Discovery of Novel Epoxyketone Peptides as Lipase Inhibitors.

Obesity is the most common nutritional disorder in the developed world and is associated with important comorbidities. Pancreatic lipase (PL) inhibitors play a key role in the metabolism of human fat. A series of novel epoxyketones peptide derivatives were investigated for their pancreatic lipase inhibitory activity. The epoxyketone moiety is a well-known reactive electrophile group that has been used as part of proteasome inhibitors in cancer therapy, and it is widely believed that these are very selective for targeting the proteasome active site. Here we investigated various peptide derivatives with an epoxide warhead for their anti-lipase activity. The assessment of these novel epoxyketones was performed by an in-house method that we developed for rapid screening and identification of lipase inhibitors using GC-FID. Herein, we present a novel anti-lipase pharmacophore based on epoxyketone peptide derivatives that showed potent anti-lipase activity. Many of these derivatives had comparable or more potent activity than the clinically used lipase inhibitors such as orlistat. In addition, the lipase appears to be inhibited by a wide range of epoxyketone analogues regardless of the configuration of the epoxide in the epoxyketone moiety. The presented data in this study shows the first example of the use of epoxyketone peptides as novel lipase inhibitors.

Cytochrome P450-derived fatty acid epoxides and diols in angiogenesis and stem cell biology.

Cytochrome P450 (CYP) enzymes are frequently referred to as the third pathway for the metabolism of arachidonic acid. While it is true that these enzymes generate arachidonic acid epoxides i.e. the epoxyeicosatrienoic acids (EETs), they are able to accept a wealth of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) to generate a large range of regio- and stereo-isomers with distinct biochemical properties and physiological actions. Probably the best studied are the EETs which have well documented effects on vascular reactivity and angiogenesis. CYP enzymes can also participate in crosstalk with other PUFA pathways and metabolize prostaglandin G2 and H2, which are the precursors of effector prostaglandins, to affect macrophage function and lymphangiogenesis. The activity of the PUFA epoxides is thought to be kept in check by the activity of epoxide hydrolases. However, rather than being inactive, the diols generated have been shown to regulate neutrophil activation, stem and progenitor cell proliferation and Notch signaling in addition to acting as exercise-induced lipokines. Excessive production of PUFA diols has also been implicated in pathologies such as severe respiratory distress syndromes, including COVID-19, and diabetic retinopathy. This review highlights some of the recent findings related to this pathway that affect angiogenesis and stem cell biology.

Total Syntheses of Pladienolide-Derived Spliceosome Modulators.

Pladienolides, an emerging class of naturally occurring spliceosome modulators, exhibit interesting structural features, such as highly substituted 12-membered macrocycles and epoxide-containing diene side chains. The potential of pladienolides as anti-cancer agents is confirmed by H3B-8800, a synthetic analog of this natural product class, which is currently under Phase I clinical trials. Since its isolation in 2004 and the first total synthesis in 2007, a dozen total syntheses and synthetic approaches toward the pladienolide class have been reported to date. This review focuses on the eight completed total syntheses of naturally occurring pladienolides or their synthetic analogs, in addition to a synthetic approach to the main framework of the natural product.