5′-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls

Abstract

Pyridoxamine (PM) is a prospective drug for treatment of diabetic complications. In order to make zwitterionic PM more lipophilic and improve its tissue distribution, PM derivatives containing medium length alkyl groups on the hydroxymethyl side-chain were prepared. The synthesis of these alkylpyridoxamines (alkyl-PMs) starting from pyridoxine offers high yields and is amenable to bulk preparations. Interestingly, alkyl-PMs were found to react with methylglyoxal (MGO), a major toxic product of glucose metabolism and autoxidation, several orders of magnitude faster than PM. This suggests the formation of non-ionic pyrido-1,3-oxazine as the key step in the reaction of PM with MGO. Since the primary target of MGO in proteins is the guanidine side-chain of arginine, alkyl-PMs were shown to be more effective than PM in reducing modification of N-α-benzoylarginine by MGO. Alkyl-PMs in the presence of MGO also protected the enzymatic activity of lysozyme that contains several arginine residues next to its active site. Alkyl-PMs can be expected to trap MGO and other toxic 1,2-carbonyl compounds more effectively than PM, especially in lipophilic tissue environments, thus protecting macromolecules from functional damage. This suggests potential therapeutic uses for alkyl-PMs in diabetes and other diseases characterized by the elevated levels of toxic dicarbonyl compounds.

The anticancer natural product ophiobolin A induces cytotoxicity by covalent modification of phosphatidylethanolamine

“…Incubation of the reaction product of OPA and ethanolamine with Ehrlich's reagent ( Amarnath et al, 2004 ) yielded a purple solution (A max = 580 nm), characteristic of pyrroles ( Figure 3e ). Addition of salicylamine and pentyl-pyridoxamine, potent scavengers of 1,4-dicarbonyls, to OPA led to its inactivation at concentrations 30- and 300-fold lower than for ethanolamine, consistent with the known kinetics of these scavengers in Paal-Knorr reactions ( Amarnath et al, 2004 , 2015 ) ( Figure 3—figure supplement 1e ). These findings, together with the results from the OPA inactivation assays, are consistent with OPA reacting with PE according to a Paal-Knorr reaction mechanism ( Figure 3f and Figure 3—figure supplement 2 ).…”

“…Phospholipids were from Sigma-Aldrich (PE, chicken egg; PC, chicken egg; PS, bovine brain) and from Avanti Polar Lipids (Alabaster, AL) (transphosphatidylated PE, chicken egg; PE, porcine brain; DOPE; DOPC; DOPS). Salicylamine and pentyl-pyridoxamine were a kind gift of V. Amarnath (Vanderbilt) ( Amarnath et al, 2004 , 2015 ). Stock solutions, unless otherwise mentioned, were prepared in DMSO (99.9%) at 500× concentration to yield a final concentration of 0.2% DMSO.…”

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

“…Another recently developed drug is pyridoxamine, which has prevented ECM thickening, adipose tissue fibrosis, activation of apoptotic pathways during heart ischemia and glucose intolerance in obese mice, through decreased AGE formation and accumulation . Pyridoxamine analogs were also recently shown to be potent dicarbonyl scavengers . NAC is a clinically approved drug with antioxidant properties, which is known as an MG scavenger and inhibitor of ROS formation both in vitro and in vivo .…”

4-oxo-2-nonenal Adducts In HDL Are Elevated In Familial Hypercholesterolemia: Identification Of Modified Sites And Functional Consequences

“…ONE was diluted as a 10 mM stock solutions in DMSO in aliquots and stored in -80ºC until use. Acetic acid salts of salicylamine (SAM), 5-chlorosalicylamine (Cl-SAM), 5-fluorosalicylamine (F-SAM), and the hydrochloride salt of 5'-Opentylpyridoxamine (PPM) were synthesized as described (53,54). Working solutions were prepared fresh before each assay and diluted in water to appropriate concentrations.…”