Kinetics and Mechanism of Thiolytic Cleavage of the Antitumor Compound 4'-methanesulfon-m-anisidide

Article abstract of DOI:10.1021/jo00135a009

The thiolysis of 4'-<(9-acridinyl)amino>methanesulfon-m-anisidide (m-AMSA) has been studied in buffer solutions of L-cysteine, glutathione, N-acetylcysteine, 2-mercaptoethanol, and cysteamine at various pH values.The thiolysis is sensitive to general-acid catalysis.Both free and protonated forms of m-AMSA have been found to be reactive for thiolysis.The Broensted-type correlation of thiol basicity to the nucleophilic rate constants with the protonated m-AMSA (m-AMSA⁺H) has a slope, β_nuc of 0.74 +/- 0.07 which indicates that probably the expulsion of the leavinggroup is the rate-determining step.The rate constants for general-acid-catalyzed thiolytic cleavage of m-AMSA⁺H reveal an insensitiveness to the acidity of catalysts.The general-acid-catalyzed rate constants for thiolysis of the free base of m-AMSA have been found to have quite high sensitivities to the pK_a of catalysts (α = 0.57 +/- 0.07) which has been interpreted by assuming a concerted type of mechanism for thiolysis.The various ionic forms of amino thiols are acting as nucleophiles as well as general-acid catalysts, depending upon the pH range of the reaction and the microscopic ionization constants of the thiols.The unionized thiol groups of most of the catalysts are acting as general acids except for cysteamine where the protonated amino group is also acting as a general-acid catalyst.A high nucleophilic rate constant for cysteamine with m-AMSA (free base) compared with those for other nucleophiles of similar basicity has been attributed to its probable ability of acting as an intramolecular general-acid catalyst.The thiolytic cleavage of m-AMSA⁺H is nearly 10³ times faster than that of m-AMSA (free base) while the ratios for general-acid-catalyzed rate constants for m-AMSA⁺H and m-AMSA (free base) vary from 20 to 300 depending upon the pK_a of the catalysts.The bimolecular nucleophilic rate constant (with m-AMSA⁺H) as well as the general-acid-catalyzed rate constant (with m-AMSA free base) for glutathione is found to be positively deviated from Broensted plots which seem as if they fall on a separate Broensted plot of essentially the same slope but with a different intercept.