A series of polypyridyl-ruthenium(II) and -iridium(III) complexes that contain labile chlorido ligands, [{M(tpy)Cl}(2){μ-bb(n)}](2/4+) {Cl-Mbb(n); where M = Ru or Ir; tpy = 2,2':6',2''-terpyridine; and bb(n) = bis[4(4'-methyl-2,2'-bipyridyl)]-1,n-alkane (n = 7, 12 or 16)} have been synthesised and their potential as antimicrobial agents examined. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of the series of metal complexes against four strains of bacteria - Gram positive Staphylococcus aureus (S. aureus) and methicillin-resistant S. aureus (MRSA), and Gram negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) - have been determined. All the ruthenium complexes were highly active and bactericidal. In particular, the Cl-Rubb(12) complex showed excellent activity against all bacterial cell lines with MIC values of 1 μg mL(-1) against the Gram positive bacteria and 2 and 8 μg mL(-1) against E. coli and P. aeruginosa, respectively. The corresponding iridium(III) complexes also showed significant antimicrobial activity in terms of MIC values; however and surprisingly, the iridium complexes were bacteriostatic rather than bactericidal. The inert iridium(III) complex, [{Ir(phen)(2)}(2){μ-bb(12)}](6+) {where phen = 1,10-phenanthroline) exhibited no antimicrobial activity, suggesting that it could not cross the bacterial membrane. The mononuclear model complex, [Ir(tpy)(Me(2)bpy)Cl]Cl(2) (where Me(2)bpy = 4,4'-dimethyl-2,2'-bipyridine), was found to aquate very rapidly, with the pK(a) of the iridium-bound water in the corresponding aqua complex determined to be 6.0. This suggests the dinuclear complexes [Ir(tpy)Cl}(2){μ-bb(n)}](4+) aquate and deprotonate rapidly and enter the bacterial cells as 4+ charged hydroxo species.

Despite the ubiquitous nature of titanium(IV) and several examples of its beneficial behavior in different organisms, the metal remains underappreciated in biology. There is little understanding of how the metal might play an important function in the human body. Nonetheless, new insight is obtained regarding the molecular mechanisms that regulate the blood speciation of the metal to maintain it in nontoxic and potentially bioavailable form for use in the body. This review surveys the literature on Ti(IV) application in prosthetics and in the development of anticancer therapeutics to gain insight into soluble Ti(IV) influx in the body and its long-term impact. The limitation in analytical tools makes it difficult to depict the full picture of how Ti(IV) is transported and distributed throughout the body. Improved understanding of Ti function and its interaction with biomolecules will be helpful in developing future technologies for its imaging in the body.

A convenient synthetic strategy is reported for the series of complexes [Ir(pp)3]3+ (where pp = phen, Me2phen and Me4phen) through the intermediacy of the appropriate [Ir(pp)2(CF3SO3)2]+ species. In the case of [Ir(phen)3]3+, the cation was resolved into its enantiomeric forms, for which the absolute configurations were determined by X-ray diffraction. The availability for the first time of the CD spectra allowed comparison with computed CD spectra. Measurement of the antimicrobial activity of the [Ir(pp)3]3+ species {and the [Ir(pp)2X2]+ (X = Cl–, CF3SO3–) precursors involved in their synthesis}, as well as cell uptake studies with the four bacterial strains S. aureus, methicillin-resistant S. aureus (MRSA), E. coli, and P. aeruginosa, indicated that they showed little activity compared with their Ru(ii) analogues. The results suggest that it is unfavourable for an individual metal centre with a 3+ charge to pass across the bacterial cell membrane.

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Triple negative breast cancer is an aggressive, heterogeneous disease with high recurrence and metastasis rates even with modern chemotherapy regimens and thus is in need of new therapeutics. Here, three novel synthetic analogues of chalcones, plant-based molecules that have demonstrated potency against a wide variety of cancers, were investigated as potential therapeutics for triple negative breast cancer. These compounds exhibit IC values of ∼5 μM in triple negative breast cancer cell lines and are more potent against triple negative breast cancer cell lines than against nontumor breast cell lines according to viability experiments. Tandem mass tag-based quantitative proteomics followed by gene set enrichment analysis and validation experiments using flow cytometry, apoptosis, and Western blot assays revealed three different anticancer mechanisms for these compounds. First, the chalcone analogues induce the unfolded protein response followed by apoptosis. Second, increases in the abundances of MHC-I pathway proteins occurs, which would likely result in immune stimulation in an organism. And third, treatment with the chalcone analogues causes disruption of the cell cycle by interfering with microtubule structure and by inducing G1 phase arrest. These data demonstrate the potential of these novel chalcone derivatives as treatments for triple negative breast cancer, though further work evaluating their efficacy in vivo is needed.

Highlights d SU086 inhibits prostate cancer growth in preclinical models of prostate cancer d SU086 targets heat shock protein 90 d SU086 alters prostate cancer glycolysis and decreases intratumoral metabolism d SU086 in combination with anti-androgens halts prostate cancer growth

Cancer remains a leading cause of death worldwide, resulting in continuous efforts to discover and develop highly efficacious anticancer drugs. High‐throughput screening of heterocyclic compound libraries is one of the promising approaches that provided several new lead molecules with a novel mechanism of action. On the basis of the promising anticancer potential of imidazoquinoxaline as well as the structurally similar imidazoquinoline‐derived scaffold, we prepared a set of C6‐substituted benzimidazo[1,2‐a]quinoxaline derivatives via two novel synthetic routes using commercially available starting materials, with good to excellent yields and evaluated their anticancer activity against the NCI‐60 cancer cell lines. The one‐dose (10 µM) anticancer screening of the synthesized compounds in the NCI‐60 cell line panel revealed that the substituents have a significant role in the activity. In particular, the indole (7f), imidazole (7g), and benzimidazole (7h) derivatives showed significant activity against the triple‐negative breast cancer cell line, MDA‐MB‐468. The lead compounds also exhibited notable IC50 values against another breast cancer cell line, MCF‐7. Furthermore, it was observed that these compounds were relatively nontoxic to normal cell lines: HEK293 (human embryonic kidney cell line) and MCF12A (nontumorigenic human breast epithelial cell line). The IC50 values against healthy cells were at least 5‐ to 11‐fold higher, offering a new class of heterocycles that can be further developed as promising therapeutics for cancer treatment.

Small molecules that disrupt leukocyte trafficking have proven effective in treating patients with multiple sclerosis (MS). We previously reported that chemerin receptor chemokine-like receptor 1 (CMKLR1) is required for maximal clinical and histological experimental autoimmune encephalomyelitis (EAE); and identified CMKLR1 small molecule antagonist 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) that significantly suppressed disease onset in vivo . Here we directly compared α-NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for α-NETA; identified structure-activity relationships among α-NETA domains and CMKLR1 inhibition; and evaluated improved α-NETA analogs for in vivo efficacy. α-NETA proved safe and superior to Tecfidera in suppressing clinical EAE. In addition, we discovered structurally differentiated α-NETA analogs (primarily ortho- or para-methoxy substitutions) with significantly improved target potency in vitro and improved efficacy in vivo . These findings suggest that α-NETA-based CMKLR1 inhibitors may prove safe and effective in treating demyelinating diseases and potentially other autoimmune disorders.