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。

• 批准号: 9765332
• 负责人: Ryan Edward Looper
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765332
• 关键词: Anchorage-Independent Growth; Anti-Infective Agents; Architecture; Binding; Biocompatible Materials; Biological; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Cell Death; Cells; Chelating Agents; 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; Periodicity; 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; malignant breast neoplasm; member; naamidine A; novel strategies; novel therapeutic intervention; prevent; protonation; scaffold; screening; small molecule; stoichiometry; tool; uptake; voltage; zetekitoxin AB

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。