Enhanced iodide sequestration by 3-biphenyl-5,6-dihydroimidazo[2,1-b]thiazole in sodium/iodide symporter (NIS)-expressing cells

The ability of the sodium/iodide symporter (NIS) to take up iodide has long provided the basis for cytoreductive gene therapy and cancer treatment with radioiodide. One of the major limitations of this approach is that radioiodide retention in NIS-expressing cells is not sufficient for their destruction. We identified and characterized a small organic molecule capable of increasing iodide retention in HEK293 cells permanently transfected with human NIS cDNA (hNIS-HEK293) and in the rat thyroid-derived cell line FRTL-5. In the presence of 3-biphenyl-4'-yl-5,6-dihydroimidazo[2,1-b]thiazole (ISA1), the transmembrane iodide concentration gradient was increased up to 4.5-fold. Our experiments indicate that the imidazothiazole derivative acts either by inhibiting anion efflux mechanisms, or by promoting the relocation of iodide into subcellular compartments. This new compound is not only an attractive chemical tool to investigate the mechanisms of iodide flux at the cellular level, but also opens promising perspectives in the treatment of cancer after NIS gene transfer.     

[6,7]‐Heterocycle‐Fused 14‐Hydroxymorphinan Derivatives: Design,Synthesis, and Opioid Receptor Activity

A series of new 14‐hydroxymorphinan analogues with a thiazole or imidazo[2,1‐b]thiazole fragment as the heterocyclic function fused to ring C were designed and synthesized. These compounds can be viewed as the result of a direct modification at ring C of the 14‐hydroxymorphinan scaffold. Among these compounds, three were identified as having potent binding affinity (～1 nM ) at both κ and μ receptors, and acting as agonists at κ and partial agonists or antagonists at μ receptors. In view of the promising results from studies on compounds with mixed κ and μ receptor activities, these new compounds warrant further investigation.     

Synthesis and Evaluation of 3,4‐Dihydropyrimidin‐2(1H)‐ones as Sodium Iodide Symporter Inhibitors

The sodium iodide symporter (NIS) is responsible for the accumulation of iodide in the thyroid gland. This transport process is involved in numerous thyroid dysfunctions and is the basis for human contamination in the case of exposure to radioactive iodine species. 4‐Aryl‐3,4‐dihydropyrimidin‐2(1H)‐ones were recently discovered by high‐throughput screening as the first NIS inhibitors. Described herein are the synthesis and evaluation of 115 derivatives with structural modifications at five key positions on the pyrimidone core. This study provides extensive structure–activity relationships for this new class of inhibitors that will serve as a basis for further development of compounds with in vivo efficacy and adequate pharmacokinetic properties. In addition, the SAR investigation provided a more potent compound, which exhibits an IC₅₀ value of 3.2 nM in a rat thyroid cell line (FRTL5).     

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

A series of chalcone conjugates featuring the imidazo[2,1‐b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF‐7, A549, HeLa, DU‐145 and HT‐29). These new hybrid molecules have shown promising cytotoxic activity with IC₅₀ values ranging from 0.64 to 30.9 μM . Among them, (E)‐3‐(6‐(4‐fluorophenyl)‐2,3‐bis(4‐methoxyphenyl)imidazo[2,1‐b]thiazol‐5‐yl)‐1‐(pyridin‐2‐yl)prop‐2‐en‐1‐one ( 11 x ) showed potent antiproliferative activity with IC₅₀ values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate ( 11 x ) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell‐cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase‐3, DNA fragmentation analysis, and Annexin V–FITC assay. Moreover, molecular docking studies indicated that this conjugate ( 11 x) interacts and binds efficiently with the tubulin protein.     

Synthesis and Biological Evaluation of Imidazo[2,1‐b][1,3,4]thiadiazole‐Linked Oxindoles as Potent Tubulin Polymerization Inhibitors

A series of imidazo[2,1‐b][1,3,4]thiadiazole‐linked oxindoles composed of an A, B, C and D ring system were synthesized and investigated for anti‐proliferative activity in various human cancer cell lines; test compounds were variously substituted at rings C and D. Among them, compounds 7 ((E)‐5‐fluoro‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)‐imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), 11 ((E)‐3‐((6‐p‐tolyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one), and 15 ((E)‐6‐chloro‐3‐((6‐phenyl‐2‐(3,4,5‐trimethoxyphenyl)imidazo[2,1‐b][1,3,4]thiadiazol‐5‐yl)methylene)indolin‐2‐one) exhibited potent anti‐proliferative activity. Treatment with these three compounds resulted in accumulation of cells in G₂/M phase, inhibition of tubulin assembly, and increased cyclin‐B1 protein levels. Compound 7 displayed potent cytotoxicity, with an IC₅₀ range of 1.1–1.6 μM , and inhibited tubulin polymerization with an IC₅₀ value (0.15 μM ) lower than that of combretastatin A‐4 (1.16 μM ). Docking studies reveal that compounds 7 and 11 bind with αAsn101, βThr179, and βCys241 in the colchicine binding site of tubulin.     

