title: Hypoxia-selective antitumor agents. 10. bis(nitroimidazoles) and related Bis(nitroheterocycles): development of derivatives with higher rates of metabolic activation under hypoxia and improved aqueous solubility.
abstract: A series of analogues of the previously described compound N-[2-(2-methyl-5-nitroimidazol-1H-yl)ethyl]-4-(2-nitroimidazol- 1H-yl)butanamide (4), a novel hypoxic cell cytotoxin and radiosensitizer, have been prepared and evaluated for hypoxia-selective cytotoxicity and hypoxic cell radiosensitization in vitro. The new derivatives were designed to overcome the low aqueous solubility of 4 and its slow kinetics of killing under hypoxia. The nitroheterocycle unit had a significant effect on solubility, with 3-nitrotriazoles being about 6-fold more soluble than the corresponding 2-nitroimidazoles. Analogues with a range of neutral linker chains (polyhydroxy, alkanesulfonamide, and bisamide) showed only slightly improved solubility and were unable to be fully evaluated. However, a series of analogues with cationic amine linkers had adequate aqueous solubility (up to 280 mM). The amine analogues could not be prepared by direct reduction of precursor amides such as 4 and were most conveniently synthesized by aza-Wittig condensation of the appropriate azide and aldehyde components. The amine-linked compounds were more cytotoxic than 4, with the symmetrical bis(2-nitroimidazole) derivatives (13 and 14) up to 9-fold more potent. They showed hypoxic selectivities comparable to that of 4 (ca. 200-fold) but had much more rapid kinetics of killing under hypoxia, resulting in high hypoxic selectivity at early times in culture. The nature of the mechanism of cytotoxicity of these compounds remains unclear but appears not to be DNA cross-linking, with the compounds showing a lack of hypersensitivity toward repair-deficient UV4 cells. The enhanced solubility and hypoxia-selective cytotoxicity (at early times) of 13 compared with 4 represent significant potential advantages.
authors.affiliation: Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
authors.forename: M P
authors.initials: MP
authors.lastname: Hay
authors.forename: H H
authors.initials: HH
authors.lastname: Lee
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
authors.forename: P B
authors.initials: PB
authors.lastname: Roberts
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001711:Biotransformation; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D003412:Cricetulus; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D014867:Water; D010100:Oxygen