TY - JOUR
T1 - Structural effects of N-aromatic acyl-amino acid conjugates on their deconjugation in the cecal contents of rats
T2 - Implication in design of a colon-specific prodrug with controlled conversion rate at the target site
AU - Kong, Hyesik
AU - Kim, Hyunjeong
AU - Do, Heejeong
AU - Lee, Yonghyun
AU - Hong, Sungchae
AU - Yoon, Jeong Hyun
AU - Jung, Yunjin
AU - Kim, Young Mi
PY - 2011/9
Y1 - 2011/9
N2 - 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/andl forms of alanine or phenylalanine in the cecal contents, the conjugates withd 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.
AB - 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/andl forms of alanine or phenylalanine in the cecal contents, the conjugates withd 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.
KW - N-aromatic acyl-amino acid conjugates
KW - colon specific prodrug
KW - colonic delivery
KW - drug design
KW - structural effect
UR - http://www.scopus.com/inward/record.url?scp=80051886852&partnerID=8YFLogxK
U2 - 10.1002/bdd.763
DO - 10.1002/bdd.763
M3 - Article
C2 - 21800327
AN - SCOPUS:80051886852
SN - 0142-2782
VL - 32
SP - 343
EP - 354
JO - Biopharmaceutics and Drug Disposition
JF - Biopharmaceutics and Drug Disposition
IS - 6
ER -