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

2-氨基咪唑衍生天然产物的合成和生物学研究。

基本信息

批准号：
9177653
负责人：
Ryan Edward Looper
金额：
$ 19.98万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177653
关键词：
Affect Anchorage-Independent Growth Anti-Infective Agents Architecture Bacterial Typing Binding Biocompatible Materials Biological Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Cell Death Cells Chemistry Cholera Collaborations Communities Complex Data Deposition Development ERBB2 gene Equilibrium Evaluation Government Grant Guanidines Hand Health Human Infection Investigation Ion Channel Ionophores Laboratories Lead Libraries Link Lysosomes Malignant Neoplasms Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Membrane Meningitis Methodology Names Natural Products Necrosis Neoplasm Metastasis Nitrogen Panamanian Pathogenesis Physiology Plague Positioning Attribute Prodrugs Property Rana Reaction Refractory Research Resistance Sampling Saxitoxin Secure Series Signal Transduction Sodium Channel Solubility Streptomyces Structure System Therapeutic Type III Secretion System Pathway Variant Zinc analog antimicrobial base cancer subtypes chelation chemical synthesis design dimer effusion experience extracellular human disease improved in vivo inhibitor/antagonist killings malignant breast neoplasm member naamidine A novel strategies novel therapeutic intervention prevent protonation receptor scaffold screening small molecule stoichiometry tool uptake voltage zetekitoxin AB

项目摘要

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.

抽象的该应用的目的是继续开发喀斯喀特圭尼烷型水力启示在我们的实验室中开发的序列，以制备高度取代的2-氨基咪唑唑和多晶鸟选择支架并研究其丰富而多样的生物学活动。具体而言，该提案针对三个重要结构：（1）我们已经确定了一类新的N2-acyl-2-氨基咪唑为Zn2+离子载体有选择地杀死乳腺癌细胞。这些化合物引起细胞的活性Zn2+，导致Zn2+ - Dyshomeostasis。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（log [Zn2+] Free），这是该支架诱导的锌dyshomeostasis和溶酶体的活性的基础膜去极化。这些化合物在体内很活跃，并且耐受性良好，提供了重要的治疗乳腺癌的治疗铅。由于这种作用机理不是受体介导的，因此这些化合物对主要的乳腺癌亚型具有活性负细胞。（2）我们已经开发了一个强大的级联水域序列，以构建Bis- （+） - 萨克西毒素的鸟根核心。该策略的扩展将针对Zetekitoxin AB（ZTX）A的合成具有共享BIS-的电压门控钠通道（NAV）抑制剂的更复杂和潜在成员鸟根核心。 ZTX代表了研究离子通道生理学的强大工具，但是，仅0.3 mg 纯化化合物存在于人类手中。产生这种化合物的青蛙非常濒危，受巴拿马政府的保护。这种天然产品的极端稀有性只有总化学合成可以为社区提供这种化合物。（3）最后，我们将瞄准瓜迪宁胺B 一种独特的卡马伊兰鸟胺，含有天然产品，我们认为这实际上与Na22598a1相同由于它们在结构上相似，并且都与链霉菌属分离出来。如果它们确实相同，则归因于3型分泌系统抑制剂的活性介导的发病机理（瓜丁胺B）和抑制独立生长 /转移的抑制（NA22598A1）表明生物学重叠目标。我们推进了这样一个普通靶标的是基质金属蛋白酶（MMP）的假设，并且它们抑制活性依赖于carbamoylguanidine的Zn2+螯合作用。如果腺苷B的目标确实是 MMP，这提供了一种新的理论策略来预防细菌发病机理，这对于治疗人类疾病（例如脑膜炎，霍乱，鼠疫），要么具有受这些天然产品启发的化合物或发达的MMP抑制剂的抽象。