Semi- and total synthesis of bioactive neoclerodane diterpenes

The genus Teucrium, a member of the family Lamiaceae, has approximately 300 species all over the world, mostly in the Mediterranean region. Teucrium is represented by 34 species (46 taxa) in Turkey, and 16 of these taxa are endemic. Teucrium species have been used in folk medicine as antidiabetic, anti-inflammatory, antiulcer, and antibacterial agent. The studies showed that Teucrium species demonstrate antimicrobial, antioxidant, and antifungal activities. The main compounds isolated from Teucrium species to date are clerodane and neoclerodane diterpenes. Therefore, it can be observed that clerodane and neoclerodane diterpenoids are responsible for those activities that Teucrium species exhibited. Considering all described activities, in this thesis, the antioxidant and anticholinesterase activities of acetone and methanol extracts of 12 Anatolian Teucrium species (Teucrium alyssifolium, T. antitauricum, T. chamaedrys, T. divaricatum, T. ekimii, T. flavum, T. leucophyllum, T. microphyllum, T. montbretii, T. polium, T. sandrasicum, T. scordium) were studied in vitro through DPPH free radical scavenging activity, ABTS cation radical scavenging activity, CUPRAC (Cupric Reducing Antioxidant Capacity), and Ellman methods. Most of Teucrium species showed high antioxidant and anticholinesterase activities. Although Teucrium species contain bioactive clerodane and neoclerodane diterpenes, the amount of these compounds are very low. Columbin is a cytotoxic clerodane diterpenoid isolated from the roots of Jateorhiza and Tinospora species. These species generally grow in Asia, Africa and have been used in folk medicine for their apparent analgesic and antipyretic activities. Columbin is of particular interest due to its structural similarity to the known kappa opioid receptor (KOR) agonist salvinorin A. Given that the KOR is of interest in the study of many serious diseases, such as anxiety, depression, and drug addiction. Obtaining natural or semisynthetic molecules with KOR activity recently has gained much interest. Thus, in the present study, derivatives of columbin were designed and synthesized using known structure-activity relationships (SAR) of salvinorin A at KORs. The structures of the columbin analogues prepared were elucidated by NMR spectroscopy and mass spectrometry, and their KOR activity was investigated in vitro by inhibition of forskolin-induced cAMP accumulation. Some improvements in KOR activity were observed in columbin derivatives over their parent compound. This work represents not only the first evaluation of columbin at the KOR, but also the first work to explore synthetic strategies that are tolerated on the columbin core. As mentioned before, salvinorin A is a potent KOR agonist, so in addition to the semisynthetic studies, the total synthesis of a salvinorin A inspired structure was successfully realised in 16 steps.