A Novel Series of N-aryltriazole and N-acridinyltriazole Hybrids as Potential Anticancer Agents

Author(s): Charles K. Rono, James Darkwa, Debra Meyer, Banothile C.E. Makhubela*.

Journal Name: Current Organic Synthesis

Volume 16 , Issue 6 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Triazoles are a class of aza-heterocycles with broad spectrum of biological importance. The synthetic tunability of the triazole moiety allows for the development of new pharmacophores with applications as drugs to contend with the burden of cancer.

Objective: In this study, we aimed to develop a series of N-aryltriazole and N-acridinyltriazole molecular hybrids and evaluate their potential as anticancer agents.

Methods: The triazole derivatives (1-10) were synthesized via a tandem nucleophilic substitution of aryl chlorides with sodium azide followed by 1,3-dipolar cycloaddition of the resulting organic azides with terminal/internal alkynes. From terminal alkynes, the well established copper(I) catalyzed azide-alkynes 1,3- dipolar cycloaddition, a premier example of click chemistry, was employed to access the 1,4-regioisomers of N-benzyl-1H-1,2,3-triazoles and N-acridynyl-1H-1,2,3-triazoles. All the compounds thus synthesized were characterized by 1D and 2D NMR spectroscopy and high resolution mass spectrometry.

Results: Thermally controlled 1,3-dipolar cycloaddition was used to deliver N-aryl-1H-1,2,3-triazoles with 1,4,5-substitution on the triazole framework. The unprecedented high regioselectivity promoted by the sterically-strained silylated 1,4,5-trisubstituted moiety 4a offers a useful synthetic precursor with the silyl group being a synthetic handle for further structural elaboration to the desired 1,(4),5-di(tri)substituted 1,2,3- triazoles. Notably, anticancer evaluation revealed good cytotoxic activities of the novel acridinyltriazole hybrids (6-10) at micromolar concentrations in the range of 12.5 µM–100 µM against cervical cancer HeLa, kidney cancer HEK293, lung cancer A549 and leukemic MT4 cancer cell lines (p < 0.05).

Conclusion: A series of novel triazole-based acridine hybrids have been developed as potential leads for the development of multifaceted anticancer agents.

Keywords: Acridine, triazole hybrids, anticancer, 5’- GMP, DNA, cytotoxicity.

