From the structural composition of purified nor-oleanane triterpenoids compounds, it is noticeably that inhibitory activities decline after the substitution of C-28 by sugar moieties. According to Liu et al, 2016, a free carboxylic group at C-28 is essential for XOD inhibition. The compounds brachyantheraoside B4 and L-rhamnopyranosyl-(1?2)- ? -L-arabinopyranosyl-30- norolean-12,20(29)-dien-28-oic acid) demonstrated the highest XOD inhibitory activities in comparison to (brachyantheraoside D1) since the hydroxyl group oxidation (brachyantheraoside B4), or exocyclic double bond (L-rhamnopyranosyl-(1?2)- ? -L-arabinopyranosyl-30- norolean-12,20(29)-dien-28-oic acid) at C-20 to the carboxylic group (brachyantheraoside D1) negatively effect.
Consequently, oxygen substitution at C-23 may augment the inhibitory activities at some level.
Two new cucurbitane triterpenoids (cucurbita-1(10),5,22, 24-tetraen-3-ol and 5,19 -epoxycucurbita-6,22,24-trien-3-ol and multiflorane triterpenoid (3 ? -hydroxymultiflora-8-en-17-oic acid) were purified from the stems of Momordica charantia by (Lin et al, 201b). The compound (cucurbita-1(10),5,22, 24-tetraen-3-ol) (IC50: 36.8 ± 20.5 M) exhibited higher XOD inhibitory activity when compared to the (5,19 -epoxycucurbita-6,22,24-trien-3 ol) (IC50: 124.9 ± 8.3 ?M). Though, the skeleton of compound cucurbita-1(10),5,22, 24-tetraen-3-ol and 5,19 -epoxycucurbita-6,22,24-trien-3 ol was similar.
It represents that association of epoxy moiety between C-5 and C-19 of compound (5,19 -epoxycucurbita-6,22,24-trien-3 ol) that weakened the XOD inhibition effect (Liu et al, 2010). Later, in 2011, Lin et al. also reported that taiwacin A and cucurbitane-type triterpene glycoside from the fruits and stems of Momordica charantia are powerful XOD inhibitors.
Still, the triterpenoids (garcinielliptones Q and S) from Garcinia subelliptica failed to show XOD inhibitory activity excepting (phloroglucinols and garcinielliptones, A) which inhibited XOD in a dose-dependent manner (IC50: 53.
8 ± 11.5 M) (Lin et al, 2012). 24-methylenelanost-8-en-3-ol (IC50: 16.96±0.69 M) also demonstrated XOD inhibitory activity when compared to other triterpenoids compounds (lupeol, betulinic acid, 24-methylenelanost-8-en-3-one, 24Z-ethylidenelanost-8-en-3-one, 3-acetyl ursolic acid and 2-hydroxy-24-methylenelanostan-1,8-dien-3-one) in stem bark of Klainedoxa gabonensis (Nkawen et al, 2013). amyrin from the Garcinia subelliptica (pericarp, heartwood, and seed) and a biterpeniod tanshinone (IC50: 11.71 ± 0.89 g/ml) likely inhibited UA synthesis(Lin et al, 2012 and Chen et al, 2016). Thymol, a monoterpenoid natural compound was reported inhibiting UA synthesis by attaching at FAD domain of XOD by hydrogen bonding (Glu 802) with the carbonyl group of the pyrimidine ring (Abbasi et al, 2018).
Another triterpenoid compound was extracted from Tribulus arabius, purified and tested by Abu-Gharbieh et al, (2018), Ursolic acid, found to have great XO inhibitory power and reported it as a promising application as anti-HUA treatment.
