{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T10:12:07Z","timestamp":1774779127854,"version":"3.50.1"},"reference-count":98,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014000","name":"Masonic Charitable Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014000","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Temozolomide and dacarbazine are untargeted anticancer prodrugs that have been widely employed in the treatment of melanoma and glioblastoma. These agents decompose into a short-lived monomethyl triazene intermediate, culminating in the release of a methyl diazonium cation that serves as the DNA-alkylating species responsible for tumour destruction. However, due to their high chemical lability, these agents have been associated with chemotherapy resistance, mutagenicity, tumour relapse, and significant off-target toxicity. One promising strategy towards the resolution of these limitations involves the design of arylmethyl triazene prodrugs, which enable targeted tumour-specific drug delivery. This review explores the various approaches used to selectively deliver alkyl aryl triazenes as alternatives to current therapies. It highlights early chemical strategies such as N-acylation and etherification of monomethyl triazenes, along with associated kinetic studies. The selective activation of novel triazenes in murine and human melanoma cells through a tyrosinase-responsive promoiety is discussed. Recent progress in nitroaromatic-based prodrugs designed to exploit the hypoxic microenvironment of glioblastoma is also examined. Additionally, we summarise the development of combi-triazenes and their underlying chemistries, which enable the simultaneous release of two active therapeutic agents.<\/jats:p>","DOI":"10.3390\/molecules31071103","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T11:32:47Z","timestamp":1774611167000},"page":"1103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploiting Methyl Triazenes as Attractive Alternatives to Temozolomide and Dacarbazine for Cancer Therapy"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5097-4933","authenticated-orcid":false,"given":"Goreti","family":"Ribeiro Morais","sequence":"first","affiliation":[{"name":"Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4258-1708","authenticated-orcid":false,"given":"Gabriel C.","family":"Nwokolo","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harriet N. L.","family":"Lamptey Mills","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2250-3384","authenticated-orcid":false,"given":"Richard T.","family":"Wheelhouse","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6426-4430","authenticated-orcid":false,"given":"Robert A.","family":"Falconer","sequence":"additional","affiliation":[{"name":"Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3243","DOI":"10.1016\/0006-2952(86)90419-3","article-title":"In vivo metabolism and reaction with dna of the cytostatic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC)","volume":"35","author":"Meer","year":"1986","journal-title":"Biochem. Pharmacol."},{"key":"ref_2","first-page":"5846","article-title":"Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine","volume":"47","author":"Stevens","year":"1987","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.phrs.2007.08.003","article-title":"Triazene compounds: Mechanism of action and related DNA repair systems","volume":"56","author":"Marchesi","year":"2007","journal-title":"Pharmacol. Res."},{"key":"ref_4","first-page":"34","article-title":"Current therapy for malignant melanoma","volume":"16","author":"Legha","year":"1989","journal-title":"Semin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Szklener, K., Mazurek, M., Wieteska, M., Wac\u0142awska, M., Bilski, M., and Ma\u0144dziuk, S. (2022). New Directions in the Therapy of Glioblastoma. Cancers, 14.","DOI":"10.3390\/cancers14215377"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/0959-8049(92)90132-L","article-title":"Phase II study of mitozolomide in advanced soft tissue sarcoma of adults: The EORTC Soft Tissue and Bone Sarcoma Group","volume":"28","author":"Somers","year":"1992","journal-title":"Eur. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s11060-007-9403-6","article-title":"Prolonged and severe myelosuppression in two patients after low-dose temozolomide treatment- case study and review of literature","volume":"85","author":"Singhal","year":"2007","journal-title":"J. Neuro-Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104148","DOI":"10.1016\/j.xphs.2025.104148","article-title":"Photodegradation of dacarbazine irradiated by common lighting sources: An examination of the differences between light-emitting diode (LED) and fluorescent light","volume":"115","author":"Takayama","year":"2026","journal-title":"J. Pharm. Sci."