(a)Majireck, M.M.; Weinreb, S.M. A study of the scope and regioselectivity of the ruthenium-catalyzed [3 + 2]-cycloaddition of azides with internal alkynes. J. Org. Chem., 2006, 71(22), 8680-8683.
[http://dx.doi.org/10.1021/jo061688m] [PMID: 17064059]
(b)Wang, Z-X.; Shi, W-M.; Bi, H-Y.; Li, X-H.; Su, G-F.; Mo, D-L. Synthesis of N-(2-hydroxyaryl)benzotriazoles via metal-free O-arylation and N-O bond cleavage. J. Org. Chem., 2016, 81(17), 8014-8021.
[http://dx.doi.org/10.1021/acs.joc.6b01390] [PMID: 27500856]
(a)Song, J-F.; Wang, J.; Li, S-Z.; Li, Y.; Zhou, R-S. Five new complexes based on 1-phenyl-1H-tetrazole-5-thiol: Synthesis, structural characterization and properties. J. Mol. Struct., 2017, 1129, 1-7.
(b)Song, D.; Park, Y.; Yoon, J.; Aman, W.; Hah, J-M.; Ryu, J-S. Click approach to the discovery of 1,2,3-triazolylsalicylamides as potent Aurora kinase inhibitors. Bioorg. Med. Chem., 2014, 22(17), 4855-4866.
[http://dx.doi.org/10.1016/j.bmc.2014.06.047] [PMID: 25042560]
(c)Deng, X.; Liang, J.; Allison, B.B.; Dvorak, C.; McAllister, H.; Savall, B.M.; Mani, N.S. Allyl-assisted, Cu(I)-catalyzed azide-alkyne cycloaddition/allylation reaction: Assembly of the [1,2,3]triazolo-4,5,6,7-tetrahydropyridine core structure. J. Org. Chem., 2015, 80(21), 11003-11012.
[http://dx.doi.org/10.1021/acs.joc.5b02174] [PMID: 26458051]
(d)Li, W.; Ajitha, M.J.; Lang, M.; Huang, K-W.; Wang, J. Catalytic intermolecular cross-couplings of azides and LUMO-activated unsaturated acyl azoliums. ACS Catal., 2017, 7(3), 2139-2144.
He, X-P.; Zeng, Y-L.; Zang, Y.; Li, J.; Field, R.A.; Chen, G-R. Carbohydrate CuAAC click chemistry for therapy and diagnosis. Carbohydr. Res., 2016, 429, 1-22.
[http://dx.doi.org/10.1016/j.carres.2016.03.022] [PMID: 27085906]
[a]Mann, B.S.; Johnson, J.R.; Cohen, M.H.; Justice, R.; Pazdur, R. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist, 2007, 12(10), 1247-1252.
[http://dx.doi.org/10.1634/theoncologist.12-10-1247] [PMID: 17962618]
[b]Zhang, W.; Li, Z.; Zhou, M.; Wu, F.; Hou, X.; Luo, H.; Liu, H.; Han, X.; Yan, G.; Ding, Z.; Li, R. Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents. Bioorg. Med. Chem. Lett., 2014, 24(3), 799-807.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.095] [PMID: 24418772]
(a)Raic-Malic, S.; Mescic, A. Recent trends in 1,2,3-triazolo-nucleosides as promising anti-infective and anticancer agents. Curr. Med. Chem., 2015, 22(12), 1462-1499.
[http://dx.doi.org/10.2174/0929867322666150227150127] [PMID: 25723510]
(b)Pertino, M.W.; Lopez, C.; Theoduloz, C.; Schmeda-Hirschmann, G. 1,2,3-triazole-substituted oleanolic Acid derivatives: synthesis and antiproliferative activity. Molecules, 2017. 18(7), 7661-7674.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.028] [PMID: 27875779]
(c)Gregorić, T.; Sedić, M.; Grbčić, P.; Tomljenović Paravić, A.; Kraljević Pavelić, S.; Cetina, M.; Vianello, R.; Raić-Malić, S. Novel pyrimidine-2,4- dione-1,2,3-triazole and furo[2,3-d]pyrimidine-2-one-1,2,3-triazole hybrids as potential anti-cancer agents: Synthesis, computational and X-ray analysis and biological evaluation. Eur. J. Med. Chem, 2017. 125, 1247-1267.
[http://dx.doi.org/10.1016/j.ejmech.2016.11.028] [PMID: 27875779]
