# Non-Cannabinoid Metabolites of _Cannabis sativa_ L. with Therapeutic Potential
## 2 Non-Cannabinoid Compounds
### Flavonoids  
Flavonoids are a large family of polyphenolic plant compounds that naturally occur in fruits, vegetables, chocolate, and beverages such as wine and tea. There are six classes of flavonoids including anthocyanidins, flavan-3-ols, flavonoids, flavanones, flavones, and isoflav. Chemically, flavonoids have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B), and a heterocyclic ring. This carbon structure can be abbreviated C6-C3-C6. Figure 3 below shows the structures of some flavonoids. Flavonoids are found in a wide range of plants and may act as physiological regulators, cell-cycle inhibitors and/or chemical messengers. They are also responsible for plant pigmentation (flower coloration to attract pollinator animals/insects), UV filtration/protection, and symbiotic nitrogen fixation. Flavonoids provide color, flavor and aroma. These class of compounds also have anticancer, antioxidant, antithrombotic, antidiabetic and neuroprotective activities via modulation of a number of cell-signaling cascades. A 2016 study by [PERSON] and colleagues explored the relationship between dietary flavonoid intake (of flavonols, flavones, flavanones, flavanones, flavan-3-ols, anthocyanins, and flavonoid polymers) and weight change at 4-year intervals between 1986 and 2011 of 124,086 men and women. In conclusion of this study, intake of foods rich in flavonoids, flavan-3-ols, anthocyanins, and flavonoid polymers, inversely related to weight gain. Anthocyanidins had the greatest negative correlation with weight maintenance [35]. See Tables 5 and 6 below for some biological properties of some common classes of flavonoids. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Flavonols** & **Phenolic Amides** & **Flavones** & **Phenolic Acids** \\ \hline \multirow{2}{*}{Catechin} & N-trans- & \multirow{2}{*}{Cannflavin A} & Hydroxycinamic \\  & caffeoyltyramine & & acids \\ \hline \multirow{2}{*}{Epicatechin} & Flavonoids & Cannflavin B & Chlorogenic acid \\ \hline \multirow{2}{*}{Flavanone} & Flavonol & \multirow{2}{*}{Luteolin-7-O-glucose} & \multirow{2}{*}{Caffeic acid} \\  & & & \\ \hline \multirow{2}{*}{Naringenin} & \multirow{2}{*}{Rutin} & Apigenin-7-O-glucose & \\  & & & \\ \hline \multirow{2}{*}{Lignanamides} & Quercetin-3- & \multirow{2}{*}{Luteolin} & \multirow{2}{*}{Ferulic acid} \\  & glucoside & & \\ \hline \multirow{2}{*}{Cannabisin A} & Kaempfer-3-O- & \multirow{2}{*}{Apigenin} & \multirow{2}{*}{} \\  & & & \\ \hline \multirow{2}{*}{Cannabisin B} & Quercetin & & \\ \hline \multirow{2}{*}{Cannabisin C} & Kaempfer & & \\ \hline \hline \end{tabular}
\end{table} 
Table 4: List of phenolic compounds in commercial _Cannabis sativa_ L. [34]. Over 20 different flavonoids have been identified in cannabis, most of which fall into the flavonoid and flavone group [2]. One such flavonoid is cannflavin A, which is considered to be 30 times more effective than Aspirin at inhibiting prostaglandin E2, a significant modulator of inflammation [37]. Cannflavin B is also an inhibitor of prostaglandin E2 [38]. Another major flavonoid derived from cannabis is caflanone. In recent studies, caflanone demonstrated activity against the human coronavirus OC43 (HCOV-OC43) also known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). HCOV-OC43 belongs to clade b of the genus _Betacoronavirus_[39]. In vitro, caflanone inhibited HCOV-OC43 with an EC50 of 0.42 uM [39]. In silico studies showed that caflanone may act by inhibiting the angiotensin-converting enzyme 2 (ACE2) receptor found in the lung and respiratory tract, and used by the virus during cell entry and infection. Caflanone was also shown to have strong binding affinity to two of the proteases (PLpro and 3 CLpro) are vital to the replication of SARS-CoV-2 in humans, thereby inhibiting viral entry to and/or replication within human cell [39]. Figure 4 shows the main interactions of caflanone with the proteins ACE2 (catalytic site/zinc metallopeptidase domain), Glu375, Glu402, ZnS803, HIS374, Phe274 and Arg 273 [39].