Abstract
A comprehensive study on anthracycline derivatives was done. A quantitative structure–activity relationship (QSAR) study on the half-maximal inhibitory concentration (IC50) of these analogs was developed. These antitumor compounds are used as topoisomerase II enzyme inhibitors. Genetic algorithm (GA) was applied for feature extraction. Multiple linear regression (MLR) was established based on the GA. High stability and robustness of the model were evaluated by leave-one-out cross-validation (LOO-CV), Y-randomization, and external test set (R2 = 0.879, Q 2LOO = 0.857, RMSE = 0.148, R 2max = 0.224, F = 45.4, PRESS = 0.541). This model was generalized to 29 analogs with the quantitative or qualitative in vitro observations for their pIC50 to be calculated. Good agreement between experimental observations and calculated pIC50, indicated that the model was reliable. This result also showed that probably the drug structural-specific is preferred to the cancer cell line-specific in such analogs. Furthermore, the developed model was generalized to 49 other analogs to select potent drug candidates. To do so, four criteria were used simultaneously including (i) effective inhibitory range, (ii) leverage value of structural similarity, (iii) GATS8v value as an important descriptor, and (iv) substituent effect. This approach resulted in the discrimination of 11 candidates.
Graphic abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Akasov R, Drozdova M, Zaytseva-Zotova D et al (2017) Novel doxorubicin derivatives: synthesis and cytotoxicity study in 2D and 3D in vitro models. Adv Pharm Bull 7:593–601. https://doi.org/10.15171/apb.2017.071
Alam S, Khan F (2017) 3D-QSAR studies on maslinic acid analogs for anticancer activity against Breast Cancer cell line MCF-7. Sci Rep 7:1–13. https://doi.org/10.1038/s41598-017-06131-0
Altreuter DH, Dordick JS, Clark DS (2002) Nonaqueous biocatalytic synthesis of new cytotoxic doxorubicin derivatives: exploiting unexpected differences in the regioselectivity of salt-activated and solubilized subtilisin. J Am Chem Soc 124:1871–1876. https://doi.org/10.1021/ja015977y
Arif IS, Hooper CL, Greco F, Williams AC, Boateng S (2013) Increasing doxorubicin activity against breast cancer cells using PPARγ-ligands and by exploiting circadian rhythms. Br J Pharmacol 169:1178–1188. https://doi.org/10.1111/bph.12202
Arnold WR, Baylon JL, Tajkhorshid E, Das A (2017) Arachidonic acid metabolism by human cardiovascular CYP2J2 is modulated by doxorubicin. Biochemistry 56:6700–6712. https://doi.org/10.1021/acs.biochem.7b01025
Bartzatt R (2011) Use of pattern recognition analysis to identify underlying relationships of doxorubicin derivatives optimized for breast cancer treatment. ISRN Oncol. https://doi.org/10.5402/2011/585192. Article ID 585192
Bellarosa D, Binaschi M, Maggi CA, Goso C, A MRS (2005) Sabarubicin- (MEN 10755) and paclitaxel show different kinetics in nuclear factor-kappaB (NF-kB) activation: effect of parthenolide on their cytotoxicity. Anticancer Res 2128:2119–2128 PMID:16158953
Berg SL, Reid J, Godwin K, Murry DJ, Poplack DG, Balis FM, Ames MM (1999) Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model. J Pediatr Hematol Oncol 21:26–30. https://doi.org/10.1097/00043426-199901000-00006
Bigioni M, Benzo A, Irrissuto C, Lopez G, Curatella B, Maggi CA, Manzini S, Crea A, Caroli S, Cubadda F, Binaschi M (2008) Antitumour effect of combination treatment with Sabarubicin (MEN 10755) and cis-platin (DDP) in human lung tumor xenograft. Cancer Chemother Pharmacol 62:621–629. https://doi.org/10.1007/s00280-007-0645-y
Breiner-goldstein E, Evron Z, Frenkel M, Cohen K, Meiron KN, Peer D, Roichman Y, Flescher E, Fridman M (2011) Targeting anthracycline-resistant tumor cells with synthetic aloe-emodin glycosides. Med Chem Lett 2:528–531. https://doi.org/10.1021/ml2001104
Caballero J, Tundidor-Camba A, Fernández M (2007) Modeling of the inhibition constant (Ki) of some cruzain ketone-based inhibitors using 2D spatial autocorrelation vectors and data-diverse ensembles of Bayesian-regularized genetic neural networks. QSAR Comb Sci 26:27–40. https://doi.org/10.1002/qsar.200610001
