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/Palaestine的赫蒙山周围地区。它通常被当地人使用，特别是在黎巴嫩，作为民间的性增强药物。正如后来所示，阿魏提取物在雄性大鼠中表现出显着的活性，增加总体交配事件，达到与西地那非（以万艾可品牌出售）相似的效果水平。直到最近，人们对这种显著的效果知之甚少，因为阿魏不含任何值得注意的生物碱或甾醇。它的作用来自一种萜类化合物，直到最近才被科学界所忽视，被称为“Jaeshkenadiol”。更具体地，其对羟基苯甲酸酯“Ferutinin”是有效的雌激素受体调节剂和激动剂，其刺激雄性和雌性哺乳动物的性活动。Ferutinin可以在30分钟内暂时增加小鼠的睾酮水平100-200%，而Teterdin（jaeshkenadiol的苯甲酸酯）显示出较慢的起效速度，但在重复剂量下同样大的积累。虽然它作为性功能障碍药物具有明显的益处，但其作为内分泌调节剂的作用可以提供广泛的潜在应用，包括用于激素药物的新结构，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）是新兴的药物类别，其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、加拿大仿生化合物公司（Canadian Biomimetic Compound corporation）或“加拿大仿生学公司”是一家专注于稀有萜类化合物分子的合成和商业化的初创和生物制药研究公司。作为活性药物成分的制造商，Canadian Biomimetics主要对具有新活性和结构的分子感兴趣，但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，这是其复杂化学结构和分离挑战的原因。Canadian Biomimetics旨在从阿魏植物中提取天然阿魏素和其他衍生物，然后在碱性条件下通过水解将其合成修饰为jaeshkenadiol。这种方法可以获得天然提取的ferutinin以及半合成的jaeshkenadiol。由于jaeshkenadiol可以从各种阿魏酸酯以比阿魏酸更高的产率获得，因此将优化通过与对羟基苯甲酸反应将jaeshkenadiol酯化回阿魏酸（半合成形式）和通过与苯甲酸反应将其酯化回替费尔定。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、浓缩和通过小窝蛋白-1转运，随后形成条纹蛋白复合物，导致NO（一氧化氮）和Ca（钙离子）水平增加，释放到细胞内空间，触发组织的血管舒张。这种机制代表了一种新的作用形式，不同于PDE 5抑制剂，如西地那非（ViagraTM）。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）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改性方案。我们共同提交了题为从阿魏属植物中生产药用活性ferutinin和teferdin的项目。