title: PABA/NO as an anticancer lead: analogue synthesis, structure revision, solution chemistry, reactivity toward glutathione, and in vitro activity.
abstract: PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in water. Here we report structure-based optimization efforts resulting in three analogues with improved solubility and stability in aqueous solution. We sought to explain PABA/NO's physicochemical uniqueness among these four compounds, whose aminobenzoic acid precursors differ structurally only in the presence or absence of the N-methyl group and/or the position of the carboxyl moiety (meta or para). Studies revealed that PABA/NO's N-methyl-p-aminobenzoic acid substituent is bound to the dinitrobenzene ring via its carboxyl oxygen while the other three are linked through the aniline nitrogen. This constitutes a revision of the previously published PABA/NO structure. All four analogues reacted with GSH to produce bioactive nitric oxide (NO), but PABA/NO was the most reactive. Consistent with PABA/NO's potent suppression of A2780 human ovarian cancer xenograft growth in mice, it was the most potent of the four in the OVCAR-3 cell line.
authors.affiliation: Basic Research Program, SAIC Frederick, Chemistry Section, Laboratory of Comparative Carcinogenesis, and Biomolecular Structure Section, Macromolecular Crystallography Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Aloka
authors.initials: A
authors.lastname: Srinivasan
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Buzard
authors.forename: Keith M
authors.initials: KM
authors.lastname: Davies
authors.forename: David J
authors.initials: DJ
authors.lastname: Waterhouse
authors.forename: Keiko
authors.initials: K
authors.lastname: Inami
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Wilde
authors.forename: Michael L
authors.initials: ML
authors.lastname: Citro
authors.forename: Matthew
authors.initials: M
authors.lastname: Cuellar
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Damon
authors.initials: D
authors.lastname: Parrish
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shami
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Findlay
authors.forename: Danyelle M
authors.initials: DM
authors.lastname: Townsend
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Tew
authors.forename: Shivendra
authors.initials: S
authors.lastname: Singh
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
authors.forename: Xinhua
authors.initials: X
authors.lastname: Ji
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
mesh_terms: D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009569:Nitric Oxide / Q000138:chemical synthesis; D012995:Solubility; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D062366:para-Aminobenzoates
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; C485370:O(2)-(2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino)phenyl 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate; D062366:para-Aminobenzoates; D009569:Nitric Oxide; D005978:Glutathione; D010129:4-Aminobenzoic Acid