Raging the War Against Inflammation With Natural Products

Abstract

Over the last few decade Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are the drugs of choice for treating numerous inflammatory diseases including rheumatoid arthritis. The NSAIDs produces anti-inflammatory activity via inhibiting cyclooxygenase enzyme, responsible for the conversation of arachidonic acid to prostaglandins. Likewise, cyclooxegenase-2 inhibitors (COX-2) selectively inhibit the COX-2 enzyme and produces significant anti-inflammatory, analgesic, and anti-pyretic activity without producing COX-1 associated gastrointestinal and renal side effects. In last two decades numerous selective COX-2 inhibitors (COXIBs) have been developed and approved for various inflammatory conditions. However, data from clinical trials have suggested that the prolong use of COX-2 inhibitors are also associated with life threatening cardiovascular side effects including ischemic heart failure and myocardial infection. In these scenario secondary metabolites from natural product offers a great hope for the development of novel anti-inflammatory compounds. Although majority of the natural product based compounds exhibit more selectively toward COX-1. However, the data suggest that slight structural modification can be helpful in developing COX-2 selective secondary metabolites with comparative efficacy and limited side effects. This review is an effort to highlight the secondary metabolites from terrestrial and marine source with significant COX-2 and COX-2 mediated PGE₂ inhibitory activity, since it is anticipated that isolates with ability to inhibit COX-2 mediated PGE₂ production would be useful in suppressing the inflammation and its classical sign and symptoms. Moreover, this review has highlighted the potential lead compounds including berberine, kaurenoic acid, α-cyperone, curcumin, and zedoarondiol for further development with the help of structure-activity relationship (SAR) studies and their current status.

Keywords: anti-inflammatory; cyclooxygenase pathway; cyclooxygenase-2; inflammation; natural products; prostaglandin E2.

Figure 1

Mechanism of action of cyclooxygenase pathway.

Figure 2

Structure of alkaloids with potent COX-2 and PGE₂ inhibitory activity (1) Berberine, (2) Rutaecarpin, (3) evodiamine, (4) Dehydroevodiamine, (5) tryptanthrin, (6) 7′-(3′,4′dihydroxyphenyl)-n-[(4-methoxyphenyl) ethyl] propenamide (Z23), (7) acetylmelodorinol.

Figure 3

Structure of terpiniods with potent COX-2 and PGE₂ inhibitory activity (8) Acanthoic acid (9)16aH,17-iso- valerate-ent-kauran-19-oic acid, (10) ent-kaur-16-en-19-oic acid, (11) ent-pimara-8(14),15-dien-19-oic acid, (12) Arteminolide B, (13) yaminterriterms B, (14) fomitopinic acid A, (15) Fomitoside, (16) fomitoside F, (17) Manoalide, (18) Scalaradial, (19) Buddledin A, (20) Crocetin monogentibiosyl ester, (21) cyclomargenyl-3-0 -beta-caffeoyl ester, (22) alpha-cyperone, (23) zedoarondiol, (24) curdione, (25) curcumin, (26) eupatolide, (27) koetjapic acid, (28) 3-oxoolean-12-en-30-oic (28), (29) betulinic acid.

Figure 4

Structure of stilbenes with potent COX-2 and PGE₂ inhibitory activity (31) transresveratrol, (32) aiphanol, (33) isorhapontigenin, (34) oxyresveratrol, (35) artocarpesin, (36) pinosylvin, (37) desoxyrhapontigenin.

Figure 5

Structure of flavanoids with potent COX-2 and PGE₂ inhibitory activity (38) scopoletin, (39) (+)-catechin, (40) (+) gallocatechin, (41) 4′−0-Me-ent- gallocatechin, (42) ouratea-catechin, (43) proanthocynidin A, (44) flavonoid c, (45) diinsinin, (46) aciculatin, (47) kaempferol, (48) gigantol, (49) myricetinglucuronide, (50) genistein, (51) anthocyanin, (52) tectorigenin, (53) tectoridin, (54) morusin, (55) kuwanon C, (56) sanggenon B, (57) sanggenon C, (58) sanggenon D, (59) wogonin, (60) oroxylin A, (61) baicalein.

Figure 6

Structure of saponins with potent COX-2 and PGE₂ inhibitory activity (62) capillarisin, (63) monodesmosides, (64) kalopanxsaponin-A, (65) ginsenosides, (66) saponin prosapogenin D methyl-ester, (67)buddlejasaponin I.

Figure 7

Structure offatty acids with potent COX-2 and PGE₂ inhibitory activity (68) 2,4,5-trimethoxybenzaldehyde, (69) oleic acid, (70) trans-asarone, (71) ergosterol, (72) ergostra-4,6,8(14),22-tetraen-3-one, (73) 1-oleoyl-2-linoleoyl-3-palmitoylglycerol, (74) eburicoic acid, (75) 13-(S)-hydroxy-9Z,11E-octadecadienoic acid [(S)-coriolic acid, (76) palmitic acid, (77) oleic acid, (78) linoleic acid, (79) linolenic acids.

Figure 8

Sturcture of miscellaneous with potent COX-2 and PGE₂ inhibitory activity (80) taiwanin C (81), balanophonin (82), sitoindoside IX (83), withanolide sulfoxide (84), gingcrol, (85) altholactone (86), goniothalmin (87), diglyccride (88), ligustilide (89), bruceine D (90), bandelin (91), guggulstcrone (92), isoliquiritin (93), isoliquiritigenin (94), sphondin (95), 4-Methoxyhonokol (96), Schisandrin (97), bocravinone B.