Chemical implications for antitumor and antiviral prostaglandins: Reaction of Delta(7)-prostaglandin A(1) and prostaglandin A(1) methyl esters with thiols

Prostaglandins (PGs) such as Delta(12)-PGJ(2) and Delta(7)-PGA(1) methyl ester that possess a cross-conjugated dienone unit exhibit unique antitumor and antiviral activities independent of intracellular cAMP levels. These compounds are transported reversibly into cultured cells and accumulate in nuclei via covalent interaction, eliciting growth inhibition. PGA(1) methyl ester, a simple cyclopentenone analog, is less potent. The unique cellular behavior of the dienone PGs correlates well with their chemical properties. The PGs react specifically with thiol nucleophiles such as glutathione. Michael addition of thiols to Delta(7)-PGA(1) methyl ester, an alkylidenecyclopentenone derivative, occurs facilely at the endocyclic C(11) position rather than at the C(7) position. This process is reversible, and in solution phase, the adducts are in equilibrium with considerable amounts of free PG and thiols. However, the reaction of this PG with Sephatose-bound thiols, regarded to be plausible mimics of protein thiols, is irreversible, and the resulting adducts are dissociated only by alkali treatment. On the other hand, PGA(1) methyl ester reacts with soluble or polymer-anchored thiols at lower rates than Delta(7)-PGA(1) methyl ester, but the resulting thiol adducts are substantially more stable than those of the dienone PGs. This tendency of the PGA(1) methyl ester causes its equilibrium to shift to the adduct formation. The reversibility of the Michael reaction of PGs with thiols is consistent with their intracellular behavior and biological activities. Since glutathione adducts of PGs have no antiproliferative activities for cancer cells, the intracellular free PGs are presumed to interact with target molecules to cause cell growth inhibition. The involvement of the ATP-dependent glutathione S-conjugate export pump (GS-X pump) in the efflux of PGs is discussed. Thus, the marked difference in potency of the dienone and enone PGs is explained by considering the combined kinetic and thermodynamic properties and the action of the GS-X pump.