Direct coloration of textiles with photochromic dyes. Part 2: The effect of solvents on the colour change of photochromic textiles†

Polyester, acrylic and nylon textile substrates dyed with two spirooxazine dyes, 1,3,3‐trimethyl‐spiroindoline‐2,3′‐3H‐naphth[2,1‐b][1,4]oxazine ( 1a ) and 6′‐piperidino‐1,3,3‐trimethyl spiroindoline‐2,3′‐3H‐naphth[2,1‐b][1,4]oxazine ( 1b ), exhibit significantly higher photochromic colour build‐up when wet compared with after drying. A study of this phenomenon, extended beyond water to the influence of a series of selected organic solvents on photochromic behaviour, using colour measurement of the photochromic textiles under controlled ultraviolet irradiation conditions, is reported. The results of molecular modelling calculations (AM1 in water and PM5 in water) have been used as a means of interpreting the observed effects, in conjunction with qualitative arguments based on solvation and fibre swelling.     

Synthesis and Biological Evaluation of Iodoglucoazomycin (I‐GAZ), an Azomycin–Glucose Adduct with Putative Applications in Diagnostic Imaging and Radiotherapy of Hypoxic Tumors

Iodoglucoazomycin (I‐GAZ; N‐(2‐iodo‐3‐(6‐O‐glucosyl)propyl)‐2‐nitroimidazole), a non‐glycosidic nitroimidazole–6‐O‐glucose adduct, was synthesized, radioiodinated, and evaluated as a substrate of glucose transporter 1 (GLUT1) for radiotheranostic (therapy+diagnostic) management of hypoxic tumors. Nucleophilic iodination of the nosylate synthon of I‐GAZ followed by deprotection afforded I‐GAZ in 74 % overall yield. I‐GAZ was radioiodinated via ‘exchange’ labeling using [^123/131I]iodide (50–70 % RCY) and then purified by Sep‐Pak? (>96 % RCP). [¹³¹I]I‐GAZ was stable in 2 % ethanolic solution in sterile water for 14 days when stored at 5 °C. In cell culture, I‐GAZ was found to be nontoxic to EMT‐6 cells at concentrations <0.5 mm , and weakly radiosensitizing (SER 1.1 at 10 % survival of EMT‐6 cells; 1.2 at 0.1 % survival in MCF‐7 cells). The hypoxic/normoxic uptake ratio of [¹²³I]I‐GAZ in EMT‐6 cells was 1.46 at 2 h, and under normoxic conditions the uptake of [¹²³I]I‐GAZ by EMT‐6 cells was unaltered in the presence of 5 mm glucose. The biodistribution of [¹³¹I]I‐GAZ in EMT‐6 tumor‐bearing Balb/c mice demonstrated rapid clearance from blood and extensive renal and hepatic excretion. Tumor/blood and tumor/muscle ratios reached ～3 and 8, respectively, at 4 h post‐injection. Regression analysis of the first order polynomial plots of the blood and tumor radioactivity concentrations supported a perfusion–excretion model with low hypoxia‐dependent binding. [¹³¹I]I‐GAZ was found to be stable in vivo, and did not deiodinate.     

Room Temperature Highly Enantioselective Nickel‐Catalyzed Hydrovinylation

At room temperature, nickel catalysts based on the new phosphoramidite (11bR)‐N‐[(S)‐1‐(naphthalen‐1‐yl)ethyl]‐N‐[(S)‐1‐(naphthalen‐2‐yl)ethyl]dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin‐4‐amine provide excellent selectivities for 3‐arylbut‐1‐enes (93–99%) with high enantioselectivities (90–95% ee) and TOFs (up to 8300 h⁻¹) in the hydrovinylation of electron‐rich and electron‐poor vinylarenes. Within a few minutes, useful chiral building blocks and intermediates can be synthesized using this practical catalytic system.     

