Structural effects of N‐aromatic acyl‐amino acid conjugates on their deconjugation in the cecal contents of rats: implication in design of a colon‐specific prodrug with controlled conversion rate at the target site

Abstract

N-aromatic acyl-amino acid conjugates possess a colon-targeted property, implying that such conjugates are stable and are not absorbable until reaching the large intestine in which they are microbially converted (hydrolysed) to the parent drugs that are therapeutically active. To investigate the structural effect of N-aromatic acyl-amino acid conjugates on the large intestinal deconjugation, the hydrolysis of various N-aromatic acyl-amino acid conjugates was examined in the cecal contents. On incubation of conjugates with glycine, D or/and L forms of alanine or phenylalanine in the cecal contents, the conjugates with D amino acids were not hydrolysed. The other conjugates are susceptible to the hydrolysis, the rates of which decreased as the size of the substituent on the 2-position of the amino acids increased. The conjugates with alkyl analogs (2-4 carbons) of glycine and taurine were resistant to the hydrolysis, while taurine- and glycine-conjugates were hydrolysed effectively. The hydrolysis of N-aromatic acyl-glycine conjugates was enhanced by para-substitution of electron withdrawing groups on the aromatic acyl moiety and vice versa for electron-donating groups. While a methyl, methoxy or chloro group on the ortho-position retarded the hydrolysis, a hydroxyl group on the position accelerated it. Our data may provide useful information for the design of a colon-specific prodrug with controlled conversion rate in the large intestine.

Evaluation of glycine-bearing celecoxib derivatives as a colon-specific mutual prodrug acting on nuclear factor-κB, an anti-inflammatory target

“…HPLC analysis of aromatic acids released from glycine-conjugated aromatic acids in the cecal contents was performed as described in previous papers. 17 , 18 …”

The Biosynthesis and Metabolism of the N-Acylated Aromatic Amino Acids: N-Acylphenylalanine, N-Acyltyrosine, N-Acyltryptophan, and N-Acylhistidine

“…Given the importance of anandamide and oleamide in mammals, the structurally related NA-ArAAs are likely of significance in living systems. A more complete understanding of the NA-ArAAs will likely lead to a better understanding of human health, identify new targets to treat human disease and control the pests that spread disease and damage our crops, and enhance their uses as food additives, drug delivery agents, and in the cosmetic and pharmaceutical industries ( Chhikara et al, 2011 ; Kong et al, 2011 ; Taresco et al, 2016 ; Bernal et al, 2018 ; Tripathy et al, 2018 ).…”