Facile Synthesis of 2-(4-Hydroxybiphenyl-3-yl)-1<i>H</i>-indoles from Anilines and 5′-Bromo-2′-hydroxyacetophenone

<div><p></p><p>2-Arylindoles are attractive scaffolds because they are found in many pharmacologically active molecules. In this study, we describe the facile synthesis of diverse 2-(2-hydroxyphenyl)-1<i>H</i>-indoles from anilines and 5′-bromo-2′-hydroxyacetophenone in two steps using palladium-catalyzed indole cyclization as a key reaction. The indole cyclization was primarily controlled by the substituent properties of anilines. Suzuki-coupling reactions of 2-(5′-bromo-2′-hydroxyphenyl)-1<i>H</i>-indoles with arylboronic acids provided the corresponding 2-(4-hydroxybiphenyl-3-yl)-1<i>H</i>-indoles in moderate yield.</p></div

Effect of Chelators on the Pharmacokinetics of ^99mTc-Labeled Imaging Agents for the Prostate-Specific Membrane Antigen (PSMA)

Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biologically important molecules through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different ^99mTc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea-based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [^99mTc­(CO)₃]⁺ core (<b>L8</b>–<b>L10</b>), traditional N_<i>x</i>S_<i>y</i>-based chelating agents with varying charge and polarity for the ^99mTc-oxo core (<b>L11</b>–<b>L18</b>), and a ^99mTc-organohydrazine-labeled radioligand (<b>L19</b>). ^99mTc­(I)-Tricarbonyl-labeled [^99mTc]<b>L8</b> produced the highest PSMA+ PC3 PIP to PSMA– PC3 flu tumor ratios and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of ^99mTc-labeled radiopharmaceuticals targeting PSMA

Synthesis and Biological Evaluation of Low Molecular Weight Fluorescent Imaging Agents for the Prostate-Specific Membrane Antigen

Targeted near-infrared (NIR) optical imaging can be used in vivo to detect specific tissues, including malignant cells. A series of NIR fluorescent ligands targeting the prostate-specific membrane antigen (PSMA) was synthesized and each compound was tested for its ability to image PSMA+ tissues in experimental models of prostate cancer. The agents were prepared by conjugating commercially available active esters of NIR dyes, including IRDye800CW, IRDye800RS, Cy5.5, Cy7, or a derivative of indocyanine green (ICG) to the terminal amine group of (<i>S</i>)-2-(3-((<i>S</i>)-5-amino-1-carboxypentyl)­ureido)­pentanedioic acid <b>1</b>, (14<i>S</i>,18<i>S</i>)-1-amino-8,16-dioxo-3,6-dioxa-9,15,17-triazaicosane-14,18,20-tricarboxylic acid <b>2</b> and (3<i>S</i>,<i>7S</i>)-26-amino-5,13,20-trioxo-4,6,12,21-tetraazahexacosane-1,3,7,22-tetracarboxylic acid <b>3</b>. The <i>K</i>_i values for the dye–inhibitor conjugates ranged from 1 to 700 pM. All compounds proved capable of imaging PSMA+ tumors selectively to varying degrees depending on the choice of fluorophore and linker. The highest tumor uptake was observed with IRDye800CW employing a poly­(ethylene glycol) or lysine–suberate linker, as in 800CW-<b>2</b> and 800CW-<b>3</b>, while the highest tumor to nontarget tissue ratios were obtained for Cy7 with these same linkers, as in Cy7-<b>2</b> and Cy7-<b>3</b>. Compounds <b>2</b> and <b>3</b> provide useful scaffolds for targeting of PSMA+ tissues in vivo and should be useful for preparing NIR dye conjugates designed specifically for clinical intraoperative optical imaging devices

Structure–Activity Relationships of 6- and 8‑Gingerol Analogs as Anti-Biofilm Agents

<i>Pseudomonas aeruginosa</i> is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with <i>P. aeruginosa</i> infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in <i>P. aeruginosa</i>. Structure–activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound <b>41</b>, an analog of (<i>R</i>)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (<i>S</i>)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat <i>P. aeruginosa</i> infections

Structure–Activity Relationships of 6- and 8‑Gingerol Analogs as Anti-Biofilm Agents

<i>Pseudomonas aeruginosa</i> is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with <i>P. aeruginosa</i> infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in <i>P. aeruginosa</i>. Structure–activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound <b>41</b>, an analog of (<i>R</i>)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (<i>S</i>)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat <i>P. aeruginosa</i> infections

Multicomponent System of NPS-1034, an Orally Administered Lung Cancer Drug Candidate, with Sulfonic Acids and Solid State Characterization

