Chemical Approach to Positional Isomers of Glucose–Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake <i>in Vitro</i> and <i>in Vivo</i>

Glycoconjugation is a promising strategy for specific targeting of cancer. In this study, we investigated the effect of d-glucose substitution position on the biological activity of glucose–platinum conjugates (Glc-Pts). We synthesized and characterized all possible positional isomers (C1α, C1β, C2, C3, C4, and C6) of a Glc-Pt. The synthetic routes presented here could, in principle, be extended to prepare glucose conjugates with different active ingredients, other than platinum. The biological activities of the compounds were evaluated both <i>in vitro</i> and <i>in vivo</i>. We discovered that varying the position of substitution of d-glucose alters not only the cellular uptake and cytotoxicity profile but also the GLUT1 specificity of resulting glycoconjugates, where GLUT1 is glucose transporter 1. The C1α- and C2-substituted Glc-Pts (<b>1α</b> and <b>2</b>) accumulate in cancer cells most efficiently compared to the others, whereas the C3-Glc-Pt (<b>3</b>) is taken up least efficiently. Compounds <b>1α</b> and <b>2</b> are more potent compared to <b>3</b> in DU145 cells. The α- and β-anomers of the C1-Glc-Pt also differ significantly in their cellular uptake and activity profiles. No significant differences in uptake of the Glc-Pts were observed in non-cancerous RWPE2 cells. The GLUT1 specificity of the Glc-Pts was evaluated by determining the cellular uptake in the absence and in the presence of the GLUT1 inhibitor cytochalasin B, and by comparing their anticancer activity in DU145 cells and a GLUT1 knockdown cell line. The results reveal that C2-substituted Glc-Pt <b>2</b> has the highest GLUT1-specific internalization, which also reflects the best cancer-targeting ability. In a syngeneic breast cancer mouse model overexpressing GLUT1, compound <b>2</b> showed antitumor efficacy and selective uptake in tumors with no observable toxicity. This study thus reveals the synthesis of all positional isomers of d-glucose substitution for platinum warheads with detailed glycotargeting characterization in cancer

Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation

Transition-metal-based approaches to selectively modify proteins hold promise in addressing challenges in chemical biology. Unique bioorthogonal chemistry can be achieved with preformed metal-based compounds; however, their utility in native protein sites within cells remain underdeveloped. Here, we tune the ancillary ligands of cyclometalated gold­(III) as a reactive group, and the gold scaffold allows for rapid modification of a desired cysteine residue proximal to the ligand binding site of a target protein. Moreover, evidence for a ligand association mechanism toward C–S bond formation by X-crystallography is established. The observed reactivity of cyclometalated gold­(III) enables the rational design of a cysteine-targeted covalent inhibitor of mutant KRAS. This work illustrates the potential of structure–activity relationship studies to tune kinetics of cysteine arylation and rational design of metal-mediated ligand affinity chemistry (MLAC) of native proteins

Singlet Oxygen Generation by Novel NIR BODIPY Dyes

Five novel near-infrared BODIPY dyes were prepared for improved singlet oxygen generation using thiophene and bromine. Theoretical, optical, photostable, and singlet oxygen generation characteristics of these dyes were assessed. Predicted excitation energies by TDDFT calculations were in good agreement (ΔE ≈ 0.06 eV) with experimental data. All five dyes showed both excitation and emission in the NIR range. In particular, two dyes having sulfur and bromine atoms showed efficient singlet oxygen generation with high photostability

Genome-wide CRISPR Screen Reveal Targets of Chiral Gold(I) Anticancer Compound in Mammalian Cells

Metal-based drugs, such as cisplatin and auranofin, are used for the treatment of cancer and rheumatoid arthritis, respectively. Auranofin and other gold-derived compounds have been shown to possess anticancer, anti-inflammatory, antimicrobial, and antiparasitic activity in preclinical and clinical trials. Unlike platinum agents which are known to target DNA, the target of gold is not well elucidated. To better understand the targets and effects of gold agents in mammalian cells, we used a targeted CRISPR (ToxCRISPR) screen in K562 cancer cells to identify genes that modulate cellular sensitivity to gold. We synthesized a novel chiral gold(I) compound, JHK-21, with potent anticancer activity. Among the most sensitizing hits were proteins involved in mitochondrial carriers, mitochondrial metabolism, and oxidative phosphorylation. Further analysis revealed that JHK-21 induced inner mitochondria membrane dysfunction and modulated ATP-binding cassette subfamily member C (ABCC1) function in a manner distinct from auranofin. Characterizing the therapeutic effects and toxicities of metallodrugs in mammalian cells is of growing interest to guide future drug discovery, and cellular and preclinical/clinical studies

Genome-wide CRISPR Screen Reveal Targets of Chiral Gold(I) Anticancer Compound in Mammalian Cells