Cashman DJ, Kellogg GE (2004) A computational model for anthracycline binding to DNA: tuning groove-binding intercalators for specific sequences. J Med Chem 47:1360–1374. https://doi.org/10.1021/jm030529h
ChemIDplus database. https://chem.nlm.nih.gov/chemidplus/. Accessed 14 Mar 2020
Chhikara BS, St. Jean N, Mandal D et al (2011) Fatty acyl amide derivatives of doxorubicin: synthesis and in vitro anticancer activities. Eur J Med Chem 46:2037–2042. https://doi.org/10.1016/j.ejmech.2011.02.056
Chhikara BS, Mandal D, Parang K (2012) Synthesis, anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate. J Med Chem 55:1500–1510. https://doi.org/10.1021/jm201653u
Denel-bobrowska M, Lukawska M, Gajek A, Oszczapowicz I (2017) Molecular mechanism of action of oxazolinoanthracyclines in cells derived from human solid tumors. Part 2. Toxicol Vitr. https://doi.org/10.1016/j.tiv.2017.10.021
Devinyak O, Havrylyuk D, Lesyk R (2014) 3D-MoRSE descriptors explained. J Mol Graph Model 54:194–203. https://doi.org/10.1016/j.jmgm.2014.10.006
DRAGON software version 5.5, R. Todeschini, V. Consonni, A. Mauri, M. Pavan, TALETE SRL: Milano, Italy, 2007. http://www.talete.mi.it
Famini GR, Penski CA, Wilson LY (1992) Using theoretical descriptors in quantitative structure activity relationships: some physicochemical properties. J Phys Org Chem 5:395–408. https://doi.org/10.1002/poc.610050704
Gajadeera C, Willby MJ, Green KD et al (2017) Antimycobacterial activity of DNA intercalator inhibitors of mycobacterium tuberculosis primase DnaG. J Antibiot 68:153–157. https://doi.org/10.1038/ja.2014.131
Ganapathi RN, Ganapathi MK (2013) Mechanisms regulating resistance to inhibitors of topoisomerase II. Front Pharmacol. https://doi.org/10.3389/fphar.2013.00089
HyperChem Software Version 8.0, Hypercube, Inc. 2007. http://www.hyper.com
Jones LW, Douglas PS, Khakoo A, Scott JM, Haykowsky MJ, Mackey JR (2011) Modulation of anthracycline-induced cardiotoxicity by aerobic exercise in breast cancer. Circulation 124:642–650. https://doi.org/10.1161/circulationaha.111.021774
Khoshneviszadeh M, Edraki N, Miri R et al (2012) QSAR study of 4-aryl-4H-chromenes as a new series of apoptosis inducers using different chemometric tools. Chem Biol Drug Des 79:442–458. https://doi.org/10.1111/j.1747-0285.2011.01284.x
Kik K, Wasowska-lukawska M, Oszczapowicz I, Szmigiero L (2009) Cytotoxicity and cellular uptake of doxorubicin and its formamidine derivatives in HL60 sensitive and HL60/MX2 resistant cells. Anticancer Res 29:1429–1434 PMID:19414398
Krohn K (2008) Anthracycline chemistry and biology II: mode of action, clinical aspects and new drugs, Ch.8: nemorubicin, 1st edn. Springer, Berlin, pp 191–206. https://doi.org/10.1007/128_2007_6
Laatsch H (2008) Naturally occurring anthracyclines. Top Curr Chem. https://doi.org/10.1007/128_2008_5
Lodhi H, Yamanishi Y (2011) Chemoinformatics and advanced machine learning perspectives: Complex computational methods and collaborative techniques. Ch. 5: structure-activity relationships by autocorrelation descriptors and genetic algorithms. Hershey, New York, pp 60–94. https://doi.org/10.4018/978-1-61520-911-8.ch005
Ma X, Tao H, YangK Feng L, Cheng L, Shi X, Li Y (2012) A functionalized graphene oxide—iron oxide nanocomposite for magnetically targeted drug delivery, photothermal therapy, and magnetic resonance imaging. Nano Res 5:199–212. https://doi.org/10.1007/s12274-012-0200-y
Ma L, Bygd HC, Bratlie KM (2017) Improving selective targeting to macrophage subpopulations through modifying liposomes with arginine based materials. Integr Biol (United Kingdom) 9:58–67. https://doi.org/10.1039/c6ib00133e
Matikonda SS, Orsi DL, Staudacher V, Jenkins IA, Fiedler F, Chen J, Gamble AB (2015) Bioorthogonal prodrug activation driven by a strain-promoted 1,3-dipolar cycloaddition. Chem Sci 6:1212–1218. https://doi.org/10.1039/C4SC02574A
Matsuzawa Y, Oki T, Takeuchi T, Umezawa H (1981) Structure-activity relationships of anthracyclines relative to cytotoxicity and effects on macromolecular synthesis in L1210 leukemia cells. J Antibiot (Tokyo) 34:1596–1607. https://doi.org/10.7164/antibiotics.34.1596
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229. https://doi.org/10.1124/pr.56.2.6.185
