Cytotoxicity and intracellular biotransformation of N-benzyladriamycin- 14-valerate (AD 198) are modulated by changes in 14-O-acyl chain length

Leonard Lothstein, Patrick J. Rodrigues, Trevor W. Sweatman, Mervyn Israel

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

N-benzyladriamycin-14-valerate (AD 198) is pharmacologically superior to Adriamycin (ADR) based upon comparable cytotoxicity, decreased cardiotoxicity and the ability of AD 198 to circumvent multidrug resistance conferred by either P-glycoprotein overexpression or reduced topoisomerase II activity. AD 198, however, suffers from systemic lability of the 14-O-valerate moiety to enzymatic and non-enzymatic cleavage to yield N-benzyladriamycin (AD 288), which is more similar to ADR in activity. The purpose of this study was to determine whether stability of the ester linkage could be achieved while preserving the favorable characteristics of AD 198 by using a series of N- benzylated ADR congeners containing 14-O-acyl substitutions of incrementally shorter carbon chain lengths. Results from this study indicate that the linear five-carbon valerate substitution is the minimum length necessary to circumvent P-glycoprotein and prevent inhibition of topoisomerase II activity. In addition, although AD 198 is not a pro-drug of AD 288, intracellular 14-O-acyl cleavage appears to contribute to the cytotoxicity of AD 198.

Original languageEnglish (US)
Pages (from-to)58-66
Number of pages9
JournalAnti-Cancer Drugs
Volume9
Issue number1
DOIs
StatePublished - 1998

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Biotransformation
Doxorubicin
Valerates
Type II DNA Topoisomerase
P-Glycoprotein
Carbon
Prodrugs
Multiple Drug Resistance
N-benzyladriamycin-14-valerate
Esters
N-benzyladriamycin

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

Cytotoxicity and intracellular biotransformation of N-benzyladriamycin- 14-valerate (AD 198) are modulated by changes in 14-O-acyl chain length. / Lothstein, Leonard; Rodrigues, Patrick J.; Sweatman, Trevor W.; Israel, Mervyn.

In: Anti-Cancer Drugs, Vol. 9, No. 1, 1998, p. 58-66.

Research output: Contribution to journalArticle

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AB - N-benzyladriamycin-14-valerate (AD 198) is pharmacologically superior to Adriamycin (ADR) based upon comparable cytotoxicity, decreased cardiotoxicity and the ability of AD 198 to circumvent multidrug resistance conferred by either P-glycoprotein overexpression or reduced topoisomerase II activity. AD 198, however, suffers from systemic lability of the 14-O-valerate moiety to enzymatic and non-enzymatic cleavage to yield N-benzyladriamycin (AD 288), which is more similar to ADR in activity. The purpose of this study was to determine whether stability of the ester linkage could be achieved while preserving the favorable characteristics of AD 198 by using a series of N- benzylated ADR congeners containing 14-O-acyl substitutions of incrementally shorter carbon chain lengths. Results from this study indicate that the linear five-carbon valerate substitution is the minimum length necessary to circumvent P-glycoprotein and prevent inhibition of topoisomerase II activity. In addition, although AD 198 is not a pro-drug of AD 288, intracellular 14-O-acyl cleavage appears to contribute to the cytotoxicity of AD 198.

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