Access to a Saxitoxin-like Library for Binding Studies of Na Voltage Channels

 描述(由申请人提供)：将进行路易斯酸性过渡金属促进的双胍基烯丙基单元的环化反应，该环化单元通向类似萨克托毒素的三环核心。这将探索一种未知的双胍取代的烯丙烯的反应性，因为它对环化反应的活性是有关的。提出了一种模块化的方法，允许访问各种替换模式和环大小非常类似于岩藻毒素，以进一步研究结构-活性关系(SAR)与人的钠电压(NAV)通道。这些NAV通道的亚型与疼痛的机制有关，这引发了人们对止痛药开发的浓厚兴趣。然而，缺乏跨膜蛋白的晶体结构数据阻碍了合理的药物设计。使用非天然的肉毒素衍生物对这些通道进行的SAR研究非常有限或未知，这将有助于阐明这些蛋白质的结构，用于未来的治疗。目前的估计是，大约30%的美国人口受到慢性疼痛的困扰；因此，对这些跨膜蛋白的进一步了解至关重要。拟议研究的完成将实现以下成果：1)更好地了解使用胍作为亲核剂的联烯单元的C−N键结构中的反应性分布；2) 获得在化学界具有广泛合成用途的金属类卡宾物种，这是避免潜在爆炸性重氮化合物的另一种途径；3)获得具有不同环大小和取代模式的双鸟苷三环核心的潜在平台；4)关联类萨曲霉毒素支架与人类Nav1.7离子通道的结构-活性关系，为未来具有治疗价值的止痛药的合理设计提供帮助。

 DESCRIPTION (provided by applicant): Development of a Lewis acidic transition-metal promoted cyclization of a bis-guanidinium allenyl unit leading toward tricyclic cores resembling saxitoxin will be undertaken. This will probe the reactivity profile of an otherwise unknown bis-guanidinium substituted allene insofar as its reactivity towards cyclizations is concerned. A modular approach is presented that allows for access to various substitution patterns and ring-sizes closely resembling saxitoxin for further structure-activity relationship (SAR) studies agains human sodium voltage (NaV) channels. Subtypes of these NaV channels have been linked to the mechanism of pain, which has sparked heavy interest in analgesic drug development. The lack of crystal structure data for the transmembrane proteins, however, hinders rational drug design. Such SAR studies with unnatural derivatives of saxitoxin against these channels are extremely limited or unknown and would help to elucidate the architecture of these proteins for future therapeutics. Current estimates conclude that ~30% of the U.S. population is afflicted with chronic pain; therefore, further understanding of these transmembrane proteins is paramount. Completion of the proposed research will achieve the following: 1) A better understanding of the reactivity profile in C−N bond construction of an allene unit using guanidine as nucleophiles; 2) Access to a metal carbenoid species in situ which has broad synthetic utility in the chemistry community, an alternative route that avoids potentially explosive diazo compounds; 3) Potential platform to access bis-guanidinium tricyclic cores with various ring-sizes and substitution patterns; 4) Correlate structure-activity relationships of saxitoxin-like scaffolds against the human NaV1.7 ion channel aiding in their structural elucidation for future rational design in analgesics of therapeutic value.