👤 RF Keyes

Cyclometalated 1,3-bis(8-quinolyl) phenyl chloroplatinum(II) (Pt1) shows selective luminescence transduction of G-quadruplex binding over duplex DNA. The effect is enhanced on association with parallel and hybrid G-quadruplex structures over other topologies. The kinetics of binding are studied for c-myc and the response is found to be partially reversible in a displacement assay. Show less

Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas Covered: Triphenylphosphonium cation (TPP + )-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP + -based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert Opinion: TPP + -based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP + -based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP + -based OXPHOS-inhibiting drugs in cancer prevention and treatment. Show less

Triphenylphosphonium (TPP+) compounds like mito-metformin (MMe) target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. Here, we present a protocol for synthesizing TPP+ analogs with selectivity for mammalian cancer cells, reduced toxicity, and quantifiability using fluorine-19 nuclear magnetic resonance (19F-NMR). We describe steps for treating mammalian cells with mitochondria-targeted compounds, treating and preparing mouse tissue with these compounds, and 19F-NMR detection of MMe analogs in cells and tissue. TPP+-conjugated metformin analogs include para-methoxy (pMeO-MMe) and para-trifluoromethyl MMe (pCF3-MMe) and meta-trifluoromethyl MMe (mCF3-MMe). Show less

Triphenylphosphonium (TPP+) conjugated compounds selectively target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. To date, studies have focused on modifying either the linker or the cargo of TPP+-conjugated compounds. Here, we investigated the biological effects of direct modification to TPP+ to improve the efficacy and detection of mito-metformin (MMe), a TPP+-conjugated probe we have shown to have promising preclinical efficacy against solid cancer cells. We designed, synthesized, and tested trifluoromethyl and methoxy MMe analogs (pCF3-MMe, mCF3-MMe, and pMeO-MMe) against multiple distinct human cancer cells. pCF3-MMe showed enhanced selectivity toward cancer cells compared to MMe, while retaining the same signaling mechanism. Importantly, pCF3-MMe allowed quantitative monitoring of cellular accumulation via 19F-NMR in vitro and in vivo. Furthermore, adding trifluoromethyl groups to TPP+ reduced toxicity in vivo while retaining anti-tumor efficacy, opening an avenue to de-risk these next-generation TPP+-conjugated compounds. Show less

Transition metal luminophores are emerging as important tools for intracellular imaging and sensing. Their putative suitability for such applications has long been recognised but poor membrane permeability and cytotoxicity were significant barriers that impeded early progress. In recent years, numerous effective routes to overcoming these issues have been reported, inspired in part, by advances and insights from the pharmaceutical and drug delivery domains. In particular, the conjugation of biomolecules but also other less natural synthetic species, from a repertoire of functional motifs have granted membrane permeability and cellular targeting. Such motifs can also reduce cytotoxicity of transition metal complexes and offer a valuable avenue to circumvent such problems leading to promising metal complex candidates for application in bioimaging, sensing and diagnostics. The advances in metal complex probes permeability/targeting are timely, as, in parallel, over the past two decades significant technological advances in luminescence imaging have occurred. In particular, super-resolution imaging is enormously powerful but makes substantial demands of its imaging contrast agents and metal complex luminophores frequently possess the photophysical characteristics to meet these demands. Here, we review some of the key vectors that have been conjugated to transition metal complex luminophores to promote their use in intra-cellular imaging applications. We evaluate some of the most effective strategies in terms of membrane permeability, intracellular targeting and what impact these approaches have on toxicity and phototoxicity which are important considerations in a luminescent contrast or sensing agent. Show less