},{"key":"ref_9","first-page":"2192","article-title":"Metabolic Activation of Dacarbazine by Human Cytochromes P450: The Role of CYP1A1, CYP1A2, and CYP2E1","volume":"5","author":"Reid","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1016\/0006-2952(72)90384-X","article-title":"Mechanism of action of 5-(3,3-dimethyl-1-triazeno)imidazole-4-caboxamide in mammalian cells in culture","volume":"21","author":"Gerulath","year":"1972","journal-title":"Biochem. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/bjc.1992.57","article-title":"Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856)","volume":"65","author":"Newlands","year":"1992","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0006-2952(76)90207-0","article-title":"Tumour inhibitory triazenes: Structural requirements for an active metabolite","volume":"25","author":"Connors","year":"1976","journal-title":"Biochem. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1139\/v77-240","article-title":"Open-chain nitrogen compounds. Part II. Preparation, characterization, and degradation of 1(3)-Aryl-3(1)-methyltriazenes; the effect of substituents on the reaction of diazonium salts with methylamine","volume":"55","author":"Ahern","year":"1977","journal-title":"Can. J. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0040-6031(93)80188-G","article-title":"Decomposition of aromatic diazonium compounds","volume":"225","author":"Ullrich","year":"1993","journal-title":"Thermochim. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1021\/jo01323a048","article-title":"Alkyl nitrite-metal halide deamination reactions. 6. Direct synthesis of arenediazonium tetrafluoroborate salts from aromatic amines, tert-butyl nitrite, and boron trifluoride etherate in anhydrous media","volume":"44","author":"Doyle","year":"1979","journal-title":"J. Org. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/anie.201408597","article-title":"Synthesis of Triazenes with Nitrous Oxide","volume":"54","author":"Kiefer","year":"2015","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1021\/acs.orglett.8b01214","article-title":"One-Pot Synthesis of Trisubstituted Triazenes from Grignard Reagents and Organic Azides","volume":"20","author":"Suleymanov","year":"2018","journal-title":"Org. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10471","DOI":"10.1021\/acs.orglett.5c03329","article-title":"Base-Promoted Synthesis of Triazenes via Formal Substitution of Arylazo Sulfones with Amines","volume":"27","author":"Zhang","year":"2025","journal-title":"Org. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1021\/jo00829a032","article-title":"Thermal decomposition of benzenediazo sulfones. II. Benzyl benzenediazo sulfone","volume":"35","author":"Kice","year":"1970","journal-title":"J. Org. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1039\/p29920000223","article-title":"Triazene drug metabolites. Part 12. Base catalysed formation of 3-alkyl-1-aryltriazenes from 3-alkyl-3-hydroxymethyl-1-aryltriazenes","volume":"2","author":"Iley","year":"1992","journal-title":"J. Chem. Soc. Perkin Trans. 2"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Fernandes, L., Francisco, A.P., Iley, J., and Rosa, E. (1994). Triazene drug metabolites. Part 14. Kinetics and mechanism of the acid-catalysed hydrolysis of 3-alkoxymethyl-3-alkyl-1-aryltriazenes. J. Chem. Soc. Perkin Trans. 2, 2313\u20132317.","DOI":"10.1039\/p29940002313"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1002\/ejoc.200400582","article-title":"The Mechanism of Hydrolysis of Aryl Ether Derivatives of3-Hydroxymethyltriazenes","volume":"2005","author":"Carvalho","year":"2005","journal-title":"Eur. J. Org. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Iley, J., Moreira, R., and Rosa, E. (1991). Triazene drug metabolites. Part 11. Synthesis of S-cysteinyl and related derivatives of N-hydroxymethyltriazenes. J. Chem. Soc. Perkin Trans. 1, 3241\u20133244.","DOI":"10.1039\/p19910003241"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1139\/v84-125","article-title":"Open-chain nitrogen compounds. Part V. Hydroxymethyltriazenes: Synthesis of some new alkyl homologues of the anti-tumour 3-methyl-3-hydroxymethyltriazenes and preparation of the derived acetoxymethyl-, benzoyloxymethyl-, and methoxymethyltriazenes","volume":"62","author":"Hemens","year":"1984","journal-title":"Can. J. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1139\/v88-391","article-title":"Open chain nitrogen compounds. XIII: 1-Aryl-3-arylthiomethyl-3-methyltriazenes and 3-(arylazo)-1,3-thiazolidines","volume":"66","author":"Vanghan","year":"1988","journal-title":"Can. J. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1139\/v92-024","article-title":"Open-chain nitrogen compounds. Part XIV. Synthesis of 1-aryl-3-aryloxymethyl-3-methyltriazenes and 1-aryl-3-(hydroxyaryl)methyl-3-methyltriazenes","volume":"70","author":"Merrin","year":"1992","journal-title":"Can. J. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Carvalho, E., Iley, J., and Rosa, E. (1993). Triazene drug metabolites. Part 13. The decomposition of 3-acyl-3-alkyl-1-aryltriazenes in aqueous sulfuric acid. J. Chem. Soc. Perkin Trans. 