Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Identification of Non-steroidal Aromatase Inhibitors via In silico and In vitro Studies

Author(s): Humaira Zafar*, Rabbia Anis, Sana Hafeez, Atia-tul-Wahab, Maria Aqeel Khan, Fatima Zehra Basha, Innokentiy Maslennikov and Muhammad Iqbal Choudhary*

Volume 19, Issue 10, 2023

Published on: 05 June, 2023

Page: [986 - 1001] Pages: 16

DOI: 10.2174/1573406419666230330082426

Price: $65

Abstract

Introduction: Breast cancer is the most common cancer affecting women worldwide, including Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer, which is developed due to the over-production of estrogen (the main hormone in breast cancer).

Methods: The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as a target for the treatment of breast cancer. During the current study, biochemical, computational, and STD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3- butene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 μM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 = 0.0147 ± 1.45 μM), anastrozole (IC50 = 0.0094 ± 0.91 μM), and exemestane (IC50 = 0.2 ± 0.032 μM). Kinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively.

Results: Docking studies on all active compounds indicated their binding adjacent to the heme group and interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme.

Conclusion: STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be non-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified new aromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research.

Keywords: Aromatase, non-steroidal aromatase inhibitors, ER+ breast cancer, STD-NMR spectroscopy, molecular docking studies, phenyl-3-butene derivatives.

