PABA/NO as an anticancer lead: analogue synthesis, structure revision, solution chemistry, reactivity toward glutathione, and in vitro activity.
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.
Saavedra
Joseph E
JE
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.
Srinivasan
Aloka
A
Buzard
Gregory S
GS
Davies
Keith M
KM
Waterhouse
David J
DJ
Inami
Keiko
K
Wilde
Thomas C
TC
Citro
Michael L
ML
Cuellar
Matthew
M
Deschamps
Jeffrey R
JR
Parrish
Damon
D
Shami
Paul J
PJ
Findlay
Victoria J
VJ
Townsend
Danyelle M
DM
Tew
Kenneth D
KD
Singh
Shivendra
S
Jia
Lee
L
Ji
Xinhua
X
Keefer
Larry K
LK
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
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