Synthesis and antitumor activity of methyltriazene prodrugs simultaneously releasing DNA-methylating agents and the antiresistance drug O(6)-benzylguanine

J Med Chem. 2004 Dec 30;47(27):6875-83. doi: 10.1021/jm049556d.

Abstract

Active resistance of tumor cells against DNA alkylating agents arises by the production of high levels of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). This resistance during treatment with, for example, the anticancer agent temozolomide can be reversed by administration of O(6)-benzylguanine, a purine that transfers its benzyl group to AGT and irreversibly inactivates it. Stimulated by the favorable therapeutic properties of temozolomide we designed and synthesized DNA-methylating triazenes built on the antiresistance benzylguanine ring system. The condensation reaction between 2-nitrosopurines and acylhydrazines proved to be very suitable to prepare acylated methyltriazenes. Fine-tuning of the release rate of both the methylating agent (diazomethane) and of O(6)-benzylguanine was accomplished by variation of the hydrolysis-sensitive acyl substituent in 5. Hydrolysis studies were performed with (1)H NMR and revealed that the p-nitrophenyl substituted triazene 26 showed an optimal hydrolysis rate (t(1/2) = 23 min) and almost 100% selectivity for the desired fragmentation route. In vitro antitumor studies in the 60 human tumor cell line panel of the National Cancer Institute confirmed the superior properties of p-nitrophenyl-protected methyl triazene 26, showing mean IC(50) values of 10 microM compared to 100 microM for temozolomide. In analogy with temozolomide, triazene 26 showed however low preference for each of the cancer subpanels, with IC(50) values between 8 and 14 microM.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • DNA Methylation*
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Diazomethane / metabolism*
  • Drug Resistance, Neoplasm
  • Guanine / analogs & derivatives*
  • Guanine / metabolism*
  • Humans
  • Hydrolysis
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • Temozolomide
  • Triazenes / chemical synthesis*
  • Triazenes / pharmacology

Substances

  • Antineoplastic Agents
  • Prodrugs
  • Triazenes
  • O(6)-benzylguanine
  • Guanine
  • Diazomethane
  • Dacarbazine
  • Temozolomide