Nepali, K.; Sharma, S.; Sharma, M.; Bedi, P.M.; Dhar, K.L. Rational approaches, design strategies, structure activity relationship and mechanistic insights for anticancer hybrids. Eur. J. Med. Chem., 2014, 77, 422-487.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.018] [PMID: 24685980]
Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Click chemistry: Diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. Engl., 2001, 40(11), 2004-2021.
[http://dx.doi.org/10.1002/1521-3773(20010601)40:11<2004:AID-ANIE2004>3.0.CO;2-5] [PMID: 11433435]
(a)Wang, Q.; Chan, T.R.; Hilgraf, R.; Fokin, V.V.; Sharpless, K.B.; Finn, M.G. Bioconjugation by copper(I)-catalyzed azide-alkyne [3 + 2] cycloaddition. J. Am. Chem. Soc., 2003, 125(11), 3192-3193.
[http://dx.doi.org/10.1021/ja021381e] [PMID: 12630856]
(b)Tiwari, V.K.; Mishra, B.B.; Mishra, K.B.; Mishra, N.; Singh, A.S.; Chen, X. Cu-catalyzed click reaction in carbohydrate chemistry. Chem. Rev., 2016, 116(5), 3086-3240.
[http://dx.doi.org/10.1021/acs.chemrev.5b00408] [PMID: 26796328]
Wang, C.; Ikhlef, D.; Kahlal, S.; Saillard, J-Y.; Astruc, D. Metal-catalyzed azide-alkyne “click” reactions: Mechanistic overview and recent trends. Coord. Chem. Rev., 2016, 316, 1-20.
(a)Tron, G.C.; Pirali, T.; Billington, R.A.; Canonico, P.L.; Sorba, G.; Genazzani, A.A. Click chemistry reactions in medicinal chemistry: Applications of the 1,3-dipolar cycloaddition between azides and alkynes. Med. Res. Rev., 2008, 28(2), 278-308.
[http://dx.doi.org/10.1002/med.20107] [PMID: 17763363]
(b)Chen, P.C.; Patil, V.; Guerrant, W.; Green, P.; Oyelere, A.K. Synthesis and structure-activity relationship of histone deacetylase (HDAC) inhibitors with triazole-linked cap group. Bioorg. Med. Chem., 2008, 16(9), 4839-4853.
[http://dx.doi.org/10.1016/j.bmc.2008.03.050] [PMID: 18397827]
(a)Sudhapriya, N.; Nandakumar, A.; Arun, Y.; Perumal, P.; Balachandran, C.; Emi, N. An expedient route to highly diversified [1, 2, 3] triazolo [1, 5-a][1, 4] benzodiazepines and their evaluation for antimicrobial, antiproliferative and in silico studies. RSC Advances, 2015, 5(81), 66260-66270.
(b)Barve, I.J.; Thikekar, T.U.; Sun, C-M. Silver(I)-Catalyzed Regioselective Synthesis of Triazole Fused-1,5-Benzoxazocinones. Org. Lett., 2017, 19(9), 2370-2373.
[http://dx.doi.org/10.1021/acs.orglett.7b00907] [PMID: 28409630]
(a)Morris, J.C.; Chiche, J.; Grellier, C.; Lopez, M.; Bornaghi, L.F.; Maresca, A.; Supuran, C.T.; Pouysségur, J.; Poulsen, S-A. Targeting hypoxic tumor cell viability with carbohydrate-based carbonic anhydrase IX and XII inhibitors. J. Med. Chem., 2011, 54(19), 6905-6918.
[http://dx.doi.org/10.1021/jm200892s] [PMID: 21851094]
(b)Ferroni, C.; Pepe, A.; Kim, Y.S.; Lee, S.; Guerrini, A.; Parenti, M.D.; Tesei, A.; Zamagni, A.; Cortesi, M.; Zaffaroni, N.; De Cesare, M.; Beretta, G.L.; Trepel, J.B.; Malhotra, S.V.; Varchi, G. 1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment. J. Med. Chem., 2017, 60(7), 3082-3093.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00105] [PMID: 28272894]
(a)Wainwright, M. Acridine-a neglected antibacterial chromophore. J. Antimicrob. Chemother., 2001, 47(1), 1-13.
[http://dx.doi.org/10.1093/jac/47.1.1] [PMID: 11152426]
