Extracellular and intracellular esterase processing of SCFA-hexosamine analogs: Implications for metabolic glycoengineering and drug delivery

Mohit P. Mathew, Elaine Tan, Shivam Shah, Rahul Bhattacharya, M. Adam Meledeo, Jun Huang, Freddy A. Espinoza, Kevin J Yarema

Research output: Contribution to journalArticle

Abstract

This report provides a synopsis of the esterase processing of short chain fatty acid (SCFA)-derivatized hexosamine analogs used in metabolic glycoengineering by demonstrating that the extracellular hydrolysis of these compounds is comparatively slow (e.g.; with a t1/2 of ∼4 h to several days) in normal cell culture as well as in high serum concentrations intended to mimic in vivo conditions. Structure-activity relationship (SAR) analysis of common sugar analogs revealed that O-acetylated and N-azido ManNAc derivatives were more refractory against extracellular inactivation by FBS than their butanoylated counterparts consistent with in silico docking simulations of Ac4ManNAc and Bu4ManNAc to human carboxylesterase 1 (hCE1). By contrast, all analogs tested supported increased intracellular sialic acid production within 2 h establishing that esterase processing once the analogs are taken up by cells is not rate limiting.

Original languageEnglish (US)
Pages (from-to)6929-6933
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2012

Fingerprint

Hexosamines
Volatile Fatty Acids
Esterases
Drug delivery
N-Acetylneuraminic Acid
Structure-Activity Relationship
Processing
Cell culture
Sugars
Pharmaceutical Preparations
Computer Simulation
Refractory materials
Hydrolysis
Cell Culture Techniques
Derivatives
Serum
human CES1 protein

Keywords

  • Drug metabolism
  • Esterase
  • ManNAc analogs
  • Metabolic oligosaccharide engineering
  • Prodrugs

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Extracellular and intracellular esterase processing of SCFA-hexosamine analogs : Implications for metabolic glycoengineering and drug delivery. / Mathew, Mohit P.; Tan, Elaine; Shah, Shivam; Bhattacharya, Rahul; Adam Meledeo, M.; Huang, Jun; Espinoza, Freddy A.; Yarema, Kevin J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 22, No. 22, 15.11.2012, p. 6929-6933.

Research output: Contribution to journalArticle

Mathew, Mohit P. ; Tan, Elaine ; Shah, Shivam ; Bhattacharya, Rahul ; Adam Meledeo, M. ; Huang, Jun ; Espinoza, Freddy A. ; Yarema, Kevin J. / Extracellular and intracellular esterase processing of SCFA-hexosamine analogs : Implications for metabolic glycoengineering and drug delivery. In: Bioorganic and Medicinal Chemistry Letters. 2012 ; Vol. 22, No. 22. pp. 6929-6933.
@article{9721aa18c69441e4a0451bccf0b27238,
title = "Extracellular and intracellular esterase processing of SCFA-hexosamine analogs: Implications for metabolic glycoengineering and drug delivery",
abstract = "This report provides a synopsis of the esterase processing of short chain fatty acid (SCFA)-derivatized hexosamine analogs used in metabolic glycoengineering by demonstrating that the extracellular hydrolysis of these compounds is comparatively slow (e.g.; with a t1/2 of ∼4 h to several days) in normal cell culture as well as in high serum concentrations intended to mimic in vivo conditions. Structure-activity relationship (SAR) analysis of common sugar analogs revealed that O-acetylated and N-azido ManNAc derivatives were more refractory against extracellular inactivation by FBS than their butanoylated counterparts consistent with in silico docking simulations of Ac4ManNAc and Bu4ManNAc to human carboxylesterase 1 (hCE1). By contrast, all analogs tested supported increased intracellular sialic acid production within 2 h establishing that esterase processing once the analogs are taken up by cells is not rate limiting.",
keywords = "Drug metabolism, Esterase, ManNAc analogs, Metabolic oligosaccharide engineering, Prodrugs",
author = "Mathew, {Mohit P.} and Elaine Tan and Shivam Shah and Rahul Bhattacharya and {Adam Meledeo}, M. and Jun Huang and Espinoza, {Freddy A.} and Yarema, {Kevin J}",
year = "2012",
month = "11",
day = "15",
doi = "10.1016/j.bmcl.2012.09.017",
language = "English (US)",
volume = "22",
pages = "6929--6933",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "22",

}

TY - JOUR

T1 - Extracellular and intracellular esterase processing of SCFA-hexosamine analogs

T2 - Implications for metabolic glycoengineering and drug delivery

AU - Mathew, Mohit P.

AU - Tan, Elaine

AU - Shah, Shivam

AU - Bhattacharya, Rahul

AU - Adam Meledeo, M.

AU - Huang, Jun

AU - Espinoza, Freddy A.

AU - Yarema, Kevin J

PY - 2012/11/15

Y1 - 2012/11/15

N2 - This report provides a synopsis of the esterase processing of short chain fatty acid (SCFA)-derivatized hexosamine analogs used in metabolic glycoengineering by demonstrating that the extracellular hydrolysis of these compounds is comparatively slow (e.g.; with a t1/2 of ∼4 h to several days) in normal cell culture as well as in high serum concentrations intended to mimic in vivo conditions. Structure-activity relationship (SAR) analysis of common sugar analogs revealed that O-acetylated and N-azido ManNAc derivatives were more refractory against extracellular inactivation by FBS than their butanoylated counterparts consistent with in silico docking simulations of Ac4ManNAc and Bu4ManNAc to human carboxylesterase 1 (hCE1). By contrast, all analogs tested supported increased intracellular sialic acid production within 2 h establishing that esterase processing once the analogs are taken up by cells is not rate limiting.

AB - This report provides a synopsis of the esterase processing of short chain fatty acid (SCFA)-derivatized hexosamine analogs used in metabolic glycoengineering by demonstrating that the extracellular hydrolysis of these compounds is comparatively slow (e.g.; with a t1/2 of ∼4 h to several days) in normal cell culture as well as in high serum concentrations intended to mimic in vivo conditions. Structure-activity relationship (SAR) analysis of common sugar analogs revealed that O-acetylated and N-azido ManNAc derivatives were more refractory against extracellular inactivation by FBS than their butanoylated counterparts consistent with in silico docking simulations of Ac4ManNAc and Bu4ManNAc to human carboxylesterase 1 (hCE1). By contrast, all analogs tested supported increased intracellular sialic acid production within 2 h establishing that esterase processing once the analogs are taken up by cells is not rate limiting.

KW - Drug metabolism

KW - Esterase

KW - ManNAc analogs

KW - Metabolic oligosaccharide engineering

KW - Prodrugs

UR - http://www.scopus.com/inward/record.url?scp=84867877369&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867877369&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2012.09.017

DO - 10.1016/j.bmcl.2012.09.017

M3 - Article

C2 - 23041156

AN - SCOPUS:84867877369

VL - 22

SP - 6929

EP - 6933

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 22

ER -