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Medicinal Chemistry

Author(s): Yanmin Huang, Zining Peng, Chang Liu, Chunling Pang, Sijing Chen, Chunfang Gan, Zhiping Liu* and Jianguo Cui*

DOI: 10.2174/1573406419666230117101950

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Synthesis and Antiproliferative Activity Evaluation of B-norcholesterol-6- amide Compounds

Page: [813 - 822] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: The structure modification of steroids is commonly used to change the biological activity of steroids in medicinal chemistry. In recent years, it has been found that some derivatives derived from the structural modification of cholesterol display good inhibitory activity against tumor cell proliferation in vitro.

Methods: Using cholesterol as the starting material, different types of B-norcholesterol-6-amide derivatives were synthesized by the reaction of 6-carboxyl-B-norcholesterol with different alkyl amines or 6-amino-B-norcholesterol with different acyl chlorides. The inhibitory activity of compounds on the proliferation of tumor cell lines was investigated by the MTT method.

Results: The results showed that the B-norcholesterol-6-amide compounds displayed distinct cytotoxicity against Sk-Ov-3 cells but caused no obvious damage against HEK-293T cells. Additionally, the steroidal amide derivatives formed from 6-amino-B-norcholesterol showed stronger cytotoxicity than those produced from 6-carboxyl-B-norcholesterol. Specially, compounds with chloroalkyl structure displayed significant inhibitory activity against all tumor cells tested. Among them, compounds 19-21 showed cytotoxicity like 2-methoxyestradiol as a positive control, and the IC50 value of compound 20 on HeLa cells was 3.9 μM.

Conclusion: After introducing chloroalkyl acyl groups into 6-position of 6-amino-B-norcholesterol, the cytotoxicity of resulting B-norcholesterol-6-amide compounds can be greatly enhanced.