2, 865\u2013870.","DOI":"10.1039\/p29930000865"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Iley, J.N., Moreira, R., and Rosa, E. (1987). Triazene drug metabolites. Part 4. Kinetics and mechanism of the decomposition of 1-aryl-3-benzoyloxymethyl-3-methyltriazenes in mixed aqueous\u2013organic solvents. J. Chem. Soc. Perkin Trans. 2, 1503\u20131508.","DOI":"10.1039\/P29870001503"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.ejmech.2008.06.022","article-title":"Towards an efficient prodrug of the alkylating metabolite monomethyltriazene: Synthesis and stability of N-acylamino acid derivatives of triazenes","volume":"44","author":"Perry","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1023\/A:1011988918476","article-title":"Triazene Drug Metabolites: Part 15. Synthesis and Plasma Hydrolysis of Anticancer Triazenes Containing Amino Acid Carriers","volume":"15","author":"Carvalho","year":"1998","journal-title":"Pharm. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1016\/S0968-0896(00)00100-0","article-title":"Triazene drug metabolites. Part 17: Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes","volume":"8","author":"Carvalho","year":"2000","journal-title":"Bioorg. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/S0968-0896(01)00039-6","article-title":"Melanocyte-Directed enzyme prodrug therapy (MDEPT): Development of second generation prodrugs for targeted treatment of malignant melanoma","volume":"9","author":"Jordan","year":"2001","journal-title":"Bioorg. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1124\/pr.56.1.3","article-title":"Enzyme-Catalyzed Activation of Anticancer Prodrugs","volume":"56","author":"Rooseboom","year":"2004","journal-title":"Pharmacol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3228","DOI":"10.1016\/j.ejmech.2009.03.025","article-title":"Dopamine- and tyramine-based derivatives of triazenes: Activation by tyrosinase and implications for prodrug design","volume":"44","author":"Perry","year":"2009","journal-title":"Eur. J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ejmech.2013.09.040","article-title":"Synthesis and evaluation of N-acylamino acids derivatives of triazenes. Activation by tyrosinase in human melanoma cell lines","volume":"70","author":"Monteiro","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.1016\/j.bmc.2017.04.049","article-title":"The selective cytotoxicity of new triazene compounds to human melanoma cells","volume":"25","author":"Sousa","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cheng, S., and Iley, J. (1983). Synthesis of 1-aryl-3-methyltriazenes by base-promoted decomposition of 1-aryl-3-hydroxymethyl3-methyltriazenes. J. Chem. Res., 320\u2013321.","DOI":"10.1002\/chin.198410104"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1021\/acsmedchemlett.1c00252","article-title":"Sulfur Analogues of Tyrosine in the Development of Triazene Hybrid Compounds: A New Strategy against Melanoma","volume":"12","author":"Granada","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1016\/0006-2952(87)90501-6","article-title":"Mechanism of selective toxicity of 4-S-cysteinylphenol and 4-S-cysteaminylphenol to melanocytes","volume":"36","author":"Shosuke","year":"1987","journal-title":"Biochem. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S231","DOI":"10.1038\/jid.1993.82","article-title":"Exploitation of Pigment Biosynthesis Pathway as a Selective Chemotherapeutic Approach for Malignant Melanoma","volume":"100","author":"Jimbow","year":"1993","journal-title":"J. Investig. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"102811","DOI":"10.1016\/j.canep.2025.102811","article-title":"Adult glioblastoma in England: Incidence, treatment, and outcomes with novel population-based strata","volume":"97","author":"Mauricaite","year":"2025","journal-title":"Cancer Epidemiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3994","DOI":"10.3390\/curroncol31070296","article-title":"Temozolomide (TMZ) in the treatment of glioblastoma multiforme-a literature review and clinical outcomes","volume":"31","author":"Nafalska","year":"2024","journal-title":"Curr. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e00454","DOI":"10.1002\/prp2.454","article-title":"pH as a potential therapeutic target to improve temozolomide antitumor efficacy: A mechanistic modeling study","volume":"7","author":"Ballesta","year":"2019","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1023\/A:1015832726054","article-title":"Change of Oxygen Pressure in Glioblastoma Tissue Under Various Conditions","volume":"58","author":"Beppu","year":"2002","journal-title":"J. Neuro-Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1039\/D4MD00876F","article-title":"Nitroaromatic-based triazene prodrugs to target the hypoxic microenvironment in glioblastoma","volume":"16","author":"Braga","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/0360-3016(94)90432-4","article-title":"Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors","volume":"29","author":"Rampling","year":"1994","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/acschemneuro.6b00029","article-title":"Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery","volume":"7","author":"Wager","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16632","DOI":"10.1039\/D5CC04472C","article-title":"Nitrogen atom insertion into N=N double bonds: Straightforward access to triazenes","volume":"61","author":"Kumar","year":"2025","journal-title":"Chem. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.2174\/092986707781058805","article-title":"Molecular hybridization: A useful tool in the design of new drug prototypes","volume":"14","author":"Danuello","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1099\u22121111","DOI":"10.1517\/17460440903341705","article-title":"Promise and challenges in drug discovery and development of hybrid anticancer drugs","volume":"4","author":"Gediya","year":"2009","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/1878-0261.12155","article-title":"Emerging functions of the EGFR in cancer","volume":"12","author":"Sigismund","year":"2018","journal-title":"Mol. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Abourehab, M.A.S., Alqahtani, A.M., Youssif, B.G.M., and Gouda, A.M. (2021). Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism. Molecules, 26.","DOI":"10.3390\/molecules26216677"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/S0022-3565(24)38824-X","article-title":"Design of a chimeric 3-methyl-1,2,3-triazene with mixed receptor tyrosine kinase and DNA damaging properties: A novel tumor targeting strategy","volume":"296","author":"Matheson","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1124\/jpet.102.039099","article-title":"Inhibition of Epidermal Growth Factor Receptor-Mediated Signaling by \u201cCombi-Triazene\u201d BJ2000, a New Probe for Combi-Targeting Postulates","volume":"303","author":"Brahimi","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3482","DOI":"10.1021\/jm00018a008","article-title":"Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-(phenylamino)quinazolines as potent adenosine 5\u2032-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor","volume":"38","author":"Rewcastle","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/jlcr.713","article-title":"Synthesis of 1-[4-(m-tolyl)amino-6-quinazolinyl]-3-[14C]-methyl triazene: A radiolabeled probe for the combi-targeting concept","volume":"46","author":"Matheson","year":"2003","journal-title":"J. Label. Compd. Radiopharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.bcp.2003.10.035","article-title":"The combi-targeting concept: Intracellular fragmentation of the binary epidermal growth factor (EGFR)\/DNA targeting \u201ccombi-triazene\u201d SMA41","volume":"67","author":"Matheson","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00280-002-0525-4","article-title":"Differential responses of EGFR-\/AGT-expressing cells to the \u201ccombi-triazene\u201d SMA41","volume":"51","author":"Matheson","year":"2003","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5546","DOI":"10.1021\/jm030423m","article-title":"Synthesis of a Prodrug Designed To Release Multiple Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase and an Alkylating Agent: A Novel Tumor Targeting Concept","volume":"46","author":"Banerjee","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1021\/jm970641d","article-title":"Tyrosine Kinase Inhibitors. 14. Structure\u2212Activity Relationships for Methyl- amino-Substituted Derivatives of 4-[(3-Bromophenyl)amino]-6-(methylamino)- pyrido[3,4-d]pyrimidine (PD 158780), a Potent and Specific Inhibitor of the Tyrosine Kinase Activity of Receptors for the EGF Family of Growth Factors","volume":"41","author":"Rewcastle","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/sj.bjc.6602098","article-title":"Sustained antiproliferative mechanisms by RB24, a targeted precursor of multiple inhibitors of epidermal growth factor receptor and a DNA alkylating agent in the A431 epidermal carcinoma of the vulva cell line","volume":"91","author":"Banerjee","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4313","DOI":"10.1021\/jm030142e","article-title":"The Combi-Targeting Concept: Chemical Dissection of the Dual Targeting Properties of a Series of \u201cCombi-Triazenes\u201d","volume":"46","author":"Rachid","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Hemens, C.M., and Vaughan, K. (1986). Kinetic study of the solvolysis reactions of 1-aryl-3-acetoxymethyl-3-alkyltriazenes: Evidence for iminium ion intermediates and the SN1 mechanism. J. Chem. Soc. Perkin Trans. 