title: Hypoxia-selective antitumor agents. 14. Synthesis and hypoxic cell cytotoxicity of regioisomers of the hypoxia-selective cytotoxin 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide.
abstract: A series of regioisomers of the novel hypoxia-selective cytotoxin (HSC) 5-[N,N-bis(2-chloroethyl)-amino]-2,4-dinitrobenzamide (2a) have been prepared by displacement of the chloro group from methyl chlorodinitrobenzoates or the corresponding carboxamides with diethanolamine, followed by dimesylation and mesylate displacement with LiCl. The compounds fall into two classes, where the two nitro groups have either a meta or an ortho (or para) disposition to each other. The four meta derivatives had one-electron reduction potentials in the range -340 to -375 mV, similar to that of the known isomer 2a, while the other isomers had much higher values (-262 to -285 mV). The meta derivatives were much less cytotoxic to AA8 cells under aerobic conditions (IC50s from 75 to 470 microM) than were the other compounds (IC50s from 1.6 to 20 microM). However, the ratios of IC50s of the compounds in repair-proficient (AA8) and repair-deficient (UV4) cell lines varied, indicating differing contributions of DNA alkylation to aerobic toxicity between the isomers, with no clear relationship between this and nitro group disposition. The hypoxic selectivities of the (dimethylamino)ethylcarboxamide analogues for each isomer were determined by clonogenic assay against both AA8 and UV4 cells. With one exception, the meta derivatives showed excellent hypoxic selectivities (ca. 45-115-fold) against UV4 cells, while the ortho or para isomers had little selectivity (ca. 2-7-fold). A possible reason may be that the latter compounds, with higher reduction potentials, undergo rapid bioreduction even under aerobic conditions. None showed hypoxic selectivities greater than 2-3-fold against AA8 cells. The 3-[N,N-bis(2-chloroethyl)amino]-2,6-dinitrobenzamide isomer (5b), which showed the highest hypoxic selectivity for UV4 cells in this series, was active against both hypoxic and aerobic cells in KHT tumors in mice at well-tolerated doses, and showed superior in vivo activity to the previously studied 2,4-dinitro isomer 2b.
authors.affiliation: Department of Pathology, University of Auckland School of Medicine, New Zealand.
authors.forename: B D
authors.initials: BD
authors.lastname: Palmer
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
authors.forename: R F
authors.initials: RF
authors.lastname: Anderson
authors.forename: M
authors.initials: M
authors.lastname: Boyd
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C076205:5-(N,N-bis(2-chloroethyl)amino)-2,4-dinitrobenzamide; D000816:Aniline Mustard