Graphical Abstract

[1]
Burbiel, J.; Bracher, F. Azasteroids as antifungals. Steroids, 2003, 68(7-8), 587-594.
[http://dx.doi.org/10.1016/S0039-128X(03)00080-1] [PMID: 12957663]
[2]
Ibrahim-Ouali, M.; Rocheblave, L. Recent advances in azasteroids chemistry. Steroids, 2008, 73(4), 375-407.
[http://dx.doi.org/10.1016/j.steroids.2007.12.013] [PMID: 18249432]
[3]
Khan, M.O.F.; Lee, H.J. Synthesis and pharmacology of anti-inflammatory steroidal antedrugs. Chem. Rev., 2008, 108(12), 5131-5145.
[http://dx.doi.org/10.1021/cr068203e] [PMID: 19035773]
[4]
Aggarwal, S.; Thareja, S.; Verma, A.; Bhardwaj, T.R.; Kumar, M. An overview on 5α-reductase inhibitors.. Steroids, 2010, 75(2), 109-153.
[http://dx.doi.org/10.1016/j.steroids.2009.10.005] [PMID: 19879888]
[5]
Steiner, J.F. Finasteride: A 5 alpha-reductase inhibitor. Clin. Pharm., 1993, 12(1), 15-23.
[PMID: 7679063]
[6]
Darren Stuart, J.; Lee, F.W.; Simpson Noel, D.; Kadwell, S.H.; Overton, L.K.; Hoffman, C.R.; Kost, T.A.; Tippin, T.K.; Yeager, R.L.; Batchelor, K.W.; Neal Bramson, H. Pharmacokinetic parameters and mechanisms of inhibition of rat type 1 and 2 steroid 5α-reductases: determinants for different in vivo activities of GI198745 and finasteride in the rat 3 3Abbreviations: r5AR1, rat 5α-reductase 1; r5AR2, rat 5α-reductase 2; and DHT, dihydrotestosterone Biochem. Pharmacol., 2001, 62(7), 933-942.
[http://dx.doi.org/10.1016/S0006-2952(01)00728-6] [PMID: 11543729]
[7]
Vatmurge, N.S.; Hazra, B.G.; Pore, V.S.; Shirazi, F.; Chavan, P.S.; Deshpande, M.V. Synthesis and antimicrobial activity of β-lactam–bile acid conjugates linked via triazole. Bioorg. Med. Chem. Lett., 2008, 18(6), 2043-2047.
[http://dx.doi.org/10.1016/j.bmcl.2008.01.102] [PMID: 18267360]
[8]
Lawrence, H.R.; Vicker, N.; Allan, G.M.; Smith, A.; Mahon, M.F.; Tutill, H.J.; Purohit, A.; Reed, M.J.; Potter, B.V.L. Novel and potent 17beta-hydroxysteroid dehydrogenase type 1 inhibitors. J. Med. Chem., 2005, 48(8), 2759-2762.
[http://dx.doi.org/10.1021/jm049045r] [PMID: 15828812]
[9]
Gigante, F.; Kaiser, M.; Brun, R.; Gilbert, I.H. SAR studies on azasterols as potential anti-trypanosomal and anti-leishmanial agents. Bioorg. Med. Chem., 2009, 17(16), 5950-5961.
[http://dx.doi.org/10.1016/j.bmc.2009.06.062] [PMID: 19620005]
[10]
Shi, X.; Wang, Z.; Xu, F.; Lu, X.; Yao, H.; Wu, D.; Sun, S.; Nie, R.; Gao, S.; Li, P.; Xia, L.; Zhang, Z.; Wang, C. Design, synthesis and antiproliferative effect of 17β-amide derivatives of 2-methoxyestradiol and their studies on pharmacokinetics. Steroids, 2017, 128, 6-14.
[http://dx.doi.org/10.1016/j.steroids.2017.09.013] [PMID: 29031938]
[11]
Wang, H.L.; Qin, N.; Liu, J.; Jin, M.N.; Zhang, X.; Jin, M.H.; Kong, D.; Jiang, S.D.; Duan, H.Q. Synthesis and antimetastatic effects of E-salignone amide derivatives. Drug Dev. Res., 2014, 75(2), 76-87.
[http://dx.doi.org/10.1002/ddr.21157] [PMID: 24648170]
[12]
Huang, Y.; Chen, S.; Cui, J.; Gan, C.; Liu, Z.; Wei, Y.; Song, H. Synthesis and cytotoxicity of A-homo-lactam derivatives of cholic acid and 7-deoxycholic acid. Steroids, 2011, 76(7), 690-694.
[http://dx.doi.org/10.1016/j.steroids.2011.03.009] [PMID: 21440565]
[13]
Huang, Y.; Cui, J.; Chen, S.; Gan, C.; Zhou, A. Synthesis and antiproliferative activity of some steroidal lactams. Steroids, 2011, 76(12), 1346-1350.
[http://dx.doi.org/10.1016/j.steroids.2011.06.013] [PMID: 21767556]
[14]