« Previous Next »
Graphical Abstract

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[http://dx.doi.org/10.3322/caac.21254] [PMID: 25559415]
[2]
Santen, R.J.; Brodie, H.; Simpson, E.R.; Siiteri, P.K.; Brodie, A. History of aromatase: Saga of an important biological mediator and therapeutic target. Endocr. Rev., 2009, 30(4), 343-375.
[http://dx.doi.org/10.1210/er.2008-0016] [PMID: 19389994]
[3]
Nishiwaki, K.; Ohigashi, K.; Deguchi, T.; Murata, K.; Nakamura, S.; Matsuda, H.; Nakanishi, I. Structure–activity relationships and docking studies of hydroxychavicol and its analogs as xanthine oxidase inhibitors. Chem. Pharm. Bull., 2018, 66(7), 741-747.
[http://dx.doi.org/10.1248/cpb.c18-00197] [PMID: 29695658]
[4]
Cui, J.; Shen, Y.; Li, R. Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends Mol. Med., 2013, 19(3), 197-209.
[http://dx.doi.org/10.1016/j.molmed.2012.12.007] [PMID: 23348042]
[5]
Ratre, P.; Mishra, K.; Dubey, A.; Vyas, A.; Jain, A.; Thareja, S. Aromatase inhibitors for the treatment of breast cancer: A journey from the scratch. Anticancer. Agents Med. Chem., 2020, 20(17), 1994-2004.
[http://dx.doi.org/10.2174/1871520620666200627204105] [PMID: 32593281]
[6]
Van Asten, K.; Neven, P.; Lintermans, A.; Wildiers, H.; Paridaens, R. Aromatase inhibitors in the breast cancer clinic: focus on exemestane. Endocr. Relat. Cancer, 2014, 21(1), R31-R49.
[http://dx.doi.org/10.1530/ERC-13-0269] [PMID: 24434719]
[7]
Sabale, P.M.; Sabale, V.P.; Potey, L.C. Aromatase and aromatase inhibitors in breast cancer treatment. J. Pharm. Res., 2018, 9(1), 2636-2655.
[http://dx.doi.org/10.33786/JCPR.2018.v09i01.008]
[8]
Hong, S.; Didwania, A.; Olopade, O.; Ganschow, P. The expanding use of third-generation aromatase inhibitors: what the general internist needs to know. J. Gen. Intern. Med., 2009, 24(S2), 383-388.
[http://dx.doi.org/10.1007/s11606-009-1037-2] [PMID: 19838836]
[9]
Usta, A. Taşkıran, H. Synthesis and antimicrobial properties of Nsubstituted derivatives of (E)-2′, 3 ″-thiazachalcones. Zeitschrift für Naturforschung C., 2015, 70(1-2), 45-50.
[10]
Rayar, A.M.; Lagarde, N.; Martin, F.; Blanchard, F.; Liagre, B.; Ferroud, C.; Zagury, J.F.; Montes, M.; Sylla-Iyarreta Veitía, M. New selective cyclooxygenase-2 inhibitors from cyclocoumarol: Synthesis, characterization, biological evaluation and molecular modeling. Eur. J. Med. Chem., 2018, 146, 577-587.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.054] [PMID: 29407982]
[11]
Zumbansen, K.; Döhring, A.; List, B. Morpholinium trifluoroacetate-catalyzed aldol condensation of acetone with both aromatic and aliphatic aldehydes. Adv. Synth. Catal., 2010, 352(7), 1135-1138.
[http://dx.doi.org/10.1002/adsc.200900902]
[12]
Reddy, P.M.; Ramachandran, K.; Anbarasan, P. Palladium-catalyzed diastereoselective synthesis of 2,2,3-trisubstituted dihydrobenzofurans via intramolecular trapping of O-ylides with activated alkenes. J. Catal., 2021, 396, 291-296.
[http://dx.doi.org/10.1016/j.jcat.2021.02.032]
[13]
Sidoryk, K.; Jaromin, A.; Filipczak, N.; Cmoch, P.; Cybulski, M. Synthesis and antioxidant activity of caffeic acid derivatives. Molecules, 2018, 23(9), 2199.
[http://dx.doi.org/10.3390/molecules23092199] [PMID: 30200272]
[14]
Xiao, J.; Li, G.; Zhang, W. Aldol reactions catalyzed by proline functionalized polyacrylonitrile fiber. Chem. Res. Chin. Univ., 2013, 29(2), 256-262.
[http://dx.doi.org/10.1007/s40242-013-2236-2]
[15]
Chen, L.; Wang, X.; Tang, X.; Xia, R.; Guo, T.; Zhang, C.; Li, X.; Xue, W. Design, synthesis, antiviral bioactivities and interaction mechanisms of penta-1,4-diene-3-one oxime ether derivatives containing a quinazolin-4(3H)-one scaffold. BMC Chem., 2019, 13(1), 34.
[http://dx.doi.org/10.1186/s13065-019-0547-1] [PMID: 31384782]
[16]
Tang, X.; He, J.; Li, Q.; Tang, X.; Chen, M.; Hao, G.; Huai, Z.; Huang, Y.; Xue, W. Discovery of 1,4-pentadien-3-one derivatives containing quinoxaline scaffolds as potential apoptosis inducers. Future Med. Chem., 2020, 12(16), 1505-1519.
[http://dx.doi.org/10.4155/fmc-2019-0371] [PMID: 32772720]
[17]
Dettori, M.A.; Fabbri, D.; Dessì, A.; Dallocchio, R.; Carta, P.; Honisch, C.; Ruzza, P.; Farina, D.; Migheli, R.; Serra, P.A.; Pantaleoni, R.A.; Fois, X.; Rocchitta, G.; Delogu, G. Synthesis and studies of the inhibitory effect of hydroxylated phenylpropanoids and biphenols derivatives on tyrosinase and laccase enzymes. Molecules, 2020, 25(11), 2709.
[http://dx.doi.org/10.3390/molecules25112709] [PMID: 32545293]
[18]
