Tumorselektiv aktivierbare Prodrugs des Cytostaticums CC‐1065

Abstract

Die O‐Glycoside l des seco‐CI‐Derivats 2, das die seco‐Form der pharmakophoren Gruppe des cytotoxisch hochwirksamen Antibioticums CC–1065 ist, weisen nur eine sehr geringe Toxizität auf. In der tumorselektiven Krebstherapie können sie mit Konjugaten aus Glycohydrolasen und monoklonalen Antikörpern, die an tumorassoziierte Antigene binden, eingesetzt werden. Die Glycohydrolasen spalten die Prodrugs 1 unter Freisetzung der cytotoxischen Komponente 2.

Synthesis and Biological Evaluation of Novel Analogues and Prodrugs of the Cytotoxic Antibiotic CC-1065 for Selective Cancer Therapy

“…Since serum-free incubation medium was employed, any enzyme activity of the medium (as observed in previous studies [12] with other media) could be ruled out. We must therefore assume either that nonenzymatic cleavage of the glycosidic bond in 5 occurs, or that direct alkylation of the DNA with 5 takes place without formation of the spirocyclopropane moiety.…”

Synthesis of New Water‐Soluble DNA‐Binding Subunits for Analogues of the Cytotoxic Antibiotic CC‐1065 and Their Prodrugs

“…[21] Some time ago we demonstrated that the formation of the spirocyclopropane moiety as the pharmacophoric group of CC-1065 from a corresponding seco compound can be halted by transforming its phenolic hydroxy group into a glycoside. [22] Such a derivative can be hydrolysed enzymatically with a glycohydrolase, which liberates the drug. Thus, the glycosidic seco compound 2 bearing a bisindolyl car-as part of the 5-alkoxy substituent or at another position of the indole moiety, retain or enhance the cytotoxicity of the parent drug and provide an increased water solubility.…”

Selective Treatment of Cancer: Synthesis, Biological Evaluation and Structural Elucidation of Novel Analogues of the Antibiotic CC‐1065 and the Duocarmycins

“…[7] Such a derivative can be hydrolyzed enzymatically using a glycohydrolase which liberates the drug. In this way, glycosidic seco-CBI-Q 3 and similar compounds bearing a bisindolyl carboxylic acid moiety as a DNA-binding subunit were developed by us for ADEPT.…”