Enzyme Alterable Alkylating Agents. V. Design of Sulfur Mustards With Varying Degrees of Hydrolytic Stability in a Search for Short Biological Half-Life Agents2

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Abstract
Short-lived alkylating agents may find application in intra-arterial chemotherapy. By proper selection of the alkylating agent, it might be possible to design agents that exert their activity within the tumors but degrade rapidly to nontoxic products in the short time required to pass through the capillary bed and return to the lungs and heart. The sulfur mustards lend themselves readily to structural variations, and a detailed analysis of the rates of hydrolysis leading to detoxification of the mustards has improved understanding of the structural factors responsible for rapid or slow hydrolysis of the carbon-to-chlorine bonds. The Taft equation was useful in relating the reactivity of sulfur mustards to some function of their structure. The rate of hydrolysis at the carbon-to-chlorine bond is influenced primarily by the nature of the polar substituents attached to the sulfur atom. Electron-withdrawing groups adjacent to the sulfur atom retard the rate of hydrolysis, while electron-donating groups in the same position result in rate acceleration. The introduction in the molecule of methylene groups between the polar substituent and the sulfur atom will minimize these effects. Based on these considerations, sulfur mustards containing β-chloroethyl groups can be designed with half lives as short as 5 to 10 seconds and as long as 5 hours or more.