COX/LOX dual inhibitors

Dual inhibitors also demonstrate other therapeutical benefits. They reduced the coronary vasoconstriction in arthritic hearts in a rat model [101], and significantly decreased angiotensin II-induced contractions in human internal mammary artery [102], Opioid receptor activation can cause a presynaptic inhibition of neurotransmitter release mediated by LOX metabolites of arachidonic acid in midbrain neurons. The efficacy of opioids was enhanced synergistically by treatment of brain neurons with COX and LOX dual inhibitors. This report might lead to development of CNS analgesic medications involving combinations of lowered doses of opioids and COX/LOX dual inhibitors [103]. The COX and 5-LOX dual inhibitors also can prevent lens protein-induced ocular inflammation in both the early and late phases [104]. 

In addition to inflammation, another potential role for natural COX and LOX dual inhibitors is in the prevention and treatment of cancers [80], Over expression of COX-2 has been demonstrated in various different human malignancies. COX-2 inhibitors have also been shown to be efficacious in the treatment of animal models of skin, breast and bladder tumors. While the mechanism of action remains to be completely defined, the over expression of COX-2, in excess of production of prostaglandin E2 and 5-hydroxyeicosatetraenoic acid (5-HETE) have been shown to inhibit apoptosis and increase the invasiveness of tumerogenic cell types [81,82]. It is probable that the enhanced production of PGE2 and 5-HETE promotes cellular proliferation, and consequently, increases angiogenesis [83]. 

Based on the structure of curcumin, a series of styrylpyrazoles, styrylisoxazole, and styrylisothiazoles were synthesized and found to be dual inhibitors of COX and 5-LOX tested in rat basophilic leukemia cells. The most potent COX and 5-LOX dual inhibitor had IC50 values at 0.9 pM and 1.2 pM, respectively [159],... 

Figure 12.15. Increased leukotriene formation as an indirect consequence of cyclooxygenase inhibition by, e g., acetylsalicylic acid (ASS a), and structure of the 5-Lox/Cox-2 dual inhibitor tepoxalin (b).

Martel-Pelletier J et al Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal antiinflammatory drugs. Ann Rheum Dis 2003 62 501. [PMID 12759283]... 

Dual inhibitors of COX and 5-LOX will not only suppress prostaglandins that contribute to acute inflammation conditions, but also address the accumulation of phagocytic leukotrienes that are directly associated with chronic inflammation symptoms. With the existence of COX-1 inhibition activities, dual inhibitors will also possess the cardio protective functions. Those characteristics suggest that there may be distinct advantages to dual inhibitors of COX and 5-LOX over selective COX-2 inhibitors and NSAIDs. This concept has been proved to be valid on in vivo models with synthetic drug candidates [105]. 

It is not surprising that fatty acids inhibit COX and LOX enzymes due to their structural similarities with arachidonic acid. A supercritical fluid extract from the fruits of Sabal serrulata (also called Serenoa repens Small. Arecaceae) has been utilized for the treatment of benign prostatic hyperplasia (BPH) and non-bacterial prostatitis. The extract was demonstrated as a dual inhibitor of COX and 5-LOX pathways with IC50 at 28.1 pg/ml and 18.0 (ig/ml, respectively. A further evaluation of the supercritical carbon dioxide extract showed the acidic lipophilic fraction, most likely fatty acids, had the same dual inhibitory activities as the parent extract [121]. 

E-isolinaridial and E-isolinaridial methylketone are two neo-clerodane diterpenoids isolated from the aerial parts of Linaria saxatilis var. glutinosa (Schrophulariaceae). Benrezzouk et al. evaluated these compounds on multiple inflammation pathways and found that they were not COX-1/COX-2 inhibitors [139]. However, E-isolinaridial and E-isolinaridial methylketone were dual inhibitors against purified phospholipase A2 and 5-lipoxygenase. E-isolinaridial and E-isolinaridial methylketone showed potent inhibition of cell-free 5-LOX enzyme with IC50 values of 0.42 pM and 1.41 pM,... 

Dihydroxy-4-methylcoumarin was the most potent COX-1 inhibitor, however without 5-LOX activity. The only dual inhibitor was 7,8-Dihydroxycoumarin (Daphnetin) with moderate and equal potency against both pathways [174]. 

Prenylated flavonoids contain one or two isoprenyl, geranyl, dimethylallyl, and lavandulyl on the skeleton. They have limited distribution and are mostly isolated from the Moraceae family. Chi et al. isolated 19 prenylated flavonoids from six different genera of Chinese medicinal plants and evaluated inhibition activities on eicosanoid metabolisms with multiple cell line models [189]. Two 8-lavandulylated flavanones, kurarinone and sophoraflavanone G, were discovered to be dual inhibitors. They possessed the most potent COX-1 inhibitory activities with IC50 less than 1 pM comparable with that of indomethacin. Sophoraflavanone G isolated from the roots of Sophora flavescense Art (Fabaceae) also had potent 5-LOX inhibition activity with an IC50 below 0.25 pM. 

Medicarpin, 6-demethylvignafuran and 6-hydroxy-2-(2-hydroxy-4-methoxy-phenyl)benzofuran were isolated from a COX and 5-LOX dual inhibitory methylene chloride extract of Dalbergia odorifera T. Chen (Leguminosae). All three compounds were potent 5-LOX inhibitors with IC50 values of 0.5 pM, 0.1 lpM, and 0.05 pM, respectively. Both 6-demethylvignafuran and 6-hydroxy-2-(2-hydroxy-4-methoxyphenyl)benzofuran inhibited prostaglandin production in the mouse mastocytoma cells with IC50 values of 1.2 pM and 3.9 pM, respectively. However, the COX enzyme inhibitory activity of 6-hydroxy-2-(2-hydroxy-4-methoxy-phenyl)benzofuran was not observed in a sheep microsomal assay [199]. 

---