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

• Published in: Journal of medicinal chemistry Vol. 47; no. 8; pp. 2062 - 2070
• Main Authors: Verbitski, Sheryl M., Mullally, James E., Fitzpatrick, Frank A., Ireland, Chris M.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.04.2004; Amer Chemical Soc
• Subjects: Animals; Anthozoa - chemistry; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Biological and medical sciences; Caspase 3; Caspases - metabolism; Cell Line, Tumor; Chemistry, Medicinal; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; Drug Screening Assays, Antitumor; Endopeptidases - chemistry; Endopeptidases - metabolism; General aspects; General pharmacology; Humans; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Pharmacognosy. Homeopathy. Health food; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prostaglandins - chemistry; Prostaglandins - isolation & purification; Prostaglandins - pharmacology; Protease Inhibitors - chemistry; Protease Inhibitors - isolation & purification; Protease Inhibitors - pharmacology; Science & Technology; Tumor Suppressor Protein p53 - biosynthesis; Ubiquitin - metabolism; APOPTOSIS; E6; CYCLOPENTENONE PROSTAGLANDINS; PROTEASOME; DEGRADATION; ANTITUMOR; PROMOTES; Antineoplastic agent; Multicatalytic endopeptidase complex; Cytotoxicity; Dienone; Marine environment; Coelenterata; Ligases; Chlorine Organic compounds; Cnidaria; Colon; Tumor cell; Ubiquitin-protein ligase; Human; Carbon-nitrogen ligases; Prostaglandin; Enzyme; Pharmacognosy; Enzyme inhibitor; Animal origin; In vitro; Biological activity; Peptidases; Cell line; Hydrolases; Isolation; Invertebrata; Enone; Structural analysis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030448l

Cyclopentenone prostaglandins exhibit unique antineoplastic activity and are potent growth inhibitors in a variety of cultured cells. Recently the dienone prostaglandin, Δ12-PGJ2, 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 β-carbon. Δ12-PGJ2, which contains a cross-conjugated α,β-unsaturated ketone, was a potent inhibitor of isopeptidase activity, whereas PGA1 and PGA2 with simple α,β-unsaturated pentenones were significantly less potent and PGB1 with a sterically hindered α,β-unsaturated ketone was inactive. To further investigate the proposed mechanism, punaglandins, which are highly functional cyclopentadienone and cyclopentenone prostaglandins chlorinated at the endocyclic α-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.