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

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 O6-position of DNA guanine residues.

Repair of O6-Benzylguanine by the Escherichia coli Ada and Ogt and the Human O6-Alkylguanine-DNA Alkyltransferases

“…Although A316P/W336A-Ada-C is clearly sensitive to these inhibitors, it is still 2 orders of magnitude more resistant than the human AGT for which the ED 50 values in the presence of DNA are 0.1 M for O 6 -benzylguanine (Table I) and 0.04 M for 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine and 2,4-diamino-6-benzyloxy-5-nitropyrimidine (16). This difference could not be reduced by changing Trp 336 to Gly, which occupies the equivalent position in AGT, or by including a third mutation in which Lys 314 was changed to Pro (Table I).…”

“…Benzyl-substituted pyrimidine derivatives have been shown to be even more potent inhibitors of AGT than O 6 -benzylguanine (16). These inhibitors, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine (Fig.…”

“…Materials-O 6 -Benzylguanine, 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine, and 2,4-diamino-6-benzyloxy-5-nitropyrimidine were synthesized as described previously (9,16). All nonalkylated oligodeoxyribonucleotides were made in the Macromolecular Core Facility, Hershey Medical Center, by using a Milligen 7500 DNA synthesizer.…”

Activities of Pt(II) and Ru(III) Triazole-Pyrimidine Complexes against <i>Trypanosoma cruzi</i> and <i>T. brucei brucei</i>

“…Different researchers have investigated them as chemotherapeutic agents, finding certain promising properties, such as growth inhibition of some microorganisms [5]. Studies Magá n/Marín/Rosales/Barrera/Salas/ Sá nchez-Moreno have also been performed on anti-tumor activity in cell lines, such as breast cancer MDA/MB-231, human colonrectal cancer COLO320 [6,7] and human colon cancer HT29 [8], where these complexes inhibit DNA synthesis. Their potential in the treatment of neurodegenerative disorders such as Parkinson's disease has also been tested [9].…”

Syntheses of 2-amino-4,6-dichloro-5-nitropyrimidine and 2-amino-4,5,6-trichloropyrimidine: an unusual aromatic substitution

“…6 The preparation of nitropyrimidines as analogues of O 6 -benzylguanine was reported previously by displacement of a chlorine from 2-amino-4-chloro-5-nitropyrimidine by an alkoxide involving very harsh experimental conditions. 7,8 Therefore, an alternative method for the preparation of these nitropyrimidine adducts needs to be devised. Considering that compound 1 is such a versatile molecule, we have explored several synthetic strategies, and in this paper, we report our efforts to prepare this compound, and on the chemistry of some of the other pyrimidines synthesised.…”