Chemistry of South African Lamiaceae: Structures and Biological Activity of Terpenoids Chemistry of South African Lamiaceae: Structures and Biological Activity of Terpenoids

South Africa flora is one of the most important mega floras with high endemic species percentage. Lamiaceae is an important family in South Africa with ±308 species in 41 genera and contains many important plants (~23%) traditionally used for treatment of different human diseases. The chemical profile of Lamiaceae is very rich in terpenoids in general and more specifically diterpenes. Genera like Leonotis and Plectranthus are well studied, while on the other hand, genus like Stachys (~41 species, ~50% endemic) didn’t receive any attention. Different classes of diterpenes were identified and some of them demonstrating important biological activities.


Introduction
The Green economy concept has been driven as an urgent need for addressing global challenges in vital fields like energy, environment, and health. Green economy is expected to play a very important role in changing the way that society manages the interaction of the environmental and economic domains. Consequently, a new paradigm has been established and shifted toward green economy or green growth. Natural products represent one of the most important elements required to build safe and effective economy especially in health sector. South Africa (SA) is recognized as one of the most biodiverse country in the world with 20,456 indigenous vascular plant taxa recorded where 13,265 (65%) are endemic [1,2].
The Lamiaceae (formerly Labiateae, mint family) is a cosmopolitan family with ~7136 species in 236 genera. Most species are shrubby or herbaceous and trees are extremely rare [3]. The Lamiaceae family has great economic value, as it contains several horticultural species, most of which are used as culinary herbs like salvia, rosemary, ocimum, mint, Leonotis, etc. Lamiaceae species are known to contain pharmacologically active terpenoids with a wide spectrum of bioactivity and expected to play more important roles in the process of drug discovery as well as cosmetic, food, and pesticides industries [4][5][6]. In the Sub-Saharan region, ~60 genera with ±980 species were reported [7]. SA considers as a diversity spot of Lamiaceae with ±308 species in 41 genera [8]. The species occur predominantly in the summer and/or winter rainfall areas. The habitats are different and vary to a great extent [9].
However, the South African flora is one of the most important mega floras for its unique diversity and endemism, it receives low attention in terms of bioprospecting, and the number of research paper every year dealing with chemical/biological profiling is still beyond the required level. This review serves as a background for the chemistry of all species belonging to the family Lamiaceae growing in SA and it covers publications till 2017. The articles information's abstracted from Sci-finder database [10] and includes all species growing in SA as well as other places. This chapter doesn't cover the essential oils and Plectranthus barbatus, which recently reviewed by others [11,12].

Terpenoids of different genera of South African Lamiaceae
Different classes of secondary metabolites have been identified from Lamiaceae, the majority of the isolated compounds are terpenoids (~71%), and additionally other classes of compounds like flavonoids, α-pyrone derivatives, phenolic acids, and alkaloids were reported. Mono-, sesqui-, and tri-terpenoids are relatively small in number (~15%) when compared to diterpenoids and it was reported that more than 100 of different diterpene skeletons were identified which indicate the high evolutionary index of Lamiaceae [13]. According to the literature, the genera Leonotis (known as wild dagga) and Plectranthus have received the highest attention where 70 (Leonotis) and 94 (Plectranthus) compounds were identified so far, the majority of the isolated compounds are labdane diterpenes. In this chapter, the different genera have been listed alphabetically and the trivial names have been retained in the cases where they were given by authors and/or chemical abstracts.

Ballota genus
Ballota is represented by one species in SA vizB africana. Hispanolone (8) was isolated from the aerial parts [16].

Cedronella genus
Cedronella genus is represented by only one species in SA viz C. canariensis. The phytochemical studies of the aerial parts resulted in isolation of a dimer of d-pinocarvone (9), cedronellone (10), and ursolic acid (11) [17].

Clerodendrum genus
Seven species were recorded in SA and clerodendrumic acid (12) was isolated from C. glabrum var. glabrum and showed weak antifungal, antibacterial, and cytotoxic activities [18].

Leonotis genus
Seven species were recorded in SA and two of them were extensively studied. Traditionally, this genus is used to substitute hemp and called as wild dagga; however, there is no much scientific biological evidences supporting such claim. The chemistry was started in early 60s of the last century by South African researchers. Many labdane diterpenes have been isolated. The chemistry of the genus was covered previously by a review published by Piozzi et al. [24].
From a commercially material, originally collected from Peru, five inseparable epimeric mixtures of bis-spirolabdane diterpenoids, resulted from biosynthetic epimerization of three different structures around C-13 and C-15, have been isolated and identified as leonepetaefolin A (63)  The absolute configuration of the epimeric mixture 63 and 64 was determined by X-ray crystallographic analysis [39].

Plectranthus genus
About 300 species distributed in tropical and warm regions of the old World, 45 species recorded in SA, from which 19 species were studied for their chemical and/or biological constituents. The genus is characterized by the presence of orange glands that distributed in the aerial parts and contain highly oxygenated (and modified) abietane-type diterpenoids. Others, e.g., kaurane, labdane, phyllocladane as well as the rare skeleton halimane diterpenoids were described.

Plectranthus ecklonii
Plectranthus ecklonii is traditionally used in South Africa for treating stomach aches, nausea, vomiting, and meningitis. Ecklonoquinone A (114) and B (115) and parviflorons D (116) and F (117) were isolated [54,55]. Compound 117 showed potent activity against Listeria monocytogenes and M. tuberculosis and both 116 and 117 were found to be very toxic against vero cell lines. The potency of parvifloron D (116) was further confirmed and showed fast and potent apoptotic inducer in leukemia cells [56].

Salvia genus
The genus Salvia is known as sage and is the largest genus in Lamiaceae, comprising over 900 species distributed throughout the world. Salvia is represented by 30 species in SA, distributed mainly in great cape region. The chemistry of Salvia is rich in diterpenoids and different skeletons have been reported, also, many members of this genus is well known for its curative and medicinal properties like S. officinalis and S. miltiorrhiza.

Conclusion
South African flora characterized by high endemism and unique floral kingdom is only located in the great cape region. Lamiaceae is represented by ~308 species widely distributed all over the country. In general, the bioprospecting of SA flora including Lamiaceae is not reached; yet the required level and more attention are required to explore the potential of their chemical constituents. The present work shades the light on the isolated terpenoids of all listed species in updated SA flora checklist. It is interesting to indicate that Plectranthus genus contains mostly abietane diterpenes and shows potent activity as demonstrated by coleon U and parviflorons F and D. On the other hand, leoleorin C from L. Leonurus showed moderate binding affinity (Ki = 2.9 μM) to the Sigma 1 receptor. These compounds and others may be considered as a model for drug discovery for human benefits.