title: 5-substituted analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en- 1-ol (EO9, NSC 382459) and their regioisomers as hypoxia-selective agents: structure-cytotoxicity in vitro.
abstract: A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en-1 -ol (EO9, NSC 382459) with the hydroxymethyl and hydroxypropenyl substituents situated at either the 2- or the 3-position of the indole ring were synthesized. The compound lacking the 2-hydroxypropenyl substituent (31) had similar properties to EO9 under both aerobic and hypoxic conditions against V79 cells and was more potent against a human tumour cell line (A549) than EO9. It was reduced by human DT-diaphorase (DTD) at more than double the rate of EO9, thus implicating the importance of the enzyme activation step. Compound 16 (lacking the 3-hydroxymethyl substituent) was a better substrate for human DTD than EO9, yet exhibited lesser toxicity under both aerobic and hypoxic conditions. The toxicity generated by 16 was attributed to the 5-aziridinyl moiety and suggests a greater contribution from the 3-substituent over the 2-substituent. The toxicity of EO9 was attributed to a combination of the aziridinyl group and the leaving group properties of the 3-hydroxymethyl substituent. In general, compounds with a 5-methylaziridinyl moiety, such as EO8, exhibited substantially better hypoxia-selectivity due to much slower reduction by DTD (20-fold), thus reducing aerobic potency. All compounds had similar electron affinities, as indicated by their one-electron reduction potentials.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jaffar
authors.forename: M A
authors.initials: MA
authors.lastname: Naylor
authors.forename: N
authors.initials: N
authors.lastname: Robertson
authors.forename: S D
authors.initials: SD
authors.lastname: Lockyer
authors.forename: R M
authors.initials: RM
authors.lastname: Phillips
authors.forename: S A
authors.initials: SA
authors.lastname: Everett
authors.forename: G E
authors.initials: GE
authors.lastname: Adams
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000332:Aerobiosis; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001388:Aziridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D015687:Cell Hypoxia; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D045563:Indolequinones; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D016660:NAD(P)H Dehydrogenase (Quinone); C060817:apaziquone