title: Hypoxia-selective antitumor agents. 5. Synthesis of water-soluble nitroaniline mustards with selective cytotoxicity for hypoxic mammalian cells.
abstract: Nitroaniline mustards have potential as hypoxia-selective cytotoxic agents, with reductive metabolism activating the nitrogen mustard by converting the electron-withdrawing nitro group to an electron-donating hydroxylamine or amine. However, the parent compounds have poor aqueous solubility, and their potencies are limited by low reduction potentials (E1/2 ca. -600 mV versus the normal hydrogen electrode) and corresponding slow rates of nitro reduction. To address these limitations, a series of 4-nitroaniline mustards bearing hydrophilic side chains attached via an electron-withdrawing carboxamide group was prepared and evaluated for hypoxia-selective cytotoxicity against Chinese hamster cell lines. The N-[(N,N-dimethylamino)ethyl]carboxamide derivatives proved to have excellent aqueous solubility and improved cytotoxic potency, but their reduction potentials, while higher than the non-carboxamide compounds, were still low and little selectivity for hypoxic cells were observed. A series of carboxamides of 2,4-dinitroaniline mustard was also prepared. These compounds had reduction potentials in the desired range (E1/2 ca. -450 mV by cyclic voltammetry) and were more toxic to hypoxic than aerobic UV4 cells. The most selective compounds were 5-[N,N-bis(2-chloroethyl)amino]-2,4-dinitrobenzamide (20, SN 23862) and its water-soluble N-[(N,N-dimethylamino)ethyl]carboxamide analogue. These showed selectivities of 60- to 70-fold for hypoxic UV4 cells. The selectivity of 20 was much superior to that of its aziridine analogue (23, CB 1954), which was only 3.6-fold more toxic to hypoxic than oxic cells in the same system. Compound 20 is a much less efficient substrate than CB 1954 for the major aerobic nitroreductase from rat Walker tumor cells, NAD(P)H:quinone oxidoreductase (DT diaphorase). Lack of aerobic bioactivation of 20 by DT diaphorases may be responsible for its higher hypoxic selectivity than that of 23.
authors.affiliation: Cancer Research Laboratory, 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: S
authors.initials: S
authors.lastname: Cliffe
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry*; D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D006801:Humans; D015394:Molecular Structure; D009150:Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014867:Water
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009150:Mustard Compounds; D014867:Water; C076205:5-(N,N-bis(2-chloroethyl)amino)-2,4-dinitrobenzamide; C076206:N-((N,N-dimethylamino)ethyl)-5-(N,N-bis(2-chloroethyl)amino)-2,4-dinitrobenzamide; C019498:4-nitroaniline; D000816:Aniline Mustard; D016660:NAD(P)H Dehydrogenase (Quinone); D010100:Oxygen