title: Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents.
abstract: The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.
authors.affiliation: Department of Medicinal Chemistry, Dagenham Research Centre, Rhône-Poulenc Ltd., Essex, U.K.
authors.forename: K R
authors.initials: KR
authors.lastname: Horspool
authors.forename: M F
authors.initials: MF
authors.lastname: Stevens
authors.forename: C G
authors.initials: CG
authors.lastname: Newton
authors.forename: E
authors.initials: E
authors.lastname: Lunt
authors.forename: R J
authors.initials: RJ
authors.lastname: Walsh
authors.forename: B L
authors.initials: BL
authors.lastname: Pedgrift
authors.forename: G U
authors.initials: GU
authors.lastname: Baig
authors.forename: F
authors.initials: F
authors.lastname: Lavelle
authors.forename: C
authors.initials: C
authors.lastname: Fizames
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D008808:Mice, Inbred CBA; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; C063787:3-(2-chloroethyl)-4-oxo-3H-imidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxylic acid; C040369:mitozolomide