Forty-two analogues and reaction products derived from T-2 toxin or neosolaniol were assayed for their cytotoxicity to cultured mouse lymphoma cells. Structure-activity relationships confirmed the stereospecific nature of the cytotoxic action of T-2. Cytotoxicity was particularly susceptible to changes at C3, C4, C9, and C10 but was relatively unaffected by changes at C8, which appears to represent a region of steric tolerance in the interaction of T-2 with a cellular constituent. The most potent compounds were T-2, diacetoxyscirpenol, and a series of C8 ester analogues 11 and 31-35.
Polymeric conjugates of 5-fluorouracil (5-FU) were synthesized by covalent attachment of tetrapeptide chains with 2-(5-fluorouracil-1-yl)glycine ethyl ester [Gly(FU)OEt] as the C-terminus, to poly(ethylene glycol) (PEG) and dextran (Dex). Cytotoxicity of these conjugates was compared with free 5-FU against the murine colorectal carcinoma cell line C26. All the conjugates displayed lower cytotoxicity than 5-FU. The chemical structure and the configuration of the tetrapeptide chains influenced the activity of the conjugates. Materials containing the tetrapeptide Gly-Phe-Gly-Gly(FU)OEt (l,d), with Dex-based conjugates were more cytotoxic than the analogue PEG-based conjugate. PEG-Gly-Phe-Gly-Gly(FU)OEt (l,d) administered to mice at doses of 150 and 250 mg 5-FU equivalent/kg, following by inoculation of C26 tumor cells, mediated much less toxicity than equivalent doses of free 5-FU. The anticancer activity achieved using free and polymer-bound drugs were comparable, although decreased toxicity of the conjugate should facilitate administration of increased doses with improved efficacy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.