(b)Loiseau, P.M.; Nguyen, D.X. Plasmodium berghei mouse model: antimalarial activity of new alkaloid salts and of thiosemicarbazone and acridine derivatives. Trop. Med. Int. Health, 1996, 1(3), 379-384.
[http://dx.doi.org/10.1046/j.1365-3156.1996.d01-50.x] [PMID: 8673843]
(c)Tomar, V.; Bhattacharjee, G. Kamaluddin; Rajakumar, S.; Srivastava, K.; Puri, S.K. Synthesis of new chalcone derivatives containing acridinyl moiety with potential antimalarial activity. Eur. J. Med. Chem., 2010, 45(2), 745-751.
[http://dx.doi.org/10.1016/j.ejmech.2009.11.022] [PMID: 20022412]
Tonelli, M.; Vettoretti, G.; Tasso, B.; Novelli, F.; Boido, V.; Sparatore, F.; Busonera, B.; Ouhtit, A.; Farci, P.; Blois, S.; Giliberti, G.; La Colla, P. Acridine derivatives as anti-BVDV agents. Antiviral Res., 2011, 91(2), 133-141.
[http://dx.doi.org/10.1016/j.antiviral.2011.05.005] [PMID: 21619897]
Toobaei, Z.; Yousefi, R.; Panahi, F.; Shahidpour, S.; Nourisefat, M.; Doroodmand, M.M.; Khalafi-Nezhad, A. Synthesis of novel poly-hydroxyl functionalized acridine derivatives as inhibitors of α-Glucosidase and α-Amylase. Carbohydr. Res., 2015, 411, 22-32.
[http://dx.doi.org/10.1016/j.carres.2015.04.005] [PMID: 25957572]
Jones, M.; Mercer, A.E.; Stocks, P.A.; La Pensée, L.J.; Cosstick, R.; Park, B.K.; Kennedy, M.E.; Piantanida, I.; Ward, S.A.; Davies, J.; Bray, P.G.; Rawe, S.L.; Baird, J.; Charidza, T.; Janneh, O.; O’Neill, P.M. Antitumour and antimalarial activity of artemisinin-acridine hybrids. Bioorg. Med. Chem. Lett., 2009, 19(7), 2033-2037.
[http://dx.doi.org/10.1016/j.bmcl.2009.02.028] [PMID: 19249201]
(a)Korth, C.; May, B.C.; Cohen, F.E.; Prusiner, S.B. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc. Natl. Acad. Sci. USA, 2001, 98(17), 9836-9841.
[http://dx.doi.org/10.1073/pnas.161274798] [PMID: 11504948]
(b)Pontinha, A.D.R.; Sparapani, S.; Neidle, S.; Oliveira-Brett, A.M. Triazole-acridine conjugates: redox mechanisms and in situ electrochemical evaluation of interaction with double-stranded DNA. Bioelectrochemistry, 2013, 89, 50-56.
[http://dx.doi.org/10.1016/j.bioelechem.2012.08.005] [PMID: 23059201]
(a)Demeunynck, M.; Charmantray, F.; Martelli, A. Interest of acridine derivatives in the anticancer chemotherapy. Curr. Pharm. Des., 2001, 7(17), 1703-1724.
[http://dx.doi.org/10.2174/1381612013397131] [PMID: 11562307]
(b)Belmont, P.; Bosson, J.; Godet, T.; Tiano, M. Acridine and acridone derivatives, anticancer properties and synthetic methods: Where are we now? Anticancer. Agents Med. Chem., 2007, 7(2), 139-169.
(c)Martínez, R.; Chacón-García, L. The search of DNA-intercalators as antitumoral drugs: what it worked and what did not work. Curr. Med. Chem., 2005, 12(2), 127-151.
[http://dx.doi.org/10.2174/0929867053363414] [PMID: 15638732]
Agrawal, A.; Dang, S.; Gabrani, R. Recent patents on anti-telomerase cancer therapy. Recent Patents Anticancer Drug Discov., 2012, 7(1), 102-117.
[http://dx.doi.org/10.2174/157489212798357958] [PMID: 21854360]
Tan, J-H.; Gu, L-Q.; Wu, J-Y. Design of selective G-quadruplex ligands as potential anticancer agents. Mini Rev. Med. Chem., 2008, 8(11), 1163-1178.
[http://dx.doi.org/10.2174/138955708785909880] [PMID: 18855731]
Kirk, S.R.; Luedtke, N.W.; Tor, Y. Neomycin-acridine conjugate: a potent inhibitor of Rev-RRE binding. J. Am. Chem. Soc., 2000, 122(5), 980-981.
