8-Substituted O6-Benzylguanine, Substituted 6(4)-(Benzyloxy)pyrimidine, and Related Derivatives as Inactivators of Human O6-Alkylguanine-DNA Alkyltransfer ase

Mi Young Chae, Kristin Swenn, Sreenivas Kanugula, M. Eileen Dolan, Anthony Pegg, Robert C. Moschel

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Several 8-substituted O6-benzylguanines, 2- and/or 8-substituted 6-(benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(benzyloxy)-s-triazine were tested for their ability to inactivate the human DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT, alkyltransferase). Two types of compounds were identified as being significantly more effective than O6-benzylguanine (the prototype low molecular weight inactivator) at inactivating AGT in human HT29 colon tumor cell extracts. These were 8-substituted O6-benzylguanines bearing electron-withdrawing groups at the 8-position (e.g. 8-aza-O6-benzylguanine and O6-benzyl-8- bromoguanine) and 5-substituted 2,4-diamino-6-(benzyloxy)pyrimidines bearing electron- withdrawing groups at the 5-position (e.g. 2,4-diamino-6-(benzyloxy)-5-nitroso- and 2,4-diamino- 6-(benzyloxy)-5-nitropyrimidine). The latter derivatives were also more effective than O6- benzylguanine at inactivating AGT in intact HT29 colon tumor cells. Provided these types of purines and pyrimidines do not exhibit undesirable toxicity, they may be superior to O6-benzylguanine as chemotherapeutic adjuvants for enhancing the effectiveness of antitumor drugs for which the mechanism of action involves modification of the Opposition of DNA guanine residues.

Original languageEnglish (US)
Pages (from-to)359-365
Number of pages7
JournalJournal of Medicinal Chemistry
Volume38
Issue number2
DOIs
StatePublished - Jan 1 1995

Fingerprint

Pyrimidines
DNA
Purines
Colon
Alkyl and Aryl Transferases
Electrons
Triazines
Guanine
Cell Extracts
DNA Repair
Antineoplastic Agents
pyrimidine
O(6)-benzylguanine
Neoplasms
Molecular Weight
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Chae, Mi Young ; Swenn, Kristin ; Kanugula, Sreenivas ; Dolan, M. Eileen ; Pegg, Anthony ; Moschel, Robert C. / 8-Substituted O6-Benzylguanine, Substituted 6(4)-(Benzyloxy)pyrimidine, and Related Derivatives as Inactivators of Human O6-Alkylguanine-DNA Alkyltransfer ase. In: Journal of Medicinal Chemistry. 1995 ; Vol. 38, No. 2. pp. 359-365.
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abstract = "Several 8-substituted O6-benzylguanines, 2- and/or 8-substituted 6-(benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(benzyloxy)-s-triazine were tested for their ability to inactivate the human DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT, alkyltransferase). Two types of compounds were identified as being significantly more effective than O6-benzylguanine (the prototype low molecular weight inactivator) at inactivating AGT in human HT29 colon tumor cell extracts. These were 8-substituted O6-benzylguanines bearing electron-withdrawing groups at the 8-position (e.g. 8-aza-O6-benzylguanine and O6-benzyl-8- bromoguanine) and 5-substituted 2,4-diamino-6-(benzyloxy)pyrimidines bearing electron- withdrawing groups at the 5-position (e.g. 2,4-diamino-6-(benzyloxy)-5-nitroso- and 2,4-diamino- 6-(benzyloxy)-5-nitropyrimidine). The latter derivatives were also more effective than O6- benzylguanine at inactivating AGT in intact HT29 colon tumor cells. Provided these types of purines and pyrimidines do not exhibit undesirable toxicity, they may be superior to O6-benzylguanine as chemotherapeutic adjuvants for enhancing the effectiveness of antitumor drugs for which the mechanism of action involves modification of the Opposition of DNA guanine residues.",
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8-Substituted O6-Benzylguanine, Substituted 6(4)-(Benzyloxy)pyrimidine, and Related Derivatives as Inactivators of Human O6-Alkylguanine-DNA Alkyltransfer ase. / Chae, Mi Young; Swenn, Kristin; Kanugula, Sreenivas; Dolan, M. Eileen; Pegg, Anthony; Moschel, Robert C.

In: Journal of Medicinal Chemistry, Vol. 38, No. 2, 01.01.1995, p. 359-365.

Research output: Contribution to journalArticle

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T1 - 8-Substituted O6-Benzylguanine, Substituted 6(4)-(Benzyloxy)pyrimidine, and Related Derivatives as Inactivators of Human O6-Alkylguanine-DNA Alkyltransfer ase

AU - Chae, Mi Young

AU - Swenn, Kristin

AU - Kanugula, Sreenivas

AU - Dolan, M. Eileen

AU - Pegg, Anthony

AU - Moschel, Robert C.

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Y1 - 1995/1/1

N2 - Several 8-substituted O6-benzylguanines, 2- and/or 8-substituted 6-(benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(benzyloxy)-s-triazine were tested for their ability to inactivate the human DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT, alkyltransferase). Two types of compounds were identified as being significantly more effective than O6-benzylguanine (the prototype low molecular weight inactivator) at inactivating AGT in human HT29 colon tumor cell extracts. These were 8-substituted O6-benzylguanines bearing electron-withdrawing groups at the 8-position (e.g. 8-aza-O6-benzylguanine and O6-benzyl-8- bromoguanine) and 5-substituted 2,4-diamino-6-(benzyloxy)pyrimidines bearing electron- withdrawing groups at the 5-position (e.g. 2,4-diamino-6-(benzyloxy)-5-nitroso- and 2,4-diamino- 6-(benzyloxy)-5-nitropyrimidine). The latter derivatives were also more effective than O6- benzylguanine at inactivating AGT in intact HT29 colon tumor cells. Provided these types of purines and pyrimidines do not exhibit undesirable toxicity, they may be superior to O6-benzylguanine as chemotherapeutic adjuvants for enhancing the effectiveness of antitumor drugs for which the mechanism of action involves modification of the Opposition of DNA guanine residues.

AB - Several 8-substituted O6-benzylguanines, 2- and/or 8-substituted 6-(benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(benzyloxy)-s-triazine were tested for their ability to inactivate the human DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT, alkyltransferase). Two types of compounds were identified as being significantly more effective than O6-benzylguanine (the prototype low molecular weight inactivator) at inactivating AGT in human HT29 colon tumor cell extracts. These were 8-substituted O6-benzylguanines bearing electron-withdrawing groups at the 8-position (e.g. 8-aza-O6-benzylguanine and O6-benzyl-8- bromoguanine) and 5-substituted 2,4-diamino-6-(benzyloxy)pyrimidines bearing electron- withdrawing groups at the 5-position (e.g. 2,4-diamino-6-(benzyloxy)-5-nitroso- and 2,4-diamino- 6-(benzyloxy)-5-nitropyrimidine). The latter derivatives were also more effective than O6- benzylguanine at inactivating AGT in intact HT29 colon tumor cells. Provided these types of purines and pyrimidines do not exhibit undesirable toxicity, they may be superior to O6-benzylguanine as chemotherapeutic adjuvants for enhancing the effectiveness of antitumor drugs for which the mechanism of action involves modification of the Opposition of DNA guanine residues.

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