High-Performance Liquid Chromatographic Studies of Reaction of Hydralazine with Biogenic Aldehydes and Ketones

O’Donnell, John P.; Proveaux, Woodrow J.; K.H., Joseph

doi:10.1002/jps.2600681216

Cited by 11 publications

(1 citation statement)

References 8 publications

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“…The compounds studied were: (i) aminoguanidine, a glycoxidation inhibitor which also scavenges malondialdehyde and 4hydroxy-2-nonenal; 7 (ii) the putative endogenous glycoxidation inhibitor carnosine, which may also trap malondialdehyde; 8 (iii) the classic carbonyl scavenger, methoxyamine; and (iv) the antihypertensive hydralazine, which acts as an aldehyde scavenger in vivo, forming hydrazones with a range of endogenous keto-acids. 9,10 Recent work indicates the highly toxic α,β-unsaturated aldehyde acrolein is formed during the peroxidation of polyunsaturated lipids, raising the possibility that it functions as a Ôtoxicological second messengerÕ during oxidative cell injury. Acrolein reacts rapidly with proteins, forming adducts that retain carbonyl groups.…”

Section: Introductionmentioning

confidence: 99%

The antihypertensive hydralazine is an efficient scavenger of acrolein

2000

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Recent work indicates the highly toxic alpha,beta-unsaturated aldehyde acrolein is formed during the peroxidation of polyunsaturated lipids, raising the possibility that it functions as a 'toxicological second messenger' during oxidative cell injury. Acrolein reacts rapidly with proteins, forming adducts that retain carbonyl groups. Damage by this route may thus contribute to the burden of carbonylated proteins in tissues. This work evaluated several amine compounds with known aldehyde-scavenging properties for their ability to attenuate protein carbonylation by acrolein. The compounds tested were: (i) the glycoxidation inhibitors, aminoguanidine and carnosine; (ii) the antihypertensive, hydralazine; and (iii) the classic carbonyl reagent, methoxyamine. Each compound attenuated carbonylation of a model protein, bovine serum albumin, during reactions with acrolein at neutral pH and 37 degrees C. However, the most efficient agent was hydralazine, which strongly suppressed carbonylation under these conditions. Study of the rate of reaction between acrolein and the various amines in a protein-free buffered system buttressed these findings, since hydralazine reacted with acrolein at rates 2-3 times faster than its reaction with the other scavengers. Hydralazine also protected isolated mouse hepatocytes against cell killing by allyl alcohol, which undergoes in situ alcohol dehydrogenase-catalysed conversion to acrolein.

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Section: Introductionmentioning

confidence: 99%

The antihypertensive hydralazine is an efficient scavenger of acrolein

2000

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Synergism through direct covalent bonding between agents: A strategy for rational design of chemotherapeutic combinations

et al. 1990

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Self-assembling chemotherapeutic agents are mixtures of relatively nontoxic precursors that can combine chemically under physiological conditions to form products with greater cytotoxic and/or antimicrobial activity than either of the precursors. Combinations that form products more rapidly in or near the target (tumor, pathogen, virally infected cell) than in normal tissues will exhibit target-selective synergism, thus exhibiting an antitarget selectivity that is greater than the selectivities of the product (e.g., a hydrazone) and of either precursor (e.g., a hydrazine derivative or ketone) used singly. This paper describes the target-selective cytotoxic synergism of a cationic aldehyde (A) and a cationic acylhydrazine (B) containing a triarylalkylphosphonium moiety against Ehrlich ascites carcinoma cells (ELA) in culture, in addition to reviewing previous work on self-assembling cytotoxins. The synergism between A and B is carcinoma selective when the ELA cells (the target) are compared to CV-1, an untransformed African green monkey kidney epithelial line. Like tetraphenylphosphonium and rhodamine 123, which are selectively concentrated in ELA cells relative to CV-1, A, B and the hydrazone C resulting from their reaction are lipophilic delocalized cations that selectively inhibit ELA growth relative to CV-1 growth. The hydrazone C is more growth inhibitory than either A or B for both cell lines. A combination of A with an unreactive analogue of B and a combination of B with an unreactive analogue of A did not synergistically inhibit ELA proliferation. The degree of synergism is greater against the ELA cells than against the CV-1 cells. These data, together with hydrazone formation kinetics, suggest that A and B are both concentrated together selectively inside the ELA due to the transmembrane potentials, reacting inside the ELA cells at a higher velocity than inside the CV-1 cells to form the more growth-inhibitory hydrazone C.

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