Huang, Y.; Cui, J.; Chen, S.; Lin, Q.; Song, H.; Gan, C.; Su, B.; Zhou, A. Synthesis and evaluation of some new aza-B-homocholestane derivatives as anticancer agents. Mar. Drugs, 2014, 12(4), 1715-1731.
[http://dx.doi.org/10.3390/md12041715] [PMID: 24670533]
[15]
Cui, J.; Lin, Q.; Huang, Y.; Gan, C.; Yao, Q.; Wei, Y.; Xiao, Q.; Kong, E. Design, synthesis and antiproliferative evaluation of some B-homo steroidal lactams. Med. Chem. Res., 2015, 24(7), 2906-2915.
[http://dx.doi.org/10.1007/s00044-015-1347-3]
[16]
Huang, Y.; Cui, J.; Chen, S.; Gan, C.; Yao, Q.; Lin, Q. Synthesis and antiproliferative activity of C-homo-lactam derivatives of 7-deoxycholic acid. Bioorg. Med. Chem. Lett., 2013, 23(7), 2265-2267.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.064] [PMID: 23466224]
[17]
Huang, Y.; Cui, J.; Zhong, Z.; Gan, C.; Zhang, W.; Song, H. Synthesis and cytotoxicity of 17a-aza-d-homo-androster-17-one derivatives. Bioorg. Med. Chem. Lett., 2011, 21(12), 3641-3643.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.093] [PMID: 21571531]
[18]
Huang, Y.; Cui, J.; Jia, L.; Gan, C.; Song, H.; Zeng, C.; Zhou, A. Synthesis and evaluation of some 17-acetamidoandrostane and N,N-dimethyl-7-deoxycholic amide derivatives as cytotoxic agents: structure/activity studies. Molecules, 2013, 18(7), 7436-7447.
[http://dx.doi.org/10.3390/molecules18077436] [PMID: 23803715]
[19]
Singh, H.; Jindal, D.P.; Yadav, M.R.; Kumar, M. Heterosteroids and drug research. Prog. Med. Chem., 1991, 28, 233-300.
[http://dx.doi.org/10.1016/S0079-6468(08)70366-7] [PMID: 1843548]
[20]
Tanabe, K.; Hayashi, R.; Takasaki, R. Steroid series. III.: Ozonization of 3-acetoxy-⊿ 5-steroids in the presence of formaldehyde. Chem. Pharm. Bull. (Tokyo), 1961, 9(1), 1-6.
[http://dx.doi.org/10.1248/cpb.9.1]
[21]
Wentworth, P., Jr; Nieva, J.; Takeuchi, C.; Galve, R.; Wentworth, A.D.; Dilley, R.B.; DeLaria, G.A.; Saven, A.; Babior, B.M.; Janda, K.D.; Eschenmoser, A.; Lerner, R.A. Evidence for ozone formation in human atherosclerotic arteries. Science, 2003, 302(5647), 1053-1056.
[http://dx.doi.org/10.1126/science.1089525] [PMID: 14605372]
[22]
Hong Lin, W.; Min Fang, J.; Cheng, Y. Diterpenoids and steroids from Taiwania cryptomerioides. Phytochemistry, 1998, 48(8), 1391-1397.
[http://dx.doi.org/10.1016/S0031-9422(98)00039-9]
[23]
Miyamoto, T.; Kodama, K.; Aramaki, Y.; Higuchi, R.; Van Soest, R.W.M. Orostanal, a novel abeo-sterol inducing apoptosis in leukemia cell from a marine sponge, Stelletta hiwasaensis. Tetrahedron Lett., 2001, 42(36), 6349-6351.
[http://dx.doi.org/10.1016/S0040-4039(01)01278-3]
[24]
Cui, J.; Qi, B.; Gan, C.; Liu, Z.; Huang, H.; Lin, Q.; Zhao, D.; Huang, Y. Synthesis and in vitro antiproliferative evaluation of some B-norcholesteryl Benzimidazole and Benzothiazole derivatives. Mar. Drugs, 2015, 13(4), 2488-2504.
[http://dx.doi.org/10.3390/md13042488] [PMID: 25913705]
[25]
Gan, C.; Fan, L.; Cui, J.; Huang, Y.; Jiao, Y.; Wei, W. Synthesis and in vitro antiproliferative evaluation of some ring B abeo-sterols. Steroids, 2012, 77(11), 1061-1068.
[http://dx.doi.org/10.1016/j.steroids.2012.05.005] [PMID: 22683671]
[26]
Gan, C.; Huang, X.; Zhan, J.; Liu, X.; Huang, Y.; Cui, J. Study on the interactions between B-norcholesteryl benzimidazole compounds with ct-DNA. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2020, 227, 117525.
[http://dx.doi.org/10.1016/j.saa.2019.117525] [PMID: 31703992]