Mao, Z.Y.; Ye, J.L.; Nie, X.D.; Si, C.M.; Wei, B.G.; Lin, G.Q. Synthesis of functionalized bicyclo[2.2.2]octan-2-ones skeleton via tandem process of amino acid involved formal [4+2] and decarboxylative–mannich sequence. J. Org. Chem., 2021, 86(4), 3276-3286.
[http://dx.doi.org/10.1021/acs.joc.0c02620] [PMID: 33530688]
[19]
Ryan, K.J. Biological aromatization of steroids. J. Biol. Chem., 1959, 234(2), 268-272.
[http://dx.doi.org/10.1016/S0021-9258(18)70286-X] [PMID: 13630892]
[20]
Nanovskaya, T.N.; Deshmukh, S.V.; Nekhayeva, I.A.; Zharikova, O.L.; Hankins, G.D.V.; Ahmed, M.S. Methadone metabolism by human placenta. Biochem. Pharmacol., 2004, 68(3), 583-591.
[http://dx.doi.org/10.1016/j.bcp.2004.04.011] [PMID: 15242824]
[21]
Lu, W.J.; Xu, C.; Pei, Z.; Mayhoub, A.S.; Cushman, M.; Flockhart, D.A. The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. Breast Cancer Res. Treat., 2012, 133(1), 99-109.
[http://dx.doi.org/10.1007/s10549-011-1699-4] [PMID: 21814747]
[22]
Harder, E.; Damm, W.; Maple, J.; Wu, C.; Reboul, M.; Xiang, J.Y.; Wang, L.; Lupyan, D.; Dahlgren, M.K.; Knight, J.L.; Kaus, J.W.; Cerutti, D.S.; Krilov, G.; Jorgensen, W.L.; Abel, R.; Friesner, R.A. OPLS3: A force field providing broad coverage of drug-like small molecules and proteins. J. Chem. Theory Comput., 2016, 12(1), 281-296.
[http://dx.doi.org/10.1021/acs.jctc.5b00864] [PMID: 26584231]
[23]
Giardina, S.F.; Werner, D.S.; Pingle, M.; Feinberg, P.B.; Foreman, K.W.; Bergstrom, D.E.; Arnold, L.D.; Barany, F. Novel, self-assembling dimeric inhibitors of human β tryptase. J. Med. Chem., 2020, 63(6), 3004-3027.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01689] [PMID: 32057241]
[24]
Ghosh, D.; Egbuta, C.; Lo, J. Testosterone complex and non-steroidal ligands of human aromatase. J. Steroid Biochem. Mol. Biol., 2018, 181, 11-19.
[http://dx.doi.org/10.1016/j.jsbmb.2018.02.009] [PMID: 29476820]
[25]
Deeb, R.S.; Muller-Eberhard, U.; Peyton, D.H. Proton NMR study of the heme complex of hemopexin. Biochim. Biophys. Acta, Gen. Subj., 1994, 1200(2), 161-166.
[http://dx.doi.org/10.1016/0304-4165(94)90131-7]
[26]
Vasile, F.; Panigada, M.; Siccardi, A.; Potenza, D.; Tiana, G. A combined NMR-computational study of the interaction between influenza virus hemagglutinin and sialic derivatives from human and avian receptors on the surface of transfected cells. Int. J. Mol. Sci., 2018, 19(5), 1267.
[http://dx.doi.org/10.3390/ijms19051267] [PMID: 29695047]
[27]
Mebi, C.A.; Frost, B.J. Effect of pH on the biphasic catalytic hydrogenation of benzylidene acetone using CpRu (PTA) 2H. Organometallics, 2005, 24(10), 2339-2346.
[http://dx.doi.org/10.1021/om048987r]
[28]
Adhikari, N.; Amin, S.A.; Saha, A.; Jha, T. Combating breast cancer with non-steroidal aromatase inhibitors (NSAIs): Understanding the chemico-biological interactions through comparative SAR/QSAR study. Eur. J. Med. Chem., 2017, 137, 365-438.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.041] [PMID: 28622580]
[29]
Souza, S.A.; Held, A.; Lu, W.J.; Drouhard, B.; Avila, B.; Leyva-Montes, R.; Ng, H.L. Mechanisms of allosteric and mixed mode aromatase inhibitors. RSC Chem. Biol., 2021, 2, 892.
[http://dx.doi.org/10.1039/D1CB00046B]
[30]
Claasen, B.; Axmann, M.; Meinecke, R.; Meyer, B. Direct observation of ligand binding to membrane proteins in living cells by a saturation transfer double difference (STDD) NMR spectroscopy method shows a significantly higher affinity of integrin α(IIb)β3 in native platelets than in liposomes. J. Am. Chem. Soc., 2005, 127(3), 916-919.
[http://dx.doi.org/10.1021/ja044434w] [PMID: 15656629]
[31]
Bhatnagar, A.S. The discovery and mechanism of action of letrozole. Breast Cancer Res. Treat., 2007, 105(S1), 7-17.
[http://dx.doi.org/10.1007/s10549-007-9696-3] [PMID: 17912633]
[32]
Chang, L.; Weiner, L.S.; Hartman, S.J.; Horvath, S.; Jeste, D.; Mischel, P.S.; Kado, D.M. Breast cancer treatment and its effects on aging. J. Geriatr. Oncol., 2019, 10(2), 346-355.
[http://dx.doi.org/10.1016/j.jgo.2018.07.010] [PMID: 30078714]
[33]
Akram, M.; Iqbal, M.; Daniyal, M.; Khan, A.U. Awareness and current knowledge of breast cancer. Biol. Res., 2017, 50(1), 33.
[http://dx.doi.org/10.1186/s40659-017-0140-9] [PMID: 28969709]
[34]
Hartkopf, A.D.; Grischke, E.M.; Brucker, S.Y. Endocrine-resistant breast cancer: Mechanisms and treatment. Breast Care, 2020, 15(4), 347-354.
[http://dx.doi.org/10.1159/000508675] [PMID: 32982644]
[35]
Rasha, F.; Sharma, M.; Pruitt, K. Mechanisms of endocrine therapy resistance in breast cancer. Mol. Cell. Endocrinol., 2021, 532, 111322.
[http://dx.doi.org/10.1016/j.mce.2021.111322] [PMID: 34000350]

Rights & Permissions Print Cite
Article Metrics
21
2
© 2024 Bentham Science Publishers | Privacy Policy