Punaglandins, Chlorinated Prostaglandins, Function as Potent Michael Receptors To Inhibit Ubiquitin Isopeptidase Activity

Abstract

Cyclopentenone prostaglandins exhibit unique antineoplastic activity and are potent growth inhibitors in a variety of cultured cells. Recently the dienone prostaglandin, Delta(12)-PGJ(2), was shown to preferentially inhibit ubiquitin isopeptidase activity of the proteasome pathway. It is theorized that isopeptidase inhibition and general cytotoxicity of prostaglandins depend on olefin-ketone conjugation, electrophilic accessibility, and the nucleophilic reactivity of the endocyclic beta-carbon. Delta(12)-PGJ(2), which contains a cross-conjugated alpha,beta-unsaturated ketone, was a potent inhibitor of isopeptidase activity, whereas PGA(1) and PGA(2) with simple alpha,beta-unsaturated pentenones were significantly less potent and PGB(1) with a sterically hindered alpha,beta-unsaturated ketone was inactive. To further investigate the proposed mechanism, punaglandins, which are highly functional cyclopentadienone and cyclopentenone prostaglandins chlorinated at the endocyclic alpha-carbon position, were isolated from the soft coral Telesto riisei. They were then assayed for inhibition of ubiquitin isopeptidase activity and antineoplastic effects. The punaglandins were shown to inhibit isopeptidase activity and exhibit antiproliferative effects more potently than A and J series prostaglandins. Also, the cross-conjugated dienone punaglandin was more potent than the simple enone punaglandin. The ubiquitin-proteasome pathway is a vital component of cellular metabolism and may be a suitable target for antineoplastic agents. These newly characterized proteasome inhibitors may represent a new chemical class of cancer therapeutics.

Identification of New Compounds That Trigger Apoptosome-Independent Caspase Activation and Apoptosis

“…Hence, it should not be surprising that also F6 and G5 act as inhibitors of the ubiquitin-proteasome system. As a matter of fact, the presence of a pharmacophore that confers inhibitory activity toward ubiquitin isopeptidases (12,(14)(15)(16) and experimental data here reported has confirmed that these new compounds can impede ubiquitin-dependent protein degradation.…”

Curcusone D, a novel ubiquitin–proteasome pathway inhibitor via ROS-induced DUB inhibition, is synergistic with bortezomib against multiple myeloma cell growth

“…1A). A similar pharmacophore was previously described in the pan-DUB inhibitor prostaglandin lipid derivatives, which function as potent Michael receptors to inhibit the activities of DUBs [28,29]. The alpha, beta-unsaturated carbonyl center in the cyclopentenone ring of prostaglandins could react with the DUB catalytic cysteine thiol group, resulting in a covalent adduct [30].…”

Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: implications for a molecular mechanism of action

“…In fact, cross-conjugated dienone prostaglandins are observed to undergo reversible conjugate additions. 18,19 While it is appreciated that the use of conjugate additions can produce tight binding ligands, there has been a reluctance to install such reactive functionality in drug candidate molecules owing to potential poor bioavailability and increased toxicity. The destruction of protein-reactive therapeutics through non-selective addition to scavenger nucleophiles, such as glutathione, would be expected to seriously jeopardize the bioavailability of the therapeutic.…”