Synthetic and biological investigations of 2-aminoimidazole derived natural products.

摘要 本申请的目的是为了继续发展串联式胍氢胺化 本实验室开发的制备高取代2-氨基咪唑和多环化合物的序列 并研究其丰富多样的生物活性。具体地说，这项提案针对三个 重要结构：(1)我们鉴定了一类新的N_2-酰基-2-氨基咪唑类化合物作为锌离子载体。 选择性地杀死乳腺癌细胞。这些化合物导致细胞对锌的主动摄取，导致锌- 稳态失调。研究将优化我们的铅结构(名为ZNA)，以实现PKA的复杂平衡 和PZN(log[zn2]Free)，它支持该支架诱导锌代谢紊乱和溶酶体的活性 膜去极化。这些化合物在体内是活性的，并且耐受性很好，提供了重要的 用于乳腺癌治疗的治疗性铅。由于这种作用机制不是由受体介导的， 这些化合物对包括ER、HER2和PR在内的主要乳腺癌亚型具有活性或三重 阴性细胞。(2)我们开发了一个强大的级联氢胺化序列来构建双- ()-肉毒杆菌毒素的金刚烷核。这一策略的扩展将以合成Zetekitoxin AB(ZTX)a为目标 电压门控钠通道(NAV)抑制剂的更复杂和更有效的成员，共享这个双- 金刚烷核。ZTX是研究离子通道生理学的有力工具，然而，只有0.3 mg 纯化的化合物存在于人的手中。产生这种化合物的青蛙是极度濒危的 受到巴拿马政府的保护。因此，这种天然产品的极端稀缺性决定了只有 全化学合成可以将这种化合物提供给群落。(3)最后，我们将目标是愈创木酚胺B， 一种独特的氨甲酰胍，含有天然产物，我们认为它实际上与NA22598A1相同， 因为它们在结构上相似，都是从链霉菌中分离出来的。如果他们确实是一样的，他们的 归因于作为3型分泌系统介导的致病(愈创木酚胺B)和 锚定非依赖性生长/转移抑制(NA22598A1)提示一种重叠的生物学 目标。我们提出了这样的假设，即这个共同的靶点是基质金属蛋白酶(MMPs)，并且它们的 抑制活性依赖于氨基甲酰基胍对锌离子的络合作用。如果愈创木酚胺B的目标确实是 这为预防细菌致病提供了一种新的治疗策略，对治疗青光眼至关重要。 人类疾病(如脑膜炎、霍乱、鼠疫)，或由这些天然产品激发的化合物 或者是大量发育良好的基质金属蛋白酶抑制剂。

ABSTRACT The purpose of this application is to continue the development of cascade guanidine hydroamination sequences, developed in our laboratory, to prepare highly substituted 2-aminoimidazoles and polyclic guanidine scaffolds and study their rich and diverse biological activities. Specifically, this proposal targets three important structures: (1) We have identified a new class of N2-acyl-2-aminoimidazoles as Zn2+ ionophores that selectively kill breast cancer cells. These compounds cause the active uptake of Zn2+ by cells, leading to Zn2+- dyshomeostasis. Studies will optimize our lead structure (named ZNA) to achieve a complex balance of pKa and pZn (log [Zn2+]free) which underpins this scaffold's activity of inducing zinc dyshomeostasis and lysosomal membrane depolarization. These compounds are active in vivo and are well tolerated, providing an important therapeutic lead for the treatment of breast cancer. Since this mechanism of action is not receptor mediated, these compounds are active against the major breast cancer subtypes including ER, HER2 and PR or triple negative cells. (2) We have developed a powerful cascade hydroamination sequence to construct the bis- guanidine core of (+)-saxitoxin. An extension of this strategy will target the synthesis of zetekitoxin AB (ZTX) a more complex and potent member of the voltage gated sodium channel (Nav) inhibitors that shares this bis- guanidine core. ZTX represents a powerful tool to study ion channel physiology, however, only 0.3 mg of the purified compound exists in human hands. The frog that produces this compound is critically endangered and protected by the Panamanian government. Thus the extreme rarity of this natural product dictates that only total chemical synthesis can provide this compound to the community. (3) Lastly, we will target guadinomine B, a unique carbamoylguanidine containing natural product that we believe is actually the same as NA22598A1, as they are structurally similar and both isolated from Streptomyces spp.. If they are indeed the same, their ascribed activities as an inhibitor of type 3 secretion system mediated pathogenesis (guadinomine B) and inhibition of anchorage independent growth / metastasis (NA22598A1) suggests an overlapping biological target. We advance the hypothesis that this common target is a matrix metalloproteinase (MMP), and that their inhibitory activity relies on Zn2+ chelation by the carbamoylguanidine. If guadinomine B's target is indeed an MMP, this offers a new therapeutic strategy to prevent bacterial pathogenesis, critical to the treatment of human disease (e.g. meningitis, cholera, the plague), either with compounds inspired by these natural products or the abundance of well-developed MMP inhibitors.