human prostatic cancer cell line in vitro. Urology 45:282–290. https://doi.org/10.1016/0090-4295(95)80019-0
Al-Masoudi NA, Sami A, Abdul-Rida NA, Fortscher M (2018) New cholic acid analogs: synthesis and 17β-hydroxydehydrogenase (17β-HSD) inhibition activity. Z Naturforsch B 73:211–223. https://doi.org/10.1515/znb-2018-0192
Mahdi KM, Abdul-Rida NA, Al-Masoudi NA (2015) Exploration of new 3α-pregnenolone ester analogues via Mitsunobu reaction, their anti-HIV activity and molecular modeling study. Euro J Chem 6:1–7. https://doi.org/10.5155/eurjchem.6.1.1-7.1139
Willker W, Leibfritz D, Kerssebaum R, Bermel W (1993) Gradient selection in inverse heteronuclear correlation spectroscopy. Magn Reson Chem 31:287–292. https://doi.org/10.1002/mrc.1260310315
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. https://doi.org/10.1016/0022-1759(83)90303-4
Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 31:455–461. https://doi.org/10.1002/jcc.21334
Miller DR, Tzeng C-C, Farmer T, Keller ET, Caplan S, Chen Y-S, Chen T-L, Lin M-F (2018) Novel CIL-102 derivatives as potential therapeutic agents for docetaxel-resistant prostate cancer. Cancer Lett 436:96–108. https://doi.org/10.1016/j.canlet.2018.07.039
We evok the spirit of Prof. W. Pfleiderer of chemistry department, University of Konstanz, Germany for providing the starting material (steroid 4).
Conflict of interest
No potential conflict of interest was reported by the authors.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Abdul-Rida, N.A., Farhan, A.M., Al-Masoudi, N.A. et al. A novel pregnene analogs: synthesis, cytotoxicity on prostate cancer of PC-3 and LNCPa-AI cells and in silico molecular docking study. Mol Divers (2020). https://doi.org/10.1007/s11030-020-10038-w
- Anticancer activity
- Molecular docking study
- Pregnene analogs