Metal-based drugs, such as cisplatin and auranofin, are used for the treatment of cancer and rheumatoid arthritis, respectively. Auranofin and other gold-derived compounds have been shown to possess anticancer, anti-inflammatory, antimicrobial, and antiparasitic activity in preclinical and clinical trials. Unlike platinum agents which are known to target DNA, the target of gold is not well elucidated. To better understand the targets and effects of gold agents in mammalian cells, we used a targeted CRISPR (ToxCRISPR) screen in K562 cancer cells to identify genes that modulate cellular sensitivity to gold. We synthesized a novel chiral gold(I) compound, JHK-21, with potent anticancer activity. Among the most sensitizing hits were proteins involved in mitochondrial carriers, mitochondrial metabolism, and oxidative phosphorylation. Further analysis revealed that JHK-21 induced inner mitochondria membrane dysfunction and modulated ATP-binding cassette subfamily member C (ABCC1) function in a manner distinct from auranofin. Characterizing the therapeutic effects and toxicities of metallodrugs in mammalian cells is of growing interest to guide future drug discovery, and cellular and preclinical/clinical studies

Distorted Gold(I)–Phosphine Complexes as Antifungal Agents

Fungi cause serious nosocomial infections including candidiasis and aspergillosis, some of which display reduced susceptibility to current antifungals. Inorganic compounds have been found to be beneficial against various medical ailments but have yet to be applied to fungal infections. Here, we explore the activity of linear and square-planar gold­(I)−phosphine complexes against a panel of 28 fungal strains including Candida spp., Cryptococcus spp., Aspergillus spp., and Fusarium spp. Notably, two square-planar gold­(I) complexes with excellent broad-spectrum activity display potent antifungal effects against strains of Candida auris, an emerging multidrug-resistant fungus that presents a serious global health threat. To characterize the biological activity of these gold­(I) complexes, we used a series of time–kill studies, cytotoxicity and hemolysis assays, as well as whole-cell uptake and development of resistance studies

Thieno-Pyrrole-Fused 4,4-Difluoro-4-bora-3a,4a-diaza‑<i>s</i>‑indacene–Fullerene Dyads: Utilization of Near-Infrared Sensitizers for Ultrafast Charge Separation in Donor–Acceptor Systems

Donor–acceptor dyads featuring near-IR sensitizers derived from thieno-pyrrole-fused BODIPY (abbreviated as SBDPiR) and fullerene, C₆₀ have been newly synthesized and characterized. Occurrence of ultrafast photoinduced electron transfer (PET) leading to the formation of charge-separated state in these dyads, capable of harvesting light energy from the near-IR region, is established from femtosecond transient absorption studies

Distorted Gold(I)–Phosphine Complexes as Antifungal Agents

Fungi cause serious nosocomial infections including candidiasis and aspergillosis, some of which display reduced susceptibility to current antifungals. Inorganic compounds have been found to be beneficial against various medical ailments but have yet to be applied to fungal infections. Here, we explore the activity of linear and square-planar gold­(I)−phosphine complexes against a panel of 28 fungal strains including Candida spp., Cryptococcus spp., Aspergillus spp., and Fusarium spp. Notably, two square-planar gold­(I) complexes with excellent broad-spectrum activity display potent antifungal effects against strains of Candida auris, an emerging multidrug-resistant fungus that presents a serious global health threat. To characterize the biological activity of these gold­(I) complexes, we used a series of time–kill studies, cytotoxicity and hemolysis assays, as well as whole-cell uptake and development of resistance studies

Circumventing Physicochemical Barriers of Cyclometalated Gold(III) Dithiocarbamate Complexes with Protein-Based Nanoparticle Delivery to Enhance Anticancer Activity

Optimizing the bioavailability of drug candidates is crucial to successful drug development campaigns, especially for metal-derived chemotherapeutic agents. Nanoparticle delivery strategies can be deployed to overcome physicochemical limitations associated with drugs to improve bioavailability, pharmacokinetics, efficacy, and minimize toxicity. Biodegradable albumin nanoconstructs offer pragmatic solutions for drug delivery of metallodrugs with translational benefits in the clinic. In this work, we explored a logical approach to investigate and resolve the physicochemical drawbacks of gold­(III) complexes with albumin nanoparticle delivery to improve solubility, enhance intracellular accumulation, circumvent premature deactivation, and enhance anticancer activity. We synthesized and characterized stable gold­(III) dithiocarbamate complexes with a variable degree of cyclometalation such as phenylpyridine (C^N) or biphenyl (C^C) Au­(III) framework and different alkyl chain lengths. We noted that extended alkyl chain lengths impaired the solubility of these complexes in biological media, thus adversely impacting potency. Encapsulation of these complexes in bovine serum albumin (BSA) reversed solubility limitations and improved cancer cytotoxicity by ∼25-fold. Further speciation and mechanism of action studies demonstrate the stability of the compounds and alteration of mitochondria bioenergetics, respectively. We postulate that this nanodelivery strategy is a relevant approach for translational small-molecule gold drug delivery