Monneret C (2001) Invited review recent developments in the field of antitumour anthracyclines. Eur J Med Chem 36:483–493. https://doi.org/10.1016/S0223-5234(01)01244-2
Mordente A, Silvestrini A, Martorana GE, Tavian D, Meucci E (2015) Inhibition of anthracycline alcohol metabolite formation in human heart cytosol: a potential role for several promising drugs. Drug Metab Dispos 43:1691–1701. https://doi.org/10.1124/dmd.115.065110
Moreau G, Broto P (1980) Autocorrelation of molecular structures: application to SAR studies. Nouv J Chim 4:757–764
Nadas J, Sun D (2006) Anthracyclines as effective anticancer drugs. Expert Opin Drug Discov 1:549–568. https://doi.org/10.1517/17460441.1.6.549
Orlandi P, Barbara C, Bocci G, Fioravanti A, Dipaolo A, Deltacca M, Danesi R (2005) Idarubicin and idarubicinol effects on breast cancer multicellular spheroids. J Chemother 17(6):663–667. https://doi.org/10.1179/joc.2005.17.6.663
Rho YS, Kim G, Kim W, Park S, Yoo DJ, Kang HS, Chung S (2001) Synthesis of new anthracycline derivatives containing acetylsalicylic or palmitic acid moiety. Bull Korean Chem Soc 22:587–592
Rho YS, Kim W, Yoo DJ (2006) Synthesis of new anthracycline derivatives containing lactic or stearic acid moiety. Bull Korean Chem Soc 27:1359–1363. https://doi.org/10.5012/bkcs.2006.27.9.1359
Sabnis N, Nair M, Israel M, McConathy WJ, Lacko AG (2012) Enhanced solubility and functionality of valrubicin (AD-32) against cancer cells upon encapsulation into biocompatible nanoparticles. Int J Nanomed 7:975–983. https://doi.org/10.2147/IJN.S28029
Salvatorelli E, Guarnieri S, Menna P, Liberi G, Calafiore AM, Mariggio MA, Mordente A, Gianni L, Minotti G (2006) Defective one- or two-electron reduction of the anticancer anthracycline epirubicin in human heart: relative importance of vesicular sequestration and impaired efficiency of electron addition. J Biol Chem 281:10990–11001. https://doi.org/10.1074/jbc.M508343200
Shaul P, Frenkel M, Goldstein EB, Mittelman L, Grunwald A, Ebenstein Y, Tsarfaty I, Fridman M (2013) The structure of anthracycline derivatives determines their subcellular localization and cytotoxic activity. ACS Med Chem Lett 4:323–328. https://doi.org/10.1021/ml3002852
Snee RD (1977) validation of regression models: methods and examples. Technometrics 19:415–428. https://doi.org/10.1080/00401706.1977.10489581
Streeter DG, Taylor DL, Acton EM, Peters JH (1985) Comparative cytotoxicities of various morpholinyl anthracyclines. Cancer Chemot Pharm 14:160–164. https://doi.org/10.1007/BF00694330
Sztaricskai F, Sum A, Roth E et al (2005) A new class of semisynthetic anthracycline glycoside antibiotics incorporating a squaric acid moiety. J Antibiot 58:704–714. https://doi.org/10.1038/ja.2005.96
Tevyashova AN, Klyosov AA, Olsufyeva EN, Preobrazhenskaya MN, Zomer E (2012) Glycobiology and drug design. Ch. 5: Synthesis and biological activity of galactomycin and doxoDavanat, new conjugates of doxorubicin with D-galactose and 1, 4-β-D-galactomannan. ACS, Washington, DC, pp 131–154. https://doi.org/10.1021/bk-2012-1102.ch005
Xu J, Pei L, Zhu RZ (2018) Application of a genetic algorithm with random crossover and dynamic mutation on the travelling salesman problem. Procedia Comput Sci 131:937–945. https://doi.org/10.1016/j.procs.2018.04.230
Yamaoka T, Hanada M, Ichii S, Morisada S, Noguchi T, Yanagi Y (1998) Cytotoxicity of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol on human tumor cells. Jpn J Cancer Res 89:1067–1073. https://doi.org/10.1111/j.1349-7006.1998.tb00498.x
Yamaoka T, Hanada M, Ichii S, Morisada S, Noguchi T (1999) Uptake and intracellular distribution of amrubicin, a novel 9-amino- anthracycline, and its active metabolite amrubicinol in P388 murine leukemia cells. Jpn J Cancer Res 90:685–690. https://doi.org/10.1111/j.1349-7006.1999.tb00801.x
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sadeghi, F., Afkhami, A., Madrakian, T. et al. Computational study to select the capable anthracycline derivatives through an overview of drug structure-specificity and cancer cell line-specificity. Chem. Pap. 75, 523–538 (2021). https://doi.org/10.1007/s11696-020-01321-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11696-020-01321-z