Cinnamoyl nitrogen mustard derivatives of pyrazole analogues of tallimustine modified at the amidino moiety: design, synthesis, molecular modeling and antitumor activity studies

Bioorg Med Chem. 2004 Jul 15;12(14):3911-21. doi: 10.1016/j.bmc.2004.04.045.

Abstract

The design, synthesis and in vitro activities of a series of cinnamoyl nitrogen mustard pyrazole analogues of tallimustine 8-13, in which the amidino moiety has been replaced by moieties of different physico-chemical features are described, and the structure-activity relationships are discussed. In spite of the relevance of these modifications on the amidino moiety, these derivatives showed significant growth inhibitory activity against mouse leukemia L1210 cells. A selected series of compounds have been evaluated for their sequence selective alkylating properties and cytotoxicity against human K562 leukemia cells. Therefore, the presence of the amidino moiety, and in general of a basic moiety, is not an absolute requirement for biological activity. Our preliminary results indicated that the compounds of this series have a pattern of alkylation similar to that of tallimustine, but they seem to be less reactive overall in alkylating naked DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Base Sequence
  • Cell Division / drug effects
  • Cell Line, Tumor
  • DNA / chemistry
  • Distamycins / chemical synthesis*
  • Distamycins / chemistry
  • Humans
  • Mice
  • Models, Molecular
  • Nitrogen Mustard Compounds / chemical synthesis*
  • Nitrogen Mustard Compounds / chemistry
  • Pyrazoles / chemistry*

Substances

  • Antineoplastic Agents
  • Distamycins
  • Nitrogen Mustard Compounds
  • Pyrazoles
  • tallimustine
  • DNA