(a)Kamkaew, A.; Fu, N.; Cai, W.; Burgess, K. Novel Small Molecule Probes for Metastatic Melanoma. ACS Med. Chem. Lett., 2016, 8(2), 179-184.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00368] [PMID: 28197308]
(b)Venugopala, K.N.; Dharma Rao, G.B.; Bhandary, S.; Pillay, M.; Chopra, D.; Aldhubiab, B.E.; Attimarad, M.; Alwassil, O.I.; Harsha, S.; Mlisana, K. Design, synthesis, and characterization of (1-(4-aryl)- 1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against Mycobacterium tuberculosis. Drug Des. Devel. Ther., 2016, 10, 2681-2690.
[http://dx.doi.org/10.2147/DDDT.S109760] [PMID: 27601885]
(a)Meldal, M.; Tornøe, C.W. Cu-catalyzed azide-alkyne cycloaddition. Chem. Rev., 2008, 108(8), 2952-3015.
[http://dx.doi.org/10.1021/cr0783479] [PMID: 18698735]
(b)Jiang, L.; Wang, Z.; Bai, S-Q.; Hor, T.S. “Click-and-click”--hybridised 1,2,3-triazoles supported Cu(I) coordination polymers for azide-alkyne cycloaddition. Dalton Trans., 2013, 42(26), 9437-9443.
[http://dx.doi.org/10.1039/c3dt50987g] [PMID: 23695801]
(a)Pauli, G.F.; Jaki, B.U.; Lankin, D.C. Quantitative 1H NMR: Development and potential of a method for natural products analysis. J. Nat. Prod., 2005, 68(1), 133-149.
[http://dx.doi.org/10.1021/np0497301] [PMID: 15679337]
(b)Pauli, G.F. qNMR--a versatile concept for the validation of natural product reference compounds. Phytochem. Anal., 2001, 12(1), 28-42.
[http://dx.doi.org/10.1002/1099-1565(200101/02)12:1<28:AID-PCA549>3.0.CO;2-D] [PMID: 11704959]
(c)Simmler, C.; Napolitano, J.G.; McAlpine, J.B.; Chen, S-N.; Pauli, G.F. Universal quantitative NMR analysis of complex natural samples. Curr. Opin. Biotechnol., 2014, 25, 51-59.
[http://dx.doi.org/10.1016/j.copbio.2013.08.004] [PMID: 24484881]
(d)Pauli, G.F.; Chen, S-N.; Simmler, C.; Lankin, D.C.; Gödecke, T.; Jaki, B.U.; Friesen, J.B.; McAlpine, J.B.; Napolitano, J.G. Importance of purity evaluation and the potential of quantitative 1H NMR as a purity assay: Miniperspective. J. Med. Chem., 2014, 57(22), 9220-9231.
[http://dx.doi.org/10.1021/jm500734a] [PMID: 25295852]
(e)[5054];Cushman, M.; Georg, G. I.; Holzgrabe, U.; Wang, S., Absolute Quantitative 1H NMR Spectroscopy for Compound Purity Determination. J. Med. Chem., 2014, 57(22), 9219-9219.
Krȩżel, A.; Bal, W. A formula for correlating pKa values determined in D2O and H2O. J. Inorg. Biochem., 2004, 98(1), 161-166.
[http://dx.doi.org/10.1016/j.jinorgbio.2003.10.001] [PMID: 14659645]
Campbell-Verduyn, L.; Elsinga, P.H.; Mirfeizi, L.; Dierckx, R.A.; Feringa, B.L. Copper-free ‘click’: 1,3-dipolar cycloaddition of azides and arynes. Org. Biomol. Chem., 2008, 6(19), 3461-3463.
[http://dx.doi.org/10.1039/b812403e] [PMID: 19082144]
(a)López-Ruiz, H.; de La Cerda-Pedro, J.E.; Rojas-Lima, S.; Pérez-Pérez, I.; Rodríguez-Sánchez, B.V.; Santillan, R.; Coreño, O. Cuprous oxide on charcoal-catalyzed ligand-free synthesis of 1, 4-disubstituted 1, 2, 3-triazoles via click chemistry. ARKIVOC, 2013, 3, 139-164.
(b)Rostovtsev, V.V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew. Chem. Int. Ed. Engl., 2002, 41(14), 2596-2599.
[http://dx.doi.org/10.1002/1521-3773(20020715)41:14<2596:AID-ANIE25 96>3.0.CO;2-4] [PMID: 12203546]
