Production of medicinally active ferutinin and teferdin from Ferula plants

黑门阿Ferula Hermonis俗称“Zallouh”，是一种开花植物，生长在黎巴嫩、叙利亚和以色列/巴勒斯坦的黑门山周围地区。当地人普遍使用它，尤其是在黎巴嫩，它是一种民间传说中的性增强药物。正如后来所显示的那样，阿魏提取物在雄性大鼠中显示出显著的活性，将总体交配事件增加到与西地那非（以伟哥的品牌出售）相似的效果。这种显著的效果直到最近才被人们所了解，因为阿魏不含任何显著的生物碱或甾醇。它的作用来源于一种萜类化合物，直到最近才被科学界所忽视，被称为“麻黄二醇”。更具体地说，它的对羟基苯甲酸酯“阿魏素”是一种有效的雌激素受体调节剂和激动剂，可以刺激雄性和雌性哺乳动物的性活动。阿魏素可以在30分钟内暂时使小鼠体内的睾酮水平增加100-200%，而铁非丁（栀子二酚的苯甲酸酯）的起效较慢，但在重复给药后也会有同样大的积累。虽然它作为性功能障碍药物有明显的好处，但作为内分泌调节剂的作用可以提供广泛的潜在应用，包括激素药物的新结构，这些选择性雌激素受体调节剂（SERMs）和选择性雄激素受体调节剂（SARMs）是一种新兴的药物类别，具有潜在的应用范围包括内分泌学，性功能障碍，年龄相关疾病管理和肿瘤学。加拿大仿生化合物公司，或“加拿大仿生”是一家初创公司和生物制药研究公司，专注于稀有萜类分子的合成和商业化。作为活性药物成分的制造商，Canadian Biomimetics主要对具有新颖活性和结构的分子感兴趣，但由于其复杂的化学结构和分离挑战，由于缺乏商业可用性，主流临床研究人员未使用或未注意到这些分子。Canadian Biomimetics旨在从阿魏植物中提取天然阿魏素及其他衍生物，然后在基本条件下水解合成为栀子二醇。该方法可自然提取阿魏素，并可获得半合成的栀子二醇。由于各种阿魏酸酯均可获得比阿魏素更高收率的栀子二醇，因此将优化栀子二醇与对羟基苯甲酸酯化反应制阿魏素（半合成版）和与苯甲酸酯化反应制铁铁素的工艺。这三种分子将针对性健康和内分泌调节剂市场。其作用机制有些复杂，包括与雌激素受体结合、浓度和通过Caveolin-1运输，随后形成纹状蛋白复合物，导致NO（一氧化氮）水平升高，Ca（钙离子）释放到细胞内空间，引发组织血管舒张。这种机制代表了一种新的作用形式，不同于西地那非（ViagraTM）等PDE5抑制剂。最后，为了消除供应和可获得性方面的挑战，已考虑用其在商业上更容易获得的品种——黄阿魏替代黑阿魏。加拿大仿生公司联系了Kemitek，一家专门从事绿色化学和工艺放大的技术转移中心，利用其先进的实验室设施和防爆中试工厂，帮助开发、优化和进一步扩大提取和合成改性协议。我们一起提交了题为“从阿魏植物中生产药用活性阿魏素和teferdin”的项目。

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.