Production of medicinally active ferutinin and teferdin from Ferula plants

从阿魏植物中生产具有药用活性的阿魏宁和特弗丁

• 批准号: 566993-2021
• 负责人: Piché, Chantal
• 金额: $ 5.46万
• 依托单位: Cégep de Thetford
• 依托单位国家: 加拿大
• 项目类别: Applied Research and Development Grants - Level 2
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=724978
• 关键词: Production; medicinally; active; ferutinin; teferdin

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.

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/巴勒斯坦黑门山周围地区。它被当地人广泛使用，尤其是在黎巴嫩，作为民间传说中的性增强药物。正如后来所显示的，阿魏提取物在雄性大鼠中表现出显着的活性，增加了总体交配事件，达到与西地那非（以商品名伟哥出售）相似的效果水平。直到最近，人们对这种显着效果知之甚少，因为阿魏不含任何值得注意的生物碱或甾醇。它的作用源自一种萜类化合物，直到最近才被科学界忽视，被称为“Jaeshkenadiol”。更具体地说，其对羟基苯甲酸酯“Ferutinin”是一种有效的雌激素受体调节剂和激动剂，可刺激雄性和雌性哺乳动物的性活动。 Ferutinin 可以在 30 分钟内暂时将小鼠的睾酮水平提高 100-200%，Teferdin（jaeshkenadiol 的苯甲酸酯）起效较慢，但重复剂量后累积量同样大。虽然它作为性功能障碍药物具有明显的好处，但其作为内分泌调节剂的作用可以提供广泛的潜在应用，包括激素药物的新颖结构，这些选择性雌激素受体调节剂（SERM）和选择性雄激素受体调节剂（SARM）是一种新兴药物类别，潜在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Biomimetics”是一家初创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但由于缺乏商业可用性而未被主流临床研究人员使用或忽视的分子感兴趣，这是其复杂的化学结构和分离挑战的原因。 Canadian Biomimetics旨在从阿魏属植物中提取天然阿魏宁等衍生物，然后在碱性条件下水解合成改性为杰西肯二醇。通过这种方式可以获得天然提取的弗卢丁素以及半合成的杰什肯二醇。由于可以从各种阿魏酯中以比阿魏宁更高的产率获得杰肯二醇，因此将优化杰肯二醇通过与对羟基苯甲酸反应返回阿魏宁（半合成版本）和通过与苯甲酸反应返回特弗丁的酯化。这三种分子将瞄准性健康和内分泌调节剂市场。作用机制有些复杂，包括与雌激素受体结合、浓缩和通过 Caveolin-1 转运，然后形成 Striatin 复合物，导致 NO（一氧化氮）和 Ca（钙离子）排放水平增加细胞内空间触发组织的血管舒张。这种机制代表了一种新颖的作用形式，不同于西地那非 (ViagraTM) 等 PDE5 抑制剂。最后，为了消除供应和可用性挑战，人们考虑用其商业上更容易获得的菌株阿魏 (Ferula Communis) 来取代阿魏 (Ferula Hermonis)。 Canadian Biomimetics 联系了专门从事绿色化学和工艺放大的技术转让中心 Kemitek，利用其先进的实验室设施和防爆中试工厂，帮助开发、优化和进一步放大提取和合成修饰方案。我们共同提交了题为“从阿魏植物中生产具有药用活性的阿魏宁和特弗丁”的项目。