Receptor Site Labeling Through Functional Groups. 2. Reactivity of Maleimide Groups

N-Alkylmaleimides are reactive groups suitable for binding drug fragments (D) linked to them via a chain (Cn) to receptor sites which bear suitable functional groups (e.g., thiol groups). To evaluate the theio-tropic (thiol-seeking) character of maleimides, rates of reaction with glutathione (GSH) in aq buffer have been examined. GSH adds to N-ethyl-2-methylmaleimide at the same atom as that which carries the Me group, demonstrating that electronic effects are far moee important than steric effects in this reaction. Addition of GSH to N-ethyl-2, 3-dimethylmaleimide reaches equilibrium in a solution containing 90-95% adduct. Based on the kinetic results, several 2-methylmaleimidylbarbiturate derivatives have been prepared and tested; modest signs qf biological activity appeared for one compound. The rate constants permit rational choice of appropriate functional groups, provide insight into the biological effects of Af-alkyl (or aryl-)-2, 3-dichloromaleimides, and lead to a logical prediction for molecular modification of the maleimide antibiotic, showdorrrycin.