Small Molecule Soluble Epoxide Hydrolase Inhibitors in Multitarget and Combination Therapies for Inflammation and Cancer

Abstract

The enzyme soluble epoxide hydrolase (sEH) plays a central role in metabolism of bioactive lipid signaling molecules. The substrate-specific hydrolase activity of sEH converts epoxyeicosatrienoic acids (EETs) to less bioactive dihydroxyeicosatrienoic acids. EETs exhibit anti-inflammatory, analgesic, antihypertensive, cardio-protective and organ-protective properties. Accordingly, sEH inhibition is a promising therapeutic strategy for addressing a variety of diseases. In this review, we describe small molecule architectures that have been commonly deployed as sEH inhibitors with respect to angiogenesis, inflammation and cancer. We juxtapose commonly used synthetic scaffolds and natural products within the paradigm of a multitarget approach for addressing inflammation and inflammation induced carcinogenesis. Structural insights from the inhibitor complexes and novel strategies for development of sEH-based multitarget inhibitors are also presented. While sEH inhibition is likely to suppress inflammation-induced carcinogenesis, it can also lead to enhanced angiogenesis via increased EET concentrations. In this regard, sEH inhibitors in combination chemotherapy are described. Urea and amide-based architectures feature prominently across multitarget inhibition and combination chemotherapy applications of sEH inhibitors.

Keywords: combination chemotherapy; inflammation; multitarget therapy; soluble epoxide hydrolase (sEH) inhibitors; urea derivatives.

Figure 1

Biphasic effect of EETs (EETs: epoxyeicosatrienoic acids; sEH: soluble epoxide hydrolase; DHETs: dihydroxyeicosatrienoic acids).

Figure 2

Potential role of sEH in inflammation-driven carcinogenesis (PLA2: phospholipase A2; EETs: epoxyeicosatrienoic acids; sEH: soluble epoxide hydrolase; DHETs: dihydroxyeicosatrienoic acids; COX: cyclooxygenase; LOX: lipoxygenase; PGs: prostaglandins; PPAR-γ: Peroxisome proliferator-activated receptor gamma; NF-κβ: (nuclear factor kappa-light-chain-enhancer of activated B cells; VCAM: vascular cell adhesion molecule; iNOS: Inducible nitric oxide synthase). (Figure adapted from [5]).

Figure 3

Urea based soluble epoxide hydrolase inhibitors.

Figure 4

Amide based soluble epoxide hydrolase inhibitors.

Figure 5

Chemical structure of small molecule inhibitors of human soluble epoxide hydrolase (sEH) in X-ray crystal structure complexes with PDB and IC₅₀ values.

Figure 6

Natural products displaying soluble epoxide hydrolase (sEH) inhibitory properties (a) Isopropylstilbene from Photorhabdus, (b) Honokiol isolated from Magnolia officinalis, (c) β-amyrin acetate isolated from Acer mandshuricum, (d,e) from Rheum undulatum, (f) MMU from Pentadiplandra brazzeana Baillon, (g) Selaginellin derivatives from Selaginella tamariscina, (h) (E)-1-(2,6-dihydroxy-3,4-dimethoxyphenyl)-3-phenylprop-2-en-1-one from Docynia indica (Wall.) Decne. (i) Isomahanine and (j) Bisisomahanine from the aerial parts of Glycosmis stenocarpa, (k) the seeds of Cassia tora, (l) phenolic glycosides from Polygala tenuifolia. (m) Prenyl-flavonoids from Epimedium koreanum Nakai (n) 4H-tomentosin from Inula helenium.

Figure 7

Chemical structures of small molecule based dual COX-2/sEH inhibitor, 5-LO/sEH inhibitor, FLAP/sEH inhibitor, sEH/ LTA4H inhibitors, sEH/FAAH inhibitors, sEH/PDE4 inhibitors, and FXR activator/sEH inhibitor. (COX: cyclooxygenase; sEH: soluble epoxide hydrolase; 5-LO: 5-lipoxygenase; FLAP: 5-lipoxygenase activating protein; LTA4H: leukotriene A4 hydrolase; FAAH: fatty acid amide hydrolase; PDE4: phosphodiesterase 4; FXR: Farnesoid X receptor).

Figure 8

Chemical structures of small molecules used in dual inhibition of sEH in combination chemotherapy.