Production of medicinally active ferutinin and teferdin from Ferula plants

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Ferula Hermonis colloquially known as "Zallouh" is a flowering plant which grows in the areas surrounding mount Hermon in Lebanon, Syria, and Israel/Palaestine. It is commonly used by locals, especially in Lebanon as a folkloric sexual enhancement drug. As it was shown later, Ferula Hermonis extracts demonstrate significant activity in male rats, increasing overall mating events to a similar level of effect as Sildenafil (sold under the brand name Viagra). This remarkable effect was poorly understood until very recently, because Ferula Hermonis does not contain any notable alkaloids or sterols. Its effect is derived from a terpenoid which until recently went unnoticed by science and known as "Jaeshkenadiol". More specifically, its para-hydroxybenzoate ester "Ferutinin" is a potent estrogen receptor modulator and agonist, which stimulates sexual activity in both male and female mammals. Ferutinin can increase testosterone levels in mice 100-200% within 30 minutes temporarily, with Teferdin (benzoate ester of jaeshkenadiol) showing a slower onset but equally large build-up over repeated doses. While it has obvious benefits as a sexual dysfunction medication its effects as an endocrine modulator could provide an extensive range of potential applications, including a novel structure for hormonal medications, these Selective estrogen receptor modulators (SERMs) and Selective androgen receptor modulators (SARMs) are an emerging drug category with potential applications ranging from endocrinology, sexual dysfunction, age-related disease management, and Oncology.The Canadian Biomimetic Compound corporation, or "Canadian Biomimetics" is a startup and biopharma research company focused on the synthesis and commercialization of rare terpenoid molecules. As a manufacturer of active pharmaceutical ingredients, Canadian Biomimetics is primarily interested in molecules which have novel activity and structure but have been unused or unnoticed by mainstream clinical researchers due to their lack of commercial availability, as a reason for their complex chemical structure and isolation challenges. Canadian Biomimetics aims to extract natural ferutinin and other derivatives from Ferula Hermonis plant and then synthetically modify them to jaeshkenadiol by hydrolysis in basic conditions. This way naturally extracted ferutinin, as well as semi-synthetic jaeshkenadiol could be obtained. As jaeshkenadiol can be obtained from various ferula esters in higher yields than ferutinin, esterification of jaeshkenadiol back to ferutinin (semisynthetic version) by reaction with para-hydroxybenzoic acid and to teferdin by reaction with benzoic acid will be optimized. These three molecules will target the sexual health and endocrine modulator markets. The mechanism of action is somewhat complex, including binding to estrogen receptors, concentration, and transport via Caveolin-1, followed by formation of a Striatin complex which leads to increased levels of NO (Nitric oxide), and Ca (Calcium ion) emission into the intracellular space triggering vasodilation of the tissue. Such mechanism represents a novel form of action, different from PDE5 inhibitors such as Sildenafil (ViagraTM).Finally, to eliminate supply and availability challenges, it has been considered replacing Ferula Hermonis by its commercially more available strain, Ferula Communis. Canadian Biomimetics contacted Kemitek, a technology transfer centre specialized in green chemistry and process scale-up, to help develop, optimize, and further scale-up the extraction and synthetic modification protocols, using its advanced laboratory facility and explosion-proof pilot plant. Together we submit the project titled Production of medicinally active ferutinin and teferdin from Ferula plants.