title: Preparation and antitumour properties of the enantiomers of a hypoxia-selective nitro analogue of the duocarmycins.
abstract: Racemic 2-{[1-(chloromethyl)-5-nitro-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}aminoethyl dihydrogen phosphate, a synthetic nitro derivative of the duocarmycins, is a hypoxia-selective prodrug active against radiation-resistant tumour cells at nontoxic doses in mice. An intermediate in the synthesis of this prodrug was resolved by chiral HPLC and the absolute configuration assigned by X-ray crystallography. The intermediate was used to prepare the prodrug's enantiomers, and also the enantiomers of the active nitro and amino metabolites. In vitro analysis in the human cervical carcinoma cell line SiHa showed that both nitro enantiomers are hypoxia-selective cytotoxins, but the "natural" S enantiomer is at least 20-fold more potent. Examination of extracellular amino metabolite concentrations demonstrated no enantioselectivity in the hypoxia-selective reduction of nitro to amino. Low levels of amino derivative were also found in aerobic cell suspensions, sufficient to account for the observed oxic toxicity of the nitro form. At an equimolar dose in SiHa-tumour bearing animals, the (-)-R enantiomer of the prodrug was inactive, while the (+)-S enantiomer caused significantly more hypoxic tumour cell kill than the racemate. At this dose, the combination of (+)-S-prodrug and radiation eliminated detectable colony-forming cells in four out of five treated tumour-bearing animals.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. m.tercel@auckland.ac.nz
authors.forename: Moana
authors.initials: M
authors.lastname: Tercel
authors.forename: Ho H
authors.initials: HH
authors.lastname: Lee
authors.forename: Shangjin
authors.initials: S
authors.lastname: Yang
authors.forename: H D Sarath
authors.initials: HD
authors.lastname: Liyanage
authors.forename: Sunali Y
authors.initials: SY
authors.lastname: Mehta
authors.forename: Peter D W
authors.initials: PD
authors.lastname: Boyd
authors.forename: Jagdish K
authors.initials: JK
authors.lastname: Jaiswal
authors.forename: Karin L
authors.initials: KL
authors.lastname: Tan
authors.forename: Frederik B
authors.initials: FB
authors.lastname: Pruijn
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology; D011839:Radiation, Ionizing; D013237:Stereoisomerism; D014183:Transplantation, Heterologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011760:Pyrrolidinones; C058289:duocarmycin A