Antitumor imidazotetrazines. 41. Conjugation of the antitumor agents mitozolomide and temozolomide to peptides and lexitropsins bearing DNA major and minor groove-binding structural motifs.
Carboxylic acids derived from the amido groups of the antitumor agents mitozolomide and temozolomide have been conjugated to simple amino acids and peptides by carbodiimide coupling. Solid-state peptide synthesis has been applied to link the acids to DNA major groove-binding peptidic motifs known to adopt alpha-helical conformations. Attachment of the acids to pyrrole and imidazole polyamidic lexitropsins gave a series of potential DNA minor groove-binding ligands. In vitro biological evaluation of a limited number of these novel conjugates failed to demonstrate any enhanced growth-inhibitory activity compared to the unconjugated drugs; sites of alkylation at tracts of multiple guanines were also unaffected. Attachment of additional residues at C-8 of the imidazotetrazines did not perturb the chemistry of activation of the bicyclic nucleus, and biological sequelae can be rationalized by invoking the liberation of a common, diffusible, reactive chemical intermediate, the methanediazonium ion.
Arrowsmith
Jill
J
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
Jennings
Sharon A
SA
Clark
Alan S
AS
Stevens
Malcolm F G
MF
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D004247:DNA / Q000737:chemistry*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008958:Models, Molecular; D009429:Netropsin / Q000031:analogs & derivatives* / Q000737:chemistry*; D009588:Nitrogen Mustard Compounds / Q000737:chemistry* / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D000596:Amino Acids; D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D010455:Peptides; C053654:lexitropsin; D009429:Netropsin; D003606:Dacarbazine; D004247:DNA; C040369:mitozolomide; D000077204:Temozolomide