NPS-1034 is a drug candidate targeted for the regulation of c-MET/AXL receptor tyrosin kinase activity. NPS-1034 was developed to improve efficacy and reduce toxicity by targeting c-MET/AXL related signaling pathways. However, NPS-1034 is practically insoluble in almost all organic solvents as well as aqueous media (pH 1, 4.5, and 7.5). We attempted to improve the physicochemical properties of NPS-1034 by forming multicomponent systems with a wide variety of sulfonic acids including methanesulfonic acid, 1,2-ethanedisulfonic acid, <i>p</i>-toluenesulfonic acid, and camphorsulfonic acid. Solid state characterization of NPS-1034 salts and amorphous with sulfonic acids was conducted, and the crystal structures of four salts and NPS-1034 were compared and investigated. Sulfonic acid salts of NPS-1034 decreased the melting point of NPS-1034 as much as −155.43 °C. Solubilities of NPS-1034 and salts of NPS-1034 were measured to develop lipid-based formulation for the GLP toxicity study. Solvents studied include oleic acid, poly­(ethylene glycol) 400, and ethanol. Solubility of amorphous of NPS-1034 with camphorsulfonic acid showed a significant increase in all three solvents. This work will give some insight into how various types of sulfonic acids interact with pharmaceutically important compounds containing the pyrrolepyridine moiety

Structure–Activity Relationships of 6- and 8‑Gingerol Analogs as Anti-Biofilm Agents

<i>Pseudomonas aeruginosa</i> is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with <i>P. aeruginosa</i> infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in <i>P. aeruginosa</i>. Structure–activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound <b>41</b>, an analog of (<i>R</i>)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (<i>S</i>)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat <i>P. aeruginosa</i> infections

Synthesis, Biological Evaluation, and Radioiodination of Halogenated <i>closo</i>-Carboranylthymidine Analogues

The synthesis and initial biological evaluation of 3-carboranylthymidine analogues (3CTAs) that are (radio)­halogenated at the <i>closo</i>-carborane cluster are described. Radiohalogenated 3CTAs have the potential to be used in the radiotherapy and imaging of cancer because they may be selectively entrapped in tumor cells through monophosphorylation by human thymidine kinase 1 (hTK1). Two strategies for the synthesis of a ¹²⁷I-labeled form of a specific 3CTA, previously designated as <b>N5</b>, are described: (1) direct iodination of <b>N5</b> with iodine monochloride and aluminum chloride to obtain <b>N5-¹²⁷I</b> and (2) initial monoiodination of <i>o</i>-carborane to 9-iodo-<i>o</i>-carborane followed by its functionalization to <b>N5-¹²⁷I</b>. The former strategy produced <b>N5-¹²⁷I</b> in low yields along with di-, tri-, and tetraiodinated <b>N5</b> as well as decomposition products, whereas the latter method produced only <b>N5-¹²⁷I</b> in high yields. <b>N5-¹²⁷I</b> was subjected to nucleophilic halogen- and isotope-exchange reactions using Na^79/81Br and Na¹²⁵I, respectively, in the presence of Herrmann’s catalyst to obtain <b>N5-^79/81Br</b> and <b>N5-¹²⁵I</b>, respectively. Two intermediate products formed using the second strategy, 1-(<i>tert</i>-butyldimethylsilyl)-9-iodo-<i>o</i>-carborane and 1-(<i>tert</i>-butyldimethylsilyl)-12-iodo-<i>o</i>-carborane, were subjected to X-ray diffraction studies to confirm that substitution at a single carbon atom of 9-iodo-<i>o</i>-carborane resulted in the formation of two structural isomers. To the best of our knowledge, this is the first report of halogen- and isotope-exchange reactions of B-halocarboranes that have been conjugated to a complex biomolecule. Human TK1 phosphorylation rates of <b>N5</b>, <b>N5-¹²⁷I</b>, and <b>N5-^79/81Br</b> ranged from 38.0% to 29.6% relative to that of thymidine, the endogenous hTK1 substrate. The in vitro uptake of <b>N5</b>, <b>N5-¹²⁷I</b>, and <b>N5-^79/81Br</b> in L929 TK1­(+) cells was 2.0, 1.8, and 1.4 times greater than that in L929 TK1(−) cells

Effects of the topical administration of MHY 966 on UVB-induced epidermal thickness and collagen destruction in HRM2 mouse dorsal skin.

<p>Histological sections of mouse dorsal skins were stained with Masson-trichrome for dermal collagen fibrates (A). Paraffin sections were photographed after H&E staining for UVB induced skin damage (B). Original magnification: 200 X.</p

MHY 966 both activated PPAR α and γ, and inhibited inflammatory responses in UVB-induced HRM2 mouse skins.

<p>Western blot analysis was performed to detect the levels of PPAR α PPAR γ (A), NF-κB (B), MMP-1, COX-2 and iNOS (C) in skin hommogenate. TFⅡB and β-actin blots were shown to clarify the same amount of protein loaded in nuclear and cytosolic fraction, respectively. 0.4 or 2 μM of MHY 966 was topically applied on dorsal skin daily at for 17 days and then exposed to UVB using a BEX-800 UVB lamp (UltraLun, Claremont, Ca, USA) at 150 mJ/cm².</p