# Biosynthesis of Nature-Inspired Unnatural Cannabinoidss
## 1 _Cannabis sativa_ and Cannabinoidss--An Introduction  
Natural products and their derivatives make up more than half of all medicine we use today [1]. The organisms that make them range widely from plants to microorganisms such as bacteria and fungi. Their structural complexity and diversity often provide a wide range of bioactivities that can be harnessed as therapeutic agents for various diseases and indications. Cannabinoidss are one such class of natural products originally isolated from the plant _Cannabis sativa_ that offers a wide range of bioactivities such as anti-bacterial [2], anti-epileptic [3] and anti-tumor effects [4]. These chemical compounds are meteropenoids characterized by a resorcinyl-polyketide core attached to a 10-carbon monoterpene [5]. They are found to interact with G protein-coupled receptors (GPCRs) such as cannabinoid receptor type 1 (CB1) receptors which are mainly found in the central nervous system (CNS), and cannabinoid receptor type 2 (CB2) receptors found predominantly in the peripheral nervous system (PNS). However, studies have also uncovered these receptors to be expressed in different tissues such as the adrenal gland, lungs, heart, spleen and tonsils [6]. The widespread expression of these receptors suggests that cannabinoidss have the potential to target a wide range of biological targets in the human body. The class of cannabinoidss derived from _C. sativa_ was latertermed phytocannabinoids due to the discovery of the endocannabinoids in humans that are also found to interact with the same GPCRs. Additionally, chemists also synthesized synthetic analogues of these compounds with interactions towards the same receptors and are hence termed the synthetic cannabinoids. This review will focus on the class of phytocannabinoids. Although extracts of the _Cannabis_ plant have been the subject of illicit use in the last few decades due to some psychoactive components such as \(\Delta^{9}\)-tetrahydrocannabinol (THC), it was first used as a traditional medicine and this suggests that there is therapeutic potential in this class of natural products. In the context of _Cannabis_ extract, the \"entourage effect\" is often discussed. The term was first proposed in 1998, where it was observed that other metabolites and similar molecules increased the activity of the primary endogenous cannabinoids [7], but now more commonly refers to the synergistic enhancement of main cannabinoids from other components in the plant extract. However, there are differing views on whether this claim of polypharmacy has strong supporting evidence. Further discussion can be found in recent reviews and references therein [8; 9; 10; 11]. Currently, _C. sativa_-derived cannabinoids are used clinically for spasticity treatment in multiple sclerosis patients who are non-responsive to other medications (Sativex(r)) in some European countries [12]. Most recently, Epidiolex(r) became the first _Cannabis_-based drug to be approved by the US Food and Drug Administration (FDA) to reduce seizures in epilepsy patients with Dravet syndrome and Lennox-Gastaut syndrome [13]. These medicines are largely based on the two major cannabinoids produced by _C. sativa_, THC and cannabidiol (CBD), which are produced as the acidic forms tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), respectively, in the plant and readily decarboxylated during storage and heating [14]. These compounds represent only less than 2% of the total repertoire of naturally occurring phytocannabinoids available. To date, more than 100 cannabinoids have been identified from _C. sativa_ alone [15], but research on the potential therapeutic uses of these other lesser known cannabinoids is still in its infancy. This is largely due to the low yield available to extract from the plant, and the inability to isolate a strain of _C. sativa_ that selectively produces more of these rarer cannabinoids. In addition, different cultivars of _Cannabis_ contain different proportions of cannabinoids.