Stilbenes are polyphenolic compounds (C6-C2-C6) broadly distributed in plants. These compounds have a wide range of therapeutic activities against many illnesses (anti-inflammatory, anti-tumour, antioxidant etc.) (Glauert et al, 2010 and Weng et al, 2010). Cajaninstilbene acid from the leaves of Cajanus cajan (L.) Millsap demonstrated strong XOD inhibitory activity (IC50: 3.62 ?M) (Wu et al, 2011). Remarkably, the compound cajaninstilbene acid showed stronger XOD inhibitory activity when measured to standard drug allopurinol (IC50: 8.95 ?M) and resveratrol (IC50: 7.14 ?M) due to C6 carboxyl group. Furthermore, revealed molecular docking study results that phenyl ring (C-C6) of cajaninstilbene acid interact/sandwich with amino acids residues Phe (914 and 1009) and generates strong (?- ?) effect with the two residues. Electrostatic interaction had a vital role in linking with XOD enzyme. An oligostilbene (vaticanol A) from the Vatica mangachapoi was also investigated for inhibition of XOD (IC50: 23.3 1.8 ?M) (Qin et al, 2011).
2.8. Phenylethanoid Glycosides
Phenylethanoid glycosides are water-soluble compounds present in various plant kingdom organisms and have numerous health benefits. Wan and Xie isolated in 2008, verbascoside (Phenylethanoid glycosides) from the seed of Plantago asiatica L and assessed for XOD inhibition. Their investigation revealed that verbascoside strongly inhibits XOD enzyme (IC50 81.11 mg mL?1). In another investigation, Wan et al. reported in 2016 that phenyl rings of verbascoside aid in the linking with XOD via MPT domain.
Ahmad et al. (2010) discussed that oxindole alkaloids from Isatis costata have a wide range potential to fight HUA. They purified six oxindole alkaloids compounds (costinones A, costinones B, isatinones A, isatinones B, indirubin, and trisindoline) from the whole plant of Isatis costata. The compound costinones A (IC50: 90.3 ± 0.06 ?M) had highest XOD inhibitory activity compared to the other compounds (IC50: costinones B 101.7 ± 0.02 ?M, isatinones A 117.5 ± 0.03 ?M, isatinones B 130.6 ± 0.05 ?M, indirubin 170.5 ± 0.01 ?M, and trisindoline 179.6 ± 0.04 ?M). Remarkably, indirubin, a red colour pigment obtained from plants and microbes, have an ample range of pharmacological properties. It is an active ingredient used in traditional Chinese medicine ‘danggui longhui wan’ and ‘Banlan Gen.’ Scientists are trying to produce a high amount of indirubin by the engineering of microbes(Han et al, 2008). The study results of Ahmad et al. (2010) advances to utilize indirubin and other alkaloids compounds for the treatment of HUA. Another recently published investigation done by Sang and coworkers (2017) also described that alkaloids from Nelumbinis folium have the power to fight HUA. The crude extract of Nelumbinis folium strong XOD inhibitory activity (3.313 ?g/mL). Furthermore, they also purified various alkaloids compounds, e.g., nuciferine, O-nornuciferin, N-nornuciferin. roemerine, N-methylisococlaurine, armepavine and asimilobine compounds by using UHPLC-Q-TOF-MS.
HUA is a menacing life disorder; prevalence rate increases significantly and becomes like a pandemic phenomenon. Tackling HUA is a very necessary assignment that, manifestly, needs the joint efforts of scientists from different disciplines. For more than 50 years the only drug inhibitor of XO available on the market was allopurinol. An increase in the search for new inhibitors of XO in the last decade occurred because the activity of the enzyme has been associated not only with hyperuricemia and gout but also with a variety of other conditions, such as diabetes, hypertension and cardiovascular disease.
According to published results, it is confirmed that plants and their metabolites may have the potential to cope with HUA disorder via inhibiting a responsible key enzyme (XOD). Bioactive compounds enter active site of XOD, formed XOD- bioactive compounds complex through hydrophobic forces, linked with surrounding XOD amino acid and occupied the active site which prevent further entrance of substrate and thus inhibit the synthesis of UA. Notably, a plethora of bioactive compounds in plants inhibits XOD enzyme close to or higher (luteolin, quercetin, isorhamnetin, galangin, chrysin, prosapogenin, cajaninstilbene acid, etc.) than reference drug (allopurinol). However, there is still a need for elucidating the mechanism of how bioactive compounds bind with XOD. Last but not least, besides the synergy from all disciplines of researchers worldwide, various novel technological amelioration in natural bioactive compounds extraction, isolation, optimization procedure, characterization, identification and evaluated for XOD inhibitory activity (in-vitro and in-vivo) should be employed to cope with this notorious disease.
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