O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases

M. Eileen Dolan, Sandip K. Roy, Bonnie J. Garbiras, Paul Helft, Phil Paras, Mi Young Chae, Robert C. Moschel, Anthony E. Pegg

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

To modulate the bioavailability and perhaps improve the tumor cell selectivity of O6-alkylguanine-DNA alkyltransferase (AGT) inactivators, pivaloyloxymethyl ester derivatives of O6-benzylguanine (BG) were synthesized and tested as AGT inactivators and as substrates for cellular esterase. The potential prodrugs examined were the 7- and 9- pivaloyloxymethyl derivatives of O6-benzylguanine (7- and 9-esterBG), and of 8-aza-O6-benzylguanine (8-aza-7-esterBG and 8-aza-9-esterBG) and the 9- pivaloyloxymethyl derivative of 8-bromo-O6-benzylguanine (8-bromo-9- esterBG). The benzylated purines were all potent inactivators of the pure AGT and of the AGT activity in HT29 cells and cell extracts. Each ester was at least 75 times less potent than the corresponding benzylated purine against the pure human AGT. In contrast, the activities of esters and their respective benzylated purine were similar in crude cell extracts and in intact cells. The increase in potency of esters in cellular extracts could be explained by a conversion of the respective prodrug to the more potent benzylated purine in the presence of cellular esterases. The apparent catalytic activity (V(max)/K(m)) of liver microsomal esterase for 8-azaBG ester prodrugs was 70-130 times greater than for BG prodrugs and 10-20 times greater than for 8-bromo-9-esterBG. Tumor cell hydrolysis of the esters varied considerably as a function of cell type and prodrug structure. These data suggest that these or related prodrugs may be advantageous for selective AGT inactivation in certain tumor types.

Original languageEnglish (US)
Pages (from-to)1701-1709
Number of pages9
JournalBiochemical Pharmacology
Volume55
Issue number10
DOIs
StatePublished - May 15 1998
Externally publishedYes

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Prodrugs
Esterases
Hydrolysis
Esters
Derivatives
Tumors
Cell Extracts
Cells
Neoplasms
HT29 Cells
Purines
Carboxylesterase
Complex Mixtures
Liver
Biological Availability
DNA alkyltransferase
O(6)-benzylguanine
Catalyst activity
Substrates
purine

Keywords

  • Alkyltransferase
  • Ester prodrug
  • Esterase
  • O-benzylguanine
  • Tumor

ASJC Scopus subject areas

  • Pharmacology

Cite this

O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases. / Dolan, M. Eileen; Roy, Sandip K.; Garbiras, Bonnie J.; Helft, Paul; Paras, Phil; Chae, Mi Young; Moschel, Robert C.; Pegg, Anthony E.

In: Biochemical Pharmacology, Vol. 55, No. 10, 15.05.1998, p. 1701-1709.

Research output: Contribution to journalArticle

Dolan, M. Eileen ; Roy, Sandip K. ; Garbiras, Bonnie J. ; Helft, Paul ; Paras, Phil ; Chae, Mi Young ; Moschel, Robert C. ; Pegg, Anthony E. / O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases. In: Biochemical Pharmacology. 1998 ; Vol. 55, No. 10. pp. 1701-1709.
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T1 - O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases

AU - Dolan, M. Eileen

AU - Roy, Sandip K.

AU - Garbiras, Bonnie J.

AU - Helft, Paul

AU - Paras, Phil

AU - Chae, Mi Young

AU - Moschel, Robert C.

AU - Pegg, Anthony E.

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AB - To modulate the bioavailability and perhaps improve the tumor cell selectivity of O6-alkylguanine-DNA alkyltransferase (AGT) inactivators, pivaloyloxymethyl ester derivatives of O6-benzylguanine (BG) were synthesized and tested as AGT inactivators and as substrates for cellular esterase. The potential prodrugs examined were the 7- and 9- pivaloyloxymethyl derivatives of O6-benzylguanine (7- and 9-esterBG), and of 8-aza-O6-benzylguanine (8-aza-7-esterBG and 8-aza-9-esterBG) and the 9- pivaloyloxymethyl derivative of 8-bromo-O6-benzylguanine (8-bromo-9- esterBG). The benzylated purines were all potent inactivators of the pure AGT and of the AGT activity in HT29 cells and cell extracts. Each ester was at least 75 times less potent than the corresponding benzylated purine against the pure human AGT. In contrast, the activities of esters and their respective benzylated purine were similar in crude cell extracts and in intact cells. The increase in potency of esters in cellular extracts could be explained by a conversion of the respective prodrug to the more potent benzylated purine in the presence of cellular esterases. The apparent catalytic activity (V(max)/K(m)) of liver microsomal esterase for 8-azaBG ester prodrugs was 70-130 times greater than for BG prodrugs and 10-20 times greater than for 8-bromo-9-esterBG. Tumor cell hydrolysis of the esters varied considerably as a function of cell type and prodrug structure. These data suggest that these or related prodrugs may be advantageous for selective AGT inactivation in certain tumor types.

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