Catechins

B0005-169265
(±)-Catechin Hydrate
B0005-159358
Catechin 3-rhamnoside
103630-03-1
Procyanidin A1
103883-03-0
105330-59-4
105330-59-4
B0005-465174
1257-08-5
130405-40-2
(-)-Catechin gallate
130405-40-2
154-23-4
Catechin
154-23-4
16198-01-9
Catechin pentaacetate
16198-01-9
162602-04-2
162602-04-2
20194-41-6
20194-41-6
225937-10-0
(+)-Catechin hydrate
225937-10-0
24808-04-6
(-)-Epiafzelechin
24808-04-6
2545-00-8
Afzelechin
2545-00-8
28543-07-9
Theaflavin-3'-Gallate
28543-07-9
30462-34-1
Theaflavin-3-Gallate
30462-34-1

Background


Introduction

Natural products (NPs) are one of the most productive libraries of drug leads and new chemical entities for drug discovery. Camellia sinensis (Theaceae) is a source of some highly bioactive compounds and has been extensively studied in last two decades. Green tea leaves are rich in catechins like (-)-epigallocatechin-3-gallate [(-)-EGCG], (-)-epigallocatechin [(-)-EGC], (-)-epicatechin-3-gallate [(-)-ECG], and (-)-epicatechin [(-)-EC]. EGCG is found to be the most abundant of all catechins and has proven to exhibit various pharmacological effects like the scavenging of free radicals, reduction in cancer mortality, reducing the risk of cardiovascular diseases, lowering of plasma cholesterol levels, decrease in fat absorption, improvement in type 2 diabetes, alleviating the effects of ageing, suppression of inflammatory conditions, protection from neurodegenerative diseases, and antimicrobial activities.

Tea catechins and their chemistry

Tea as a beverage is categorized into three major types such as ‘non-fermented’ green tea, ‘semi-fermented’ oolong tea, and ‘fermented’ black tea and puerh tea. Green tea is produced by drying and steaming the fresh leaves which inactivates the polyphenol oxidase. During the fermentation of black tea, the majority of catechins are transformed into the aflavins by the action of polyphenol oxidase. Green tea leaves contain (-)-EGCG, (-)-ECG, (-)-EGC, (-)-EC, and (+)-catechin as major constituents. The basic skeleton of tea catechins consists of two A and B benzene rings and a dihydropyran heterocycle C-ring along with two chiral centers on carbons 2 and 3. Catechin, EC, and EGC carry catechol as a B-ring, while pyrogallol is present as a B-ring in EGC and EGCG. Epicatechin gallate and epigallocatechin gallate are comprised of an extra gallate moiety as a D-ring. Tea catechins are also classified according to their stereochemical configurations such as 2,3-cis type catechins [(-)-EGCG, (-)-(ECG), (-)-EGC, and (-)-EC] and 2,3-trans type catechins [(+)-catechin, (+)-catechin-3-gallate [(+)-CG], (+)-gallocatechin [(+)-GC], and (+)-galloca-techin3-gallate [(+)-GCG]]. Thermodynamically, 2,3-trans type catechins are more stable than 2,3-cis type catechins. The 2,3-cis type catechins isomerize into 2,3-trans type catechins during heat treatment. Tea catechins are very stable in acidic solutions (pH < 4), while they are highly unstable in alkaline solutions (pH > 8). Moreover, EGCG and EGC are more prone to hydrolysis compared to EC and ECG in basic solution. Tea catechins are also classified as catechol-catechins (ECG and EC) and gallo-catechins (EGCG and EGC) according to the number of hydroxyl groups attached to the B ring. It has been proved that rings possessing three hydroxyl groups oxidize more rapidly than rings possessing two hydroxyl groups due to the formation of free radicals. Oxidation resulted in the removal of a single hydrogen radical and formation of a semiquinone radical with an unpaired electron on the oxygen atom. The oxidative degradation tendency of tea catechins is reported to be in the order of EGCG > EGC > ECG > EC.

Bioavailability and toxicity issues of tea catechins

Numerous pharmacokinetic studies have reported the low bioavailability of green tea extract or pure EGCG. In Phase I clinical trials of EGCG, Pisters et al. reported that only a small percentage of orally administered catechin was available in the blood. The mean peak level of EGCG reached 0.17 μM after 1.5 h with 2 cups of green tea and only 4 to 8% of the ingested EGCG was excreted in urine. In another study, with an oral dose of EGCG in the morning after overnight fasting, the plasma concentration level decreased gradually in 24 h. The elimination half-life of EGCG was measured to be 3.4±0.3 h. The major factors influencing the bioavailability of EGCG are:

Oxidative degradation:

Tea catechins with a pyrogallol moiety on the B-ring possess a strong tendency to oxidize and form dimerized products which have relatively lower pharma-cological potential compared to the parent molecule.

Gastrointestinal instability:

Tea catechins, especially EGCG, are hydrolyzed to phenolic acids by the attack of intestinal bacteria. EGCG is highly incompatible with divalent cations such as Ca2+ and Mg2+. In the presence of milk, the vascular protective effect of EGCG is reduced.

Metabolic transformations:

Tea catechins undergo phase-II biotransformations rapidly such as methylation, glucuronidation, and sulfation. Rapid methylation by catechol-O-methyltransferase (COMT) of EGCG results in a significant reduction of the plasma EGCG concentration.

Poor permeability:

Due to their hydrophilic nature, tea catechins do not cross cell membranes. Suganuma et al. reported the inability of EGCG to treat neurodegenerative diseases, due to its insignificant level in brain tissue.

Substrate of multidrug resistance-associated protein (MRP):

Active efflux of EGCG and its methyl metabolites for MRP has been reported by Hong et al.

Reference:

Bansal, S., Vyas, S., Bhattacharya, S., & Sharma, M. (2013). Catechin prodrugs and analogs: a new array of chemical entities with improved pharmacological and pharmacokinetic properties. Natural product reports, 30(11), 1438-1454.