Arrowsmith Jill, Jennings Sharon A, Clark Alan S, Stevens Malcolm F G
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
J Med Chem. 2002 Dec 5;45(25):5458-70. doi: 10.1021/jm020936d.
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.
来自抗肿瘤药物米托唑胺和替莫唑胺酰胺基团的羧酸已通过碳二亚胺偶联与简单氨基酸和肽缀合。固态肽合成已用于将这些酸与已知采用α-螺旋构象的DNA大沟结合肽基序连接起来。将这些酸连接到吡咯和咪唑聚酰胺类左旋视蛋白上，得到了一系列潜在的DNA小沟结合配体。对有限数量的这些新型缀合物进行的体外生物学评估未能证明与未缀合药物相比有任何增强的生长抑制活性；多个鸟嘌呤区域的烷基化位点也未受影响。在咪唑并四嗪的C-8位连接额外的残基不会干扰双环核的活化化学，并且可以通过调用一种常见的、可扩散的、反应性化学中间体甲二氮鎓离子来合理解释生物学后果。
