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

摘要 本申请的目的是继续发展级联胍氢胺化 序列，在我们的实验室开发，以制备高度取代的2-氨基咪唑和多环 胍类支架材料，研究其丰富多样的生物活性。具体而言，该提案针对三个 重要结构：（1）我们鉴定了一类新的N 2-酰基-2-氨基咪唑类锌离子载体， 选择性地杀死乳腺癌细胞。这些化合物引起细胞对Zn 2+的主动摄取，导致Zn 2 +- 稳态失调研究将优化我们的铅结构（命名为ZNA），以实现pKa的复杂平衡 和pZn（不含Zn 2+），其支持该支架诱导锌稳态异常和溶酶体的活性。 膜去极化这些化合物在体内是有活性的，并且耐受性良好，提供了重要的生物活性。 治疗乳腺癌的治疗铅。由于这种作用机制不是受体介导的， 这些化合物对主要的乳腺癌亚型有活性，包括ER β、HER 2 β和PR β或三重 阴性细胞。(2)我们已经开发了一个强大的级联氢胺化序列来构建双- （+）-石房蛤毒素的胍核。该策略的扩展将靶向合成zetekitoxin AB（ZTX）a 电压门控钠通道（Nav）抑制剂的更复杂和有效的成员，共享这种双- 胍核ZTX代表了研究离子通道生理学的有力工具，然而，仅0.3mg的ZTX就可用于研究离子通道生理学。 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有性决定了只有 全化学合成可以为社区提供这种化合物。(3)最后，我们将靶向胍丁胺B， 一种独特的含有氨基甲酰基胍的天然产物，我们认为它实际上与NA 22598 A1相同， 因为它们在结构上相似并且都是从链霉菌属分离的。如果他们真的是一样的， 作为3型分泌系统介导的发病机制的抑制剂（胍丁胺B）的活性， 锚定非依赖性生长/转移的抑制（NA 22598 A1）提示重叠的生物学效应， 目标我们提出假设，这种共同的目标是基质金属蛋白酶（MMP）， 抑制活性依赖于Zn 2+被氨基甲酰基胍螯合。如果胍丁胺B的目标确实是 MMP，这提供了一种新的治疗策略，以防止细菌的发病机制，关键的治疗 人类疾病（例如脑膜炎、霍乱、鼠疫），或者使用由这些天然产物激发的化合物 或者是大量的MMP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.