Mifepristone Treatment Results in Differential Regulation of Glycerolipid Biosynthesis in Baby Hamster Kidney Cells Expressing a Mifepristone-Inducible ABCA1

ATP binding cassette A1 (ABCA1) transports cholesterol, phospholipids and lipophilic molecules to and across cellular membranes. We examined if ABCA1 expression altered cellular de novo glycerolipid biosynthesis in growing Baby hamster kidney (BHK) cells. Mock BHK cells or cells expressing a mifepristone-inducible ABCA1 (ABCA1) were incubated plus or minus mifepristone and then with [³H]serine or [³H]inositol or [³H]ethanolamine or [methyl-³H]choline or [³H]glycerol or [¹⁴C]oleate and radioactivity incorporated into glycerolipids determined. Mifepristone did not affect [1,3-³H]glycerol or [¹⁴C]oleate or [³H]ethanolamine or [methyl-³H]choline uptake in BHK cells. In contrast, [³H]glycerol and [¹⁴C]oleate incorporated into phosphatidylserine (PtdSer) were elevated 2.4-fold (p < 0.05) and 54% (p < 0.05), respectively, upon ABCA1 induction confirming increased PtdSer biosynthesis from these precursors. However, mifepristone inhibited [³H]serine uptake and incorporation into PtdSer indicating that PtdSer synthesis from serine in BHK cells is dependent on serine uptake. Mifepristone stimulated [³H]inositol uptake in mock and ABCA1 cells but not its incorporation into phosphatidylinositol indicating that its synthesis from inositol is independent of inositol uptake in BHK cells. [³H]glycerol and [¹⁴C]oleate incorporated into triacylglycerol were reduced and into diacylglycerol elevated only in mifepristone-induced ABCA1 expressing cells due to a decrease in diacylglycerol acyltransferase-1 (DGAT-1) activity. The presence of trichostatin A, a class I and II histone deacetylase inhibitor, reversed the ABCA1-mediated reduction in DGAT-1 activity but did not affect DGAT-1 mRNA expression. Thus, mifepristone has diverse effects on de novo glycerolipid synthesis. We suggest that caution should be exercised when using mifepristone-inducible systems for studies of glycerolipid metabolism in cells expressing glucocorticoid responsive receptors.     

Direct coloration of textiles with photochromic dyes. Part 1: Application of spiroindolinonaphthoxazines as disperse dyes to polyester,nylon and acrylic fabrics†

1,3,3‐Trimethylspiroindoline‐2,3′‐3H‐naphth[2,1‐b][1,4]oxazine ( 1a ) and 6′‐piperidino‐1,3,3‐trimethylspiroindoline‐2,3′‐3H‐naphth[2,1‐b][1,4]oxazine ( 1b ) were applied as disperse dyes to polyester, nylon and acrylic fabrics. Under optimised dyeing conditions, photochromic fabrics were produced which, on irradiation with ultraviolet or exposure to sunlight, turned blue ( 1a) or blueish‐purple ( 1b ). Dye 1a showed enhanced photochromic colour change performance compared with dye 1b . The photochromic colour build was highest on nylon and lowest on acrylic fabric. The colour change properties and the technical performance (wash fastness and photostability) of the photochromic fabrics were evaluated using specifically adapted colour measurement methods. The data were analysed in terms of variation of lightness, a*, b*, chroma, hue angle and ΔE, colour difference before and after exposure, and K/S curves as a function of irradiation time. The fabrics generally showed good wash fastness. Although the colour build‐up decreased with exposure to the Xenotest fadeometer, some residual photochromism remained after prolonged exposure.     

Synthesis and characterization of light‐absorbing cyclopentadithiophene‐based donor–acceptor copolymers