Li, Z.; Seo, T.S.; Ju, J. 1, 3-Dipolar cycloaddition of azides with electron-deficient alkynes under mild condition in water. Tetrahedron Lett., 2004, 45(15), 3143-3146.
Xu, J.; Filion, T.M.; Prifti, F.; Song, J. Cytocompatible poly(ethylene glycol)-co-polycarbonate hydrogels cross-linked by copper-free, strain-promoted click chemistry. Chem. Asian J., 2011, 6(10), 2730-2737.
[http://dx.doi.org/10.1002/asia.201100411] [PMID: 21954076]
(a)Matsuoka, M.; Jeang, K-T. Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation. Nat. Rev. Cancer, 2007, 7(4), 270-280.
[http://dx.doi.org/10.1038/nrc2111] [PMID: 17384582]
(b)Kitada, S.; Leone, M.; Sareth, S.; Zhai, D.; Reed, J.C.; Pellecchia, M. Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins. J. Med. Chem., 2003, 46(20), 4259-4264.
[http://dx.doi.org/10.1021/jm030190z] [PMID: 13678404]
(c)Soman, G.; Yang, X.; Jiang, H.; Giardina, S.; Vyas, V.; Mitra, G.; Yovandich, J.; Creekmore, S.P.; Waldmann, T.A.; Quiñones, O.; Alvord, W.G. MTS dye based colorimetric CTLL-2 cell proliferation assay for product release and stability monitoring of interleukin-15: assay qualification, standardization and statistical analysis. J. Immunol. Methods, 2009, 348(1-2), 83-94.
[http://dx.doi.org/10.1016/j.jim.2009.07.010] [PMID: 19646987]
(a)Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
(b)Lappalainen, K.; Jääskeläinen, I.; Syrjänen, K.; Urtti, A.; Syrjänen, S. Comparison of cell proliferation and toxicity assays using two cationic liposomes. Pharm. Res., 1994, 11(8), 1127-1131.
[http://dx.doi.org/10.1023/A:1018932714745] [PMID: 7971713]
Moosa, B.A.; Sagar, S.; Li, S.; Esau, L.; Kaur, M.; Khashab, N.M. Synthesis and anticancer evaluation of spermatinamine analogues. Bioorg. Med. Chem. Lett., 2016, 26(6), 1629-1632.
[http://dx.doi.org/10.1016/j.bmcl.2016.01.083] [PMID: 26874403]
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
Sebastián-Pérez, V.; Roca, C.; Awale, M.; Reymond, J-L.; Martinez, A.; Gil, C.; Campillo, N.E. Medicinal and Biological Chemistry (MBC) library: An efficient source of new hits. J. Chem. Inf. Model., 2017, 57(9), 2143-2151.
[http://dx.doi.org/10.1021/acs.jcim.7b00401] [PMID: 28813151]
Lipinski, C.A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods, 2000, 44(1), 235-249.
[http://dx.doi.org/10.1016/S1056-8719(00)00107-6] [PMID: 11274893]
(a)Baguley, B.C.; Le Bret, M. Quenching of DNA-ethidium fluorescence by amsacrine and other antitumor agents: a possible electron-transfer effect. Biochemistry, 1984, 23(5), 937-943.
[http://dx.doi.org/10.1021/bi00300a022] [PMID: 6546881]
(b)Hinds, M.; Deisseroth, K.; Mayes, J.; Altschuler, E.; Jansen, R.; Ledley, F.D.; Zwelling, L.A. Identification of a point mutation in the topoisomerase II gene from a human leukemia cell line containing an amsacrine-resistant form of topoisomerase II. Cancer Res., 1991, 51(17), 4729-4731.
[PMID: 1651812]
Connors, T. Prodrugs in cancer chemotherapy. In: Enzyme-Prodrug Strategies for Cancer Therapy; Melton, R.G.; Knox, R.J., Eds.; Springer: Boston, MA, 1999; pp. 11-37.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [900 - 912]
Pages: 13
DOI: 10.2174/1570179416666190704112904
Price: $58

Article Metrics

PDF: 16