Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents

J Med Chem. 1990 May;33(5):1393-9. doi: 10.1021/jm00167a018.

Abstract

The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Chemical Phenomena
  • Chemistry
  • Leukemia, Experimental / drug therapy
  • Mice
  • Mice, Inbred CBA
  • Nitrogen Mustard Compounds / chemical synthesis*
  • Nitrogen Mustard Compounds / therapeutic use
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Nitrogen Mustard Compounds
  • 3-(2-chloroethyl)-4-oxo-3H-imidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxylic acid
  • mitozolomide