Cyclopentadithiophene and benzothiadiazole based donor–acceptor polymers are fast emerging as the most promising class of materials for organic solar cells. Here we report on a series of Cyclopentadithiophene and benzothiadiazole based conjugated polymers, namely poly[4,7‐bis(4,4‐dioctyl‐4H‐cyclopenta[2,1‐b;3,4‐b′]dithiophene‐2‐yl)benzo[1,2,5]thiadiazole] (P1), poly[4,7‐bis(4,4‐dioctyl‐4H‐cyclopenta[2,1‐b;3,4‐b′]dithiophene‐2‐yl)benzo[1,2,5]thiadiazole‐alt‐9‐(heptadecan‐9‐yl)‐2,7‐bis(4,4,5,5‐tetramethyl)‐1,3,2‐dioxaborolan‐2‐yl)‐9H‐carbazole] (P2) and poly[4,7‐bis(4,4‐dioctyl‐4H‐cyclopenta[2,1‐b;3,4‐b′]dithiophene‐2‐yl)benzo[1,2,5]thiadiazole‐alt‐5,11‐bis(2‐hexyldecyl)‐3,9‐bis(4,4,5,5‐tetramethyl)‐1,3,2‐dioxaborolan‐2‐yl)‐5,11‐dihydroindolo[3,2‐b]carbazole] (P3), with alternating donor and acceptor units and discuss their photophysical and electrochemical properties. Stille coupling of 2‐tributylstannyl‐4,4‐dioctylcyclopenta[2,1‐b:3,4‐b′]dithiophene with 4,7‐dibromobenzo[1,2,5]thiadiazole generated the alternating donor–acceptor monomer 4,7‐bis(4,4‐dioctyl‐4H‐cyclopenta[2,1‐b;3,4‐b′]dithiophene‐2‐yl)benzo[1,2,5]thiadiazole (CPDT‐BT‐CPDT). Homopolymer P1 of CPDT‐BT‐CPDT was synthesized by oxidative polymerization using FeCl₃. Copolymers P2 and P3 were synthesized by palladium‐catalysed Suzuki polycondensation. The synthesized polymers showed good solubility in common organic solvents, and UV‐visible measurements showed that the absorption maxima of the polymers lie in the range 624 to 670 nm. The energy gaps of these polymers were found to lie in the range 1.29 to 1.50 eV. Gel permeation chromatography measurements against polystyrene standards showed the number‐average molecular weight to be in the range (2.2–6.0) × 10⁴ g mol^?1. Thermogravimetric analysis showed the polymers to possess high thermal stability. A preliminary study of photodiode devices prepared using polymers P1, P2 and P3 when blended with the PC₇₁BM electron acceptor found that P2 is the optimum chemical structure for pursuing further device optimization.© 2015 Society of Chemical Industry     

Domino Sonogashira Coupling/Cyclization Reaction Catalyzed by Copper and ppb Levels of Palladium: A Concise Route to Indoles and Benzo[b]furans

Both indoles and benzo[b]furans can be obtained in high yield by the reactions of 2‐iodoaniline derivatives and 2‐iodophenols with terminal alkynes under mild conditions, namely in the presence of cuprous iodide (10 mol%) and a base in ethanol or 1,4‐dioxane. Further investigation reveals that palladium contaminants as low as 100 ppb are responsible for these successful couplings. It is worth noting that simple aliphatic substituted terminal alkynes could be tolerated to smoothly produce indole and benzo[b]furan derivatives.     

3-substituted 2-phenylimidazo[2,1-b]benzothiazoles: synthesis, anticancer activity, and inhibition of tubulin polymerization

A new series of 3‐substituted 2‐phenylimidazo[2,1‐b]benzothiazoles ( 3 a – h ) were synthesized by C‐arylation of 2‐arylimidazo[2,1‐b]benzothiazoles using palladium acetate as catalyst, and the resulting compounds were evaluated for their anticancer activity. Compounds 3 a , 3 e , and 3 h exhibited good antiproliferative activity, with GI₅₀ values in the range of 0.19–83.1 μM . Compound 3 h showed potent anticancer efficacy against 60 human cancer cell lines, with a mean GI₅₀ value of 0.88 μM . This compound also induced cell‐cycle arrest in the G₂/M phase and inhibited tubulin polymerization followed by activation of caspase‐3 and apoptosis. A high‐throughput tubulin polymerization assay showed that the level of inhibition for compound 3 h is similar to that of combretastatin A‐4. Molecular modeling studies provided a molecular basis for the favorable binding of compounds 3 a , 3 e , and 3 h to the colchicine binding pocket of tubulin.     

A convenient [hydroxy(tosyloxy)iodo]benzene-mediated one-pot synthesis of 2-arylimidazo[2,1-b]benzothiazoles

Several 2-arylimidazo[2,1-b]benzothiazoles (4) have been conveniently synthesized in one-pot reactions via α-tosyloxylation of enolizable ketones (1) using [hydroxy(tosyloxy)iodo]benzene 2 in acetonitrile, followed by treatment with 2-amino-6-(substituted)benzothiazoles (3). The present protocol offers several advantages towards general access of 2-arylimidazo[2,1-b]benzothiazoles, including an intriguing alternative to the literature protocols, a readily available nontoxic reagent, operational simplicity and an environmentally benign procedure.     

