Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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

Antimetastatic Potential of Quercetin Analogues with Improved Pharmacokinetic Profile: A Pharmacoinformatic Preliminary Study

Author(s): Nebojša Pavlović*, Nastasija Milošević, Maja Đjanić, Svetlana Goločorbin-Kon, Bojan Stanimirov, Karmen Stankov and Momir Mikov

Volume 22, Issue 7, 2022

Published on: 08 June, 2021

Page: [1407 - 1413] Pages: 7

DOI: 10.2174/1871520621666210608102452

Price: $65

Abstract

Background: Urokinase-type plasminogen activator (uPA) system is a crucial pathway for tumor invasion and metastasis. Recently, multiple anticancer effects of quercetin have been described, including inhibitory activity against uPA. However, the clinical use of this flavonoid has been limited due to its low oral bioavailability.

Objective: The objectives of the study were to assess the antimetastatic potential of quercetin analogues by analyzing their binding affinity for uPA, and to select the compounds with improved pharmacological profiles.

Methods: Binding affinities of structural analogues of quercetin to uPA receptor were determined by molecular docking analysis using Molegro Virtual Docker software, and molecular descriptors relevant for estimating pharmacological profile were calculated from ligand structures using computational models.

Results: Among 44 quercetin analogues, only one quercetin analogue (3,6,2’,4’,5’-pentahydroxyflavone) was found to possess higher aqueous solubility and membrane permeability, and stronger affinity for uPA than quercetin, which makes it a potential lead compound for anticancer drug development. Like quercetin, this compound has five hydroxyl groups, but arranged differently, which contributes to the higher aqueous solubility and higher amphiphilic moment in comparison to quercetin. Since membrane permeability is not recognized as the limiting factor for quercetin absorption, analogues with higher aqueous solubility and retained or stronger uPA inhibitory activity should also be further experimentally validated for potential therapeutic use.

Conclusion: Identified quercetin analogues with better physicochemical and pharmacological properties have a high potential to succeed in later stages of research in biological systems as potential anticancer agents with antimetastatic activity.

Keywords: Molecular docking, quercetin, analogues, cancer, uPA, pharmacokinetics.

« Previous Next »
Graphical Abstract

[1]
Xu, D.; Hu, M.J.; Wang, Y.Q.; Cui, Y.L. Antioxidant activities of quercetin and its complexes for medicinal application. Molecules, 2019, 24(6), 1123.
[http://dx.doi.org/10.3390/molecules24061123] [PMID: 30901869]
[2]
Nam, J.S.; Sharma, A.R.; Nguyen, L.T.; Chakraborty, C.; Sharma, G.; Lee, S.S. Application of bioactive quercetin in oncotherapy: From nutrition to nanomedicine. Molecules, 2016, 21(1), E108.
[http://dx.doi.org/10.3390/molecules21010108] [PMID: 26797598]
[3]
Tang, S.M.; Deng, X.T.; Zhou, J.; Li, Q.P.; Ge, X.X.; Miao, L. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed. Pharmacother., 2020, 121, 109604.
[http://dx.doi.org/10.1016/j.biopha.2019.109604] [PMID: 31733570]
[4]
Rauf, A.; Imran, M.; Khan, I.A.; Ur-Rehman, M.; Gilani, S.A.; Mehmood, Z.; Mubarak, M.S. Anticancer potential of quercetin: A comprehensive review. Phytother. Res., 2018, 32(11), 2109-2130.
[http://dx.doi.org/10.1002/ptr.6155] [PMID: 30039547]
[5]
Conlon, G.A.; Murray, G.I. Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis. J. Pathol., 2019, 247(5), 629-640.
[http://dx.doi.org/10.1002/path.5225] [PMID: 30582157]
[6]
Lin, C.W.; Hou, W.C.; Shen, S.C.; Juan, S.H.; Ko, C.H.; Wang, L.M.; Chen, Y.C. Quercetin inhibition of tumor invasion via suppressing PKC δ/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis, 2008, 29(9), 1807-1815.
[http://dx.doi.org/10.1093/carcin/bgn162] [PMID: 18628248]
[7]
Xue, G.; Gong, L.; Yuan, C.; Xu, M.; Wang, X.; Jiang, L.; Huang, M. A structural mechanism of flavonoids in inhibiting serine proteases. Food Funct., 2017, 8(7), 2437-2443.
[http://dx.doi.org/10.1039/C6FO01825D] [PMID: 28644504]
[8]
Mahmood, N.; Mihalcioiu, C.; Rabbani, S.A. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): Diagnostic, prognostic, and therapeutic applications. Front. Oncol., 2018, 8, 24.
[http://dx.doi.org/10.3389/fonc.2018.00024] [PMID: 29484286]
[9]
Santibanez, J.F.; Obradović, H.; Kukolj, T.; Krstić, J. Transforming growth factor-β, matrix metalloproteinases, and urokinase-type plasminogen activator interaction in the cancer epithelial to mesenchymal transition. Dev. Dyn., 2018, 247(3), 382-395.
[http://dx.doi.org/10.1002/dvdy.24554] [PMID: 28722327]
[10]
Li, H.; Chen, C. Quercetin has antimetastatic effects on gastric cancer cells via the interruption of uPA/uPAR function by modulating NF-κb, PKC-δ, ERK1/2, and AMPKα. Integr. Cancer Ther., 2018, 17(2), 511-523.
[http://dx.doi.org/10.1177/1534735417696702] [PMID: 28627240]
[11]
Cai, X.; Fang, Z.; Dou, J.; Yu, A.; Zhai, G. Bioavailability of quercetin: Problems and promises. Curr. Med. Chem., 2013, 20(20), 2572-2582.
[http://dx.doi.org/10.2174/09298673113209990120] [PMID: 23514412]
[12]
Gadhwal, M.K.; Patil, S.; D’Mello, P.; Joshi, U.; Sinha, R.; Govil, G. Synthesis, characterisation and antitumour activity of some quercetin analogues. Indian J. Pharm. Sci., 2013, 75(2), 233-237.
[PMID: 24019576]
[13]
Magar, R.T.; Sohng, J.K. A review on structure, modifications and structure-activity relation of quercetin and its derivatives. J. Microbiol. Biotechnol., 2020, 30(1), 11-20.
[http://dx.doi.org/10.4014/jmb.1907.07003] [PMID: 31752056]
[14]
Bruno, A.; Costantino, G.; Sartori, L.; Radi, M. The in silico drug discovery toolbox: Applications in lead discovery and optimization. Curr. Med. Chem., 2019, 26(21), 3838-3873.
[http://dx.doi.org/10.2174/0929867324666171107101035] [PMID: 29110597]
[15]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[16]
Irwin, J.J.; Sterling, T.; Mysinger, M.M.; Bolstad, E.S.; Coleman, R.G. ZINC: A free tool to discover chemistry for biology. J. Chem. Inf. Model., 2012, 52(7), 1757-1768.
[http://dx.doi.org/10.1021/ci3001277] [PMID: 22587354]
[17]
Thomsen, R.; Christensen, M.H. MolDock: A new technique for high-accuracy molecular docking. J. Med. Chem., 2006, 49(11), 3315-3321.
[http://dx.doi.org/10.1021/jm051197e] [PMID: 16722650]
[18]
Kerns, E.; Di, L. Drug-like properties: Concepts, structure design and methods: From ADME to toxicity optimization; Academic press: New York, 2008.
[19]
Cruciani, G.; Pastor, M.; Guba, W. VolSurf: A new tool for the pharmacokinetic optimization of lead compounds. Eur. J. Pharm. Sci., 2000, 11(Suppl. 2), S29-S39.
[http://dx.doi.org/10.1016/S0928-0987(00)00162-7] [PMID: 11033425]
[20]
Walle, T.; Walle, U.K.; Halushka, P.V. Carbon dioxide is the major metabolite of quercetin in humans. J. Nutr., 2001, 131(10), 2648-2652.
[http://dx.doi.org/10.1093/jn/131.10.2648] [PMID: 11584085]
[21]
Chen, X.; Yin, O.Q.; Zuo, Z.; Chow, M.S. Pharmacokinetics and modeling of quercetin and metabolites. Pharm. Res., 2005, 22(6), 892-901.
[http://dx.doi.org/10.1007/s11095-005-4584-1] [PMID: 15948033]
[22]
Pavlović, N.; Đanić, M.; Stanimirov, B.; Goločorbin-Kon, S.; Stankov, K.; Lalić-Popović, M.; Mikov, M. In silico discovery of resveratrol analogues as potential agents in treatment of metabolic disorders. Curr. Pharm. Des., 2019, 25(35), 3776-3783.
[http://dx.doi.org/10.2174/1381612825666191029095252] [PMID: 31663474]
[23]
Singh, S.P.; Konwar, B.K. Molecular docking studies of quercetin and its analogues against human inducible nitric oxide synthase. Springerplus, 2012, 1(1), 69.
[http://dx.doi.org/10.1186/2193-1801-1-69] [PMID: 23556141]
[24]
Zhu, M.; Gokhale, V.M.; Szabo, L.; Munoz, R.M.; Baek, H.; Bashyam, S.; Hurley, L.H.; Von Hoff, D.D.; Han, H. Identification of a novel inhibitor of urokinase-type plasminogen activator. Mol. Cancer Ther., 2007, 6(4), 1348-1356.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0520] [PMID: 17431113]
[25]
Li, L.; Kong, J.; Yao, C.H.; Liu, X.F.; Liu, J.H. Rapid identification of urokinase plasminogen activator inhibitors from Traditional Chinese Medicines based on ultrafiltration, LC-MS and in silico docking. J. Pharm. Biomed. Anal., 2019, 164, 241-248.
[http://dx.doi.org/10.1016/j.jpba.2018.10.036] [PMID: 30396051]
[26]
Murota, K.; Matsuda, N.; Kashino, Y.; Fujikura, Y.; Nakamura, T.; Kato, Y.; Shimizu, R.; Okuyama, S.; Tanaka, H.; Koda, T.; Sekido, K.; Terao, J. alpha-Oligoglucosylation of a sugar moiety enhances the bioavailability of quercetin glucosides in humans. Arch. Biochem. Biophys., 2010, 501(1), 91-97.
[http://dx.doi.org/10.1016/j.abb.2010.06.036] [PMID: 20638359]
[27]
Sheng, Y.; Li, W.; Zhu, F.; Liu, K.; Chen, H.; Yao, K.; Reddy, K.; Lim, D.Y.; Oi, N.; Li, H.; Peng, C.; Ma, W.Y.; Bode, A.M.; Dong, Z.; Dong, Z. 3,6,2′,4′,5′-Pentahydroxyflavone, an orally bioavailable multiple protein kinase inhibitor, overcomes gefitinib resistance in non-small cell lung cancer. J. Biol. Chem., 2014, 289(41), 28192-28201.
[http://dx.doi.org/10.1074/jbc.M114.593475] [PMID: 25122774]
[28]
Malisauskas, R.; Botyriute, A.; Cannon, J.G.; Smirnovas, V. Flavone derivatives as inhibitors of insulin amyloid-like fibril formation. PLoS One, 2015, 10(3), e0121231.
[http://dx.doi.org/10.1371/journal.pone.0121231] [PMID: 25799281]
[29]
Kleffman, K.; Levinson, G.; Wong, E.; Galán-Echevarría, F.; Von-Itter, R.; Rose, I.; Blumenberg, L.; Floristán, A.; Tranos, J.; Argibay, D. Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis. bioRxiv, 2019, •••, 854885.
[30]
Davis, J.; Wagner, M.R.; Zhang, W.; Xu, F.; Van Nostrand, W.E. Amyloid β-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells. J. Biol. Chem., 2003, 278(21), 19054-19061.
[http://dx.doi.org/10.1074/jbc.M301398200] [PMID: 12754271]
[31]
Jin, H.; Lee, W.S.; Eun, S.Y.; Jung, J.H.; Park, H.S.; Kim, G.; Choi, Y.H.; Ryu, C.H.; Jung, J.M.; Hong, S.C.; Shin, S.C.; Kim, H.J. Morin, a flavonoid from Moraceae, suppresses growth and invasion of the highly metastatic breast cancer cell line MDA-MB 231 partly through suppression of the Akt pathway. Int. J. Oncol., 2014, 45(4), 1629-1637.
[http://dx.doi.org/10.3892/ijo.2014.2535] [PMID: 24993541]
[32]
Adebambo, K.; Gunaratnam, S. Molecular docking investigation of new inhibitors of Falciparum vivax. Comput. Mol. Biosci., 2018, 8(2), 43-67.
[http://dx.doi.org/10.4236/cmb.2018.82002]
[33]
Singh, S.P.; Konwar, B.K. Virtual screening and molecular descriptor analysis on dietary phytochemicals against heat shock protein 90 enzyme. Lett. Drug Des. Discov., 2014, 11, 40-49.
[http://dx.doi.org/10.2174/15701808113109990044]

Rights & Permissions Print Cite
Article Metrics
16
1
© 2024 Bentham Science Publishers | Privacy Policy