A new Korean Research Investment for Global Health Technology (RIGHT) Fund to advance innovative neglected-disease technologies.

In 2018, the government of the Republic of Korea (ROK), South Korean life science companies, and a group of international funders led by the Bill & Melinda Gates Foundation launched a new and innovative funding agency to support neglected-disease research and development (R&D). The new venture is known as the Research Investment for Global Health Technology (RIGHT) Fund.

Multifunctional Fluorescent Nanoprobe for Sequential Detections of Hg2+ Ions and Biothiols in Live Cells.

Herein, we report an amphiphilic fluorescent probe consisting of a dansyl fluorophore as a reporter and a hydrophobic cetyl chain bridged by a triazole unit. The cetyl-based probe can self-assemble to form nanoaggregates in aqueous solution, as confirmed by Tyndall effect, dynamic light scattering (DLS), and transmission electron microscopy (TEM) measurements. This probe exhibited an "on-off" fluorescence quenching response toward Hg2+ ions in aqueous solution over other tested metal ions. In contrast, the analogous methyl-based probe barely exhibits Hg2+ ion sensing behavior under the same conditions. Moreover, the resulting complex of the cetyl-based probe and Hg2+ (1-Hg2+, 1:1 stoichiometry) exhibited an efficient fluorescence "off-on" sensing for thiol-containing amino acids, including cysteine (Cys), homocysteine (Hcy), and glutathione (GSH). This nanoprobe exhibited minimal cytotoxicity with excellent cell permeability and was efficiently tested for the imaging of intracellular Hg2+ and cysteine in live cells.

Self-assembly of a 1D hydrogen-bonded polymer from a hexamethyltetraaza macrocyclic nickel(II) complex and isophthalic acid.

The compound [Ni(L)(isoph)2][Ni(L)]·8H2O (1; L = C-meso-5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane; H2-isoph = isophthalic acid) has been synthesized and structurally characterized. Complex 1 exhibits a geometrically symmetric core with a {4/6} coordination number set. The coordination environment around the Ni(1) ion is a distorted octahedron, while the geometry around the four-coordinate Ni(2) is depicted as square planar in 1D hydrogen-bonded infinite chain. The compound crystallizes in the triclinic system P-1 with a = 8.602(2), b = 10.684(7), c = 16.550(3) Å, a = 91.04(4), b = 94.09(2), g = 111.09(4)°, V = 1413.9(10) ų, Z = 1. The cyclic voltammogram of 1 undergoes one-electron wave corresponding to NiII/NiI process. The electronic spectra, electrochemical and TGA behavior of the complex are significantly affected by the nature of the hexamethyltetraaza macrocycle and the axial isoph²â» ligand.

One-dimensional hydrogen-bonded infinite chain from nickel(II) tetraaza macrocyclic complex and 1,2-cyclopentanedicarboxylate ligand.

The reaction of [Ni(L)]Cl(2)·2H(2)O (L = 3,14-dimethyl-2,6,13,17-tetraazatricyclo [14,4,0(1.18),0(7.12)]docosane) with trans-1,2-cyclopentanedicarboxylic acid (H(2)-cpdc) yields a 1D hydrogen-bonded infinite chain with formula [Ni(L)(H-cpdc(-))(2)] (1). This complex has been characterized by X-ray crystallography, spectroscopy and cyclic voltammetry. The crystal structure of 1 exhibits a distorted octahedral geometry about Ni atom with four nitrogen atoms of the macrocycle and two oxygen atoms of the H-cpdc(-) ligand at the axial position. Compound 1 crystallizes in the monoclinic system P2(1)/c with a = 8.7429(17), b = 10.488(2), c = 18.929(4) Å, ß = 91.82(2), V = 1734.8(6) Å(3), Z = 2. Electronic spectrum of 1 reveals a high-spin octahedral environment. Cyclic voltammetry of 1 undergoes two waves of a one-electron transfer corresponding to Ni(II)/Ni(III) and Ni(II)/Ni(I) processes.

Effects of the anti-sepsis drug, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD-712), on mortality, inflammation, and organ injuries in rodent sepsis models.