2, 11\u201315.","DOI":"10.1039\/p29860000011"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/187231209787176344","article-title":"Molecular analysis of the in vivo metabolism and biodistribution of metabolically and non-metabolically activated combi-molecules of the triazene class","volume":"3","author":"Qiu","year":"2009","journal-title":"Drug Metab. Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5505","DOI":"10.1016\/j.bmcl.2009.05.060","article-title":"Design and synthesis of new stabilized combi-triazenes for targeting solid tumors expressing the epidermal growth factor receptor (EGFR) or its closest homologue HER2","volume":"19","author":"Rachid","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2174\/187231211795305212","article-title":"In vitro and in vivo biodistribution of ZRS1, a stabilized type I N-acetoxymethyl carbamate-containing combi-molecule","volume":"5","author":"Golabi","year":"2011","journal-title":"Drug Metab. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1124\/jpet.104.071977","article-title":"The Combi-Targeting Concept: Dissection of the Binary Mechanism of Action of the Combi-Triazene SMA41 in Vitro and Antitumor Activity in Vivo","volume":"311","author":"Matheson","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.bcp.2005.04.037","article-title":"Mechanism of action of a novel \u201ccombi-triazene\u201d engineered to possess a polar functional group on the alkylating moiety: Evidence for enhancement of potency","volume":"70","author":"Brahimi","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.bmcl.2004.12.015","article-title":"Synthesis of half-mustard combi-molecules with fluorescence properties: Correlation with EGFR status","volume":"15","author":"Rachid","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"19701","DOI":"10.1073\/pnas.0609580103","article-title":"The structural basis for the mutagenicity of O6-methyl-guanine lesions","volume":"103","author":"Warren","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/ijc.20383","article-title":"Multiple mechanisms of action of ZR2002 in human breast cancer cells: A novel combi-molecule designed to block signaling mediated by the ERB family of oncogenes and to damage genomic DNA","volume":"112","author":"Brahimi","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1021\/jm070144p","article-title":"Novel Nitrogen Mustard-Armed Combi-Molecules for the Selective Targeting of Epidermal Growth Factor Receptor Overexperessing Solid Tumors:\u2009 Discovery of an Unusual Structure\u2212Activity Relationship","volume":"50","author":"Rachid","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.leukres.2004.11.012","article-title":"Engineering 3-alkyltriazenes to block bcr-abl kinase: A novel strategy for the therapy of advanced bcr-abl expressing leukemias","volume":"29","author":"Katsoulas","year":"2005","journal-title":"Leuk. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1182\/blood.V114.22.2165.2165","article-title":"BCR-ABL Tyrosine Kinase Activity Modulates the Phosphorylation, Localization and Function of Interferon Regulatory Factor 5 (irf-5) in Chronic Myeloid Leukemia (CML) Cells","volume":"114","author":"Massimino","year":"2009","journal-title":"Blood"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1182\/blood.V97.7.1999","article-title":"In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents","volume":"97","author":"Kano","year":"2001","journal-title":"Blood"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1158\/1535-7163.MCT-07-0179","article-title":"Combi-targeting concept: An optimized single-molecule dual-targeting model for the treatment of chronic myelogenous leukemia","volume":"7","author":"Katsoulas","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"TPS4191","DOI":"10.1200\/JCO.2023.41.16_suppl.TPS4191","article-title":"Alliance A021804: A prospective, multi-institutional phase II trial evaluating temozolomide versus temozolomide and olaparib for advanced pheochromocytoma and paraganglioma","volume":"41","author":"Perez","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Senhaji Mouhri, Z., Goodfellow, E., Kelley, S.P., Stein, R.S., Rogers, R.D., and Jean-Claude, B.J. (2017). 15N-, 13C- and 1H-NMR Spectroscopy Characterization and Growth Inhibitory Potency of a Combi-Molecule Synthesized by Acetylation of an Unstable Monoalkyltriazene. Molecules, 22.","DOI":"10.3390\/molecules22071183"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Senhaji Mouhri, Z., Goodfellow, E., and Jean-Claude, B. (2017). A type I combi-targeting approach for the design of molecules with enhanced potency against BRCA1\/2 mutant- and O6-methylguanine-DNA methyltransferase (mgmt)- expressing tumour cells. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3504-1"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s12943-020-01227-0","article-title":"PARP inhibitor resistance: The underlying mechanisms and clinical implications","volume":"19","author":"Li","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Yu, W., Zhang, L., Wei, Q., and Shao, A. (2020). O6-Methylguanine-DNA Methyltransferase (MGMT): Challenges and New Opportunities in Glioma Chemotherapy. