Supramolecular strategies to target cellular membranes

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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.