CKD-712 is a 1-naphthyl analog of higenamine that has been reported to have potent antiinflammatory and thus anti-sepsis effects. The purpose of this study was to investigate the potential of CKD-712 as a medicine for sepsis and to confirm its protective effects on organs in animal sepsis models. Pretreatment with CKD-712 dose-dependently increased survival rate in a lipopolysaccharide-induced sepsis model in mice. Body temperature decrease, an important pre-symptom of septic death, was also prevented by CKD-712. CKD-712 still significantly increased survival rate even when administered one and four hours after lipopolysaccharide injection. Therapeutic efficacy of CKD-712 was also confirmed against sepsis following zymosan-induced endotoxemia and in cecal ligation and puncture surgery in mice. In a disseminated intravascular coagulation model in rats, CKD-712 showed organ-protective effect by reducing serum glutamate-oxaloacetate transaminase, glutamate-pyruvate transferase, blood urea nitrogen, and creatinine levels. CKD-712 also prevented histological damage to the lung and liver. In this same model, CKD-712 showed anti-inflammatory effects through decreases in tumor necrosis factor-α and interleukin-6 in the blood and reduced translocation of nuclear factor-κB to the nuclei of lung cells. CKD-712 administration also diminished infiltration of leukocytes into the lung and liver. Taken together, these results show that CKD-712 has excellent potential as an effective medicine for sepsis.

Identification of CKD-516: a potent tubulin polymerization inhibitor with marked antitumor activity against murine and human solid tumors.

Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SAR analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G(2)/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (l)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice.

Strategy in inhibition of cathepsin B, a target in tumor invasion and metastasis.

Cathepsin B, a cysteine protease, is an important target in fighting cancer. This enzyme has been implicated in enhancing tumor invasiveness and metastasis, therefore inhibitors for cathepsin B are highly sought as potential anticancer and antimetastatic agents. A structure-based design effort was pursued in arriving at a template for inhibition of cathepsin B. Focused compound libraries were synthesized based on this template, which were screened for cathepsin B inhibitory properties. Compound 2, 1-(2(R)-[1(S)-acetoxy-2-[2(S)-(2,4-difluoro-benzoylamino)-3-phenyl-propionylaminooxy]-2-oxo-ethyl]-pentanoyl)-pyrrolidine-2(S)-carboxylic acid benzyl ester, is the prototype of this novel class of cysteine protease inhibitor that emerged from the search. The molecule modifies the active site of cathepsin B covalently, irreversibly, and efficiently, a process for which the kinetic parameters were evaluated. A set of three judiciously altered variants of compound 2 was also synthesized to explore the details of the proposed mechanism of action by this inhibitor. Compound 2 and its analogues may prove useful tools in reversing the deleterious effect of cathepsin B in fighting cancer.

A convenient synthesis of a selective gelatinase inhibitor as an antimetastatic agent.

Compound 1, 2-(4-phenoxyphenylsulfonylmethyl)thiirane, is a potent and selective inhibitor for human gelatinases (J. Am. Chem. Soc. 2000, 122, 6799-6800), enzymes implicated in a number of diseases, including cancer. This compound is showing excellent promise in animal trials in a number of disease models. Large quantities of this compound were necessary for these studies. A convenient four-step synthetic route for compound 1 is described herein. The synthesis is amenable to scale-up to tens of grams and gives an overall yield of 57% for this important compound.

Constraints of opsin structure on the ligand-binding site: studies with ring-fused retinals.

Ring-fused retinal analogs were designed to examine the hula-twist mode of the photoisomerization of the 9-cis retinylidene chromophore. Two 9-cis retinal analogs, the C11-C13 five-membered ring-fused and the C12-C14 five-membered ring-fused retinal derivatives, formed the pigments with opsin. The C11-C13 ring-fused analog was isomerized to a relaxed all-trans chromophore (lambda(max) > 400 nm) at even -269 degrees C and the Schiff base was kept protonated at 0 degrees C. The C12-C14 ring-fused analog was converted photochemically to a bathorhodopsin-like chromophore (lambda(max) = 583 nm) at -196 degrees C, which was further converted to the deprotonated Schiff base at 0 degrees C. The model-building study suggested that the analogs do not form pigments in the retinal-binding site of rhodopsin but form pigments with opsin structures, which have larger binding space generated by the movement of transmembrane helices. The molecular dynamics simulation of the isomerization of the analog chromophores provided a twisted C11-C12 double bond for the C12-C14 ring-fused analog and all relaxed double bonds with a highly twisted C10-C11 bond for the C11-C13 ring-fused analog. The structural model of the C11-C13 ring-fused analog chromophore showed a characteristic flip of the cyclohexenyl moiety toward transmembrane segments 3 and 4. The structural models suggested that hula twist is a primary process for the photoisomerization of the analog chromophores.