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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Saavedra JE,Srinivasan A,Buzard GS,Davies KM,Waterhouse DJ,Inami K,Wilde TC,Citro ML,Cuellar M,Deschamps JR,Parrish D,Shami PJ,Findlay VJ,Townsend DM,Tew KD,Singh S,Jia L,Ji X,Keefer LK

doi

10.1021/jm050700k

keywords:

subject

Has Abstract

pub_date

2006-02-09 00:00:00

pages

1157-64

issue

3

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

杂志文章

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