Supramolecular strategies to target cellular membranes

近年来，人们对识别能够自组装并能够促进离子通过磷脂膜的传输的小分子有机化合物越来越感兴趣。我们的计划旨在通过一条未被探索的途径--控制或破坏细胞和细胞器膜中的离子运输--开发治疗传染病和癌症的新疗法。这项建议利用我们团队在离子传输基础化学方面的专业知识来开发新类别的抗生素和化疗药物。我们的长期目标是对如何利用磷脂膜或更复杂的介质中的离子传输来产生新一代的化合物有一个新的理解，这些化合物专门定位于膜和细胞器，并有效地杀死细胞。我们的重点是优化有机阳离子衍生物作为选择性抗菌剂和抗肿瘤药物，如以下短期目标所建议的那样。目的1：合成双胍类化合物，并对其离子输运性质、选择性和动力学进行基础研究。我们将研究它们对广泛的侵袭性微生物菌株的活性，以便将离子传输特性与抗菌和抗生物膜活性联系起来。目的2.研究被提出的抑制细胞器功能的离子载体作为治疗恶性肿瘤特别是癌症的靶点。我们将利用所提出的合成离子转运体诱导的动态平衡潜在性质。细胞内离子和pH水平的扰动将被用作细胞凋亡的触发因素。我们的目标是了解人工合成的离子载体促进离子渗透和细胞的自然传输机制之间的相互作用。目的3.我们将使用有机金属半夹心配合物作为高度通用的药物设计平台。我们将合成并研究IrIII与双胍和亚氨基胍的配合物的抗微生物和抗癌性能。我们团队开发的高效合成路线和与不同离子载体家族的第一手经验有可能产生新的化合物，并发现作为抗生素和抗癌剂的新应用。这项工作极有可能产生提供和靶向治疗的新方法。

In recent years, there has been increasing interest in identifying small organic compounds that self-assemble and are capable of facilitating the transport of ions across phospholipid membranes. Our program aims to develop novel therapeutics for infectious diseases and cancer via an underexplored route - the control or disruption of ion transport in cellular and organelle membranes. This proposal leverages our groups' expertise in the fundamental chemistry of ion transport to develop new classes of antibiotics and chemotherapeutic agents. Our long-term goal is to acquire a new understanding of how ion transport in phospholipid membranes or more complex media can be exploited to produce new generations of compounds that specifically localize in the membrane and organelles, and effectively kill cells. Our specific focus is the optimization of organic cationic derivatives as selective antimicrobial and antitumor agents, as proposed in the following short-term objectives. Objective 1: The synthesis of biguanides and iminoguanidines and fundamental studies of their ion transport properties, transport selectivity and kinetics. We will study their activity against a broad range of invasive microbial strains in order to correlate ion transport properties to antimicrobial and antibiofilm activity. Objective 2. The study of the proposed ionophores to compromise organelles function as target for the treatment of malignancies and cancer in particular. We will exploit the homeostasis-upsetting potential properties induced by the proposed synthetic ion transporters. The perturbation of intracellular ion and pH levels will be used as an apoptosis trigger. Our goal here is to understand the interplay between the facilitated ion permeation by the synthetic ionophores and the natural transport mechanisms of the cell. Objective 3. We will use organometallic half-sandwich complexes as highly versatile platforms for drug design. We will synthesize and study the antimicrobial and anticancerous properties of IrIII complexes with biguanides and iminoguanidines. Efficient synthetic routes and first-hand experience with diverse families of ionophores developed in our group have the potential to yield new compounds and uncover new applications as antibiotics and anticancer agents. This work is highly likely to yield new ways to deliver and target therapeutics.