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01547"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6875","DOI":"10.1021\/jm049556d","article-title":"Synthesis and Antitumor Activity of Methyltriazene Prodrugs Simultaneously Releasing DNA-Methylating Agents and the Antiresistance Drug O6-Benzylguanine","volume":"47","author":"Wanner","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Wanner, M.J., and Koomen, G.J. (2002). A new synthesis of temozolomide. J. Chem. Soc. Perkin Trans. 1, 1877\u20131880.","DOI":"10.1039\/b205614c"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1021\/jm021074j","article-title":"N 6 -Cyclopentyl-2-(3-phenylaminocarbonyltriazene-1-yl)adenosine (TCPA), a Very Selective Agonist with High Affinity for the Human Adenosine A 1 Receptor","volume":"46","author":"Beukers","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"35004","DOI":"10.18632\/oncotarget.5253","article-title":"Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells","volume":"6","author":"Thotala","year":"2015","journal-title":"Oncotarget"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"987495","DOI":"10.1155\/2012\/987495","article-title":"Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells","volume":"2012","author":"Ryu","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1021\/acschemneuro.6b00169","article-title":"Targeting Gliomas: Can a New Alkylating Hybrid Compound Make a Difference?","volume":"8","author":"Pinheiro","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ejmech.2019.03.048","article-title":"Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability","volume":"172","author":"Braga","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1111\/cbdd.13776","article-title":"Expedient synthesis and anticancer evaluation of dual-action 9-anilinoacridine methyl triazene chimeras","volume":"97","author":"Walunj","year":"2021","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1039\/C8MD00384J","article-title":"Medicinal chemistry of acridine and its analogues","volume":"9","author":"Prasher","year":"2018","journal-title":"MedChemComm"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"101115","DOI":"10.1016\/j.jbior.2025.101115","article-title":"DNA intercalating drugs: Mechanisms of action in cancer treatment","volume":"98","author":"Oyeyode","year":"2025","journal-title":"Adv. Biol. Regul."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Varakumar, P., Rajagopal, K., Aparna, B., Raman, K., Byran, G., Lima, C.M.G., Rashid, S., Nafady, M.H., Emran, T.B., and Wybraniec, S. (2023). Acridine as an Anti-Tumour Agent: A Critical Review. Molecules, 28.","DOI":"10.3390\/molecules28010193"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.ejmech.2017.06.066","article-title":"Discovery of potent molecular chimera (CM358) to treat human metastatic melanoma","volume":"138","author":"Gilad","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"113811","DOI":"10.1016\/j.ejmech.2021.113811","article-title":"Targeted methylation facilitates DNA double strand breaks and enhances cancer suppression: A DNA intercalating\/methylating dual-action chimera Amonafidazene","volume":"225","author":"Walunj","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"102722","DOI":"10.1016\/j.pdpdt.2022.102722","article-title":"A novel, dual action chimera comprising DNA methylating agent and near-IR xanthene-cyanine photosensitizer for combined anticancer therapy","volume":"37","author":"Thankarajan","year":"2022","journal-title":"Photodiagn. Photodyn. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1002\/cmdc.201900464","article-title":"Peptide-Driven Targeted Drug-Delivery System Comprising Turn-On Near-Infrared Fluorescent Xanthene\u2013Cyanine Reporter for Real-Time Monitoring of Drug Release","volume":"14","author":"Ebaston","year":"2019","journal-title":"ChemMedChem"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"26982","DOI":"10.1021\/acsami.0c07471","article-title":"Activatable Photosensitizer for Smart Photodynamic Therapy Triggered by Reactive Oxygen Species in Tumor Cells","volume":"12","author":"Yuan","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"10607","DOI":"10.1038\/s41598-025-94373-8","article-title":"Novel dual action chimera doxorubizen demonstrates superior efficacy to doxorubicin in acute leukemia","volume":"15","author":"Walunj","year":"2025","journal-title":"Sci. Rep."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/7\/1103\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T04:14:56Z","timestamp":1774757696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/7\/1103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":98,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["molecules31071103"],"URL":"https:\/\/doi.org\/10.3390\/molecules31071103","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]}}}