Hepoxilin Analogs, Potential New Therapeutics in Disease

Abstract

We have chemically synthesized several stable analogs of the naturally occurring hepoxilins, 12-LO products derived from arachidonic acid, which we found to have promising actions in a variety of test systems of disease. The analogs, PBTs, afford chemical and biological stability to the hepoxilin molecule. This article reviews some of our latest observations with the PBTs in the areas of inflammation (inhibition of the bleomycin-evoked lung fibrosis in mice in vivo), platelet aggregation (antagonism of the thromboxane receptor in human platelets in vitro) and thrombosis (inhibitors in vivo), and cancer (apoptosis of the human leukemia cell line, K562 in vitro and in vivo). The demonstration that the PBTs are active in vivo suggests that they can serve as a platform for their further development as novel therapeutics in disease.

Pathophysiology of the hepoxilins

“…They selectively antagonize the binding of tritiated hepoxilin A 3 to intact human neutrophils and neutrophil membranes [75] and they inhibit the hepoxilin A 3 evoked release of intracellular calcium in these cells [138]. Additionally the PBTs block aggregation of human platelets in vitro [56].…”

“…The PBTs displayed interesting actions in vivo as anti inflammatory and anti cancer drugs which will be described below. Other actions reviewed earlier relate to anti-thrombotic and anti-diabetic actions [53,138,139].…”

Structure, biochemistry and biology of hepoxilins

“…The stability of the molecule HXA 3 was achieved by stabilizing the unstable epoxide ring with a methylene group to form a cyclopropane ring. The compounds thus obtained were resistant to catabolic reactions and were utilized for in vivo studies [65].…”

“…PBT‐1 was also intradermally applied to assess vascular permeability in the skin. Both bleomycin‐provoked lung fibrosis and permeability changes in the skin were abolished by PBT‐1 at a low dosis of 10 µg per mouse [65]. In conclusion, the in vivo data on stable hepoxilin analogues show their use in suppression of chronic lung inflammation and lung fibrosis in a mouse model.…”

Editorial [Hot Topic: Latest Developments in Pharmaceutical Design of Arachidonic Acid Metabolites: Prostaglandins, Thromboxanes, Hepoxilins and Isoprostanes (Executive Editors: J.-M. Dogne and K.-H. Ruan )]

“…These are produced through the isomerization of 12(S)-HPETE, a metabolite of arachidonic acid formed via the 12(S)-lipoxygenase, via a putative hepoxilin synthase. Some of the latest observations with the PBTs in the areas of inflammation (inhibition of the bleomycin-evoked lung fibrosis in mice in vivo), platelet aggregation (antagonism of the thromboxane receptor in human platelets in vitro) thrombosis (inhibitors in vivo), and cancer (apoptosis of the human leukemia cell line, K562 in vitro and in vivo) are reviewed [6].…”