Intramolecular Photochemical Cross‐Coupling Reactions of 3‐Acyl‐2‐haloindoles and 2‐Chloropyrrole‐3‐carbaldehydes with Substituted Benzenes

Highly efficient syntheses of indolo[2,1‐a]isoquinolines, indolo[2,1‐a][2]benzazepines, pyrrolo[2,1‐a]isoquinolines and pyrrolo[1,2‐a]benzazepines in excellent yields have been achieved by the intramolecular photochemical cross‐coupling reactions of 3‐acyl‐2‐halo‐N‐(ω‐arylalkyl)indoles and 2‐chloro‐N‐(ω‐arylalkyl)pyrrole‐3‐carbaldehydes in acetone. A new heterocyclic ring system – pyrrolo[1,2‐d][1,4]benzoxazepine – has also been constructed for the first time in this work by the photocyclization of 2‐chloro‐N‐(2‐phenoxyethyl)pyrrole‐3‐carbaldehyde.     

咪唑并[2,1-b]噻唑衍生物的合成及生物活性进展

根据环上取代基的不同咪唑并[2,1-b]噻唑衍生物具有多种多样的生物活性。通过对咪唑并[2,1-b]噻唑衍生物合成方法的不同进行分类,综述了近年来咪唑并[2,1-b]噻唑衍生物的合成及其生物活性,结果表明在咪唑并噻唑环上引入药理活性基团会增强其生物活性。咪唑并[2,1-b]噻唑环一般由Hanzstch方法合成,近年来也出现了一些新的合成方法,如Sonogashira、Suzuki反应和金属催化芳基化,对这些新方法合成咪唑并噻唑环及其衍生物也进行了综述。     

Synthesis and Biological Evaluation of Pyrrolo[2,1‐f][1,2,4]triazine C‐Nucleosides with a Ribose, 2′‐Deoxyribose,and 2′,3′‐Dideoxyribose Sugar Moiety

The synthesis of hitherto unknown pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4‐aza‐7,9‐dideazaadenine. In addition, pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides bearing a 2′‐deoxy‐, 2′,3′‐dideoxy‐, and 2′,3′‐dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1‐f][1,2,4]triazine C‐ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines.     

Palladium(II) Complexes of C2‐Bridged Chiral Diphosphines: Application to Enantioselective Carbonyl‐Ene Reactions

(11bR,11′bR)‐4,4′‐(1,2‐Phenylene)bis[4,5‐dihydro‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin] [abbreviated as (R)‐BINAPHANE], (3R,3′R,4S,4′S,11bS,11′bS)‐4,4′‐bis(1,1‐dimethylethyl)‐4,4′,5,5′‐tetrahydro‐3,3′‐bi‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin [(S)‐BINAPINE], (1S,1′S,2R,2′R)‐1,1′‐bis(1,1‐dimethylethyl)‐2,2′‐biphospholane [(S,S,R,R)‐TANGPHOS] and (2R,2′R,5R,5′R)‐1,1′‐(1,2‐phenylene)bis[2,5‐bis(1‐methylethyl)phospholane] [(R,R)‐i‐Pr‐DUPHOS] are C₂‐bridged chiral diphosphines that form stable complexes with palladium(II) and platinum(II) containing a five‐membered chelate ring. The Pd(II)‐BINAPHANE catalyst displayed good to excellent enantioselectivities with ee values as high as 99.0% albeit in low yields for the carbonyl‐ene reaction between phenylglyoxal and alkenes. Its Pt(II) counterpart afforded improved yields while retaining satisfactory enantioselectivity. For the carbonyl‐ene reaction between ethyl trifluoropyruvate and alkenes, the Pd(II)‐BINAPHANE catalyst afforded both good yields and extremely high enantioselectivities with ees as high as 99.6%. A comparative study on the Pd(II) catalysts of the four C₂‐bridged chiral diphosphines revealed that Pd(II)‐BINAPHANE afforded the best enantioselectivity. The ee values derived from Pd(II)‐BINAPHANE are much higher than those derived from the other three Pd(II) catalysts. A comparison of the catalyst structures shows that the Pd(II)‐BINAPHANE catalyst is the only one that has two bulky (R)‐binaphthyl groups close to the reaction site. Hence it creates a deep chiral space that can efficiently control the reaction behavior in the carbonyl‐ene reactions resulting in excellent enantioselectivity.     

A ¹⁸F-labeled fluorobutyl-substituted spirocyclic piperidine derivative as a selective radioligand for PET Imaging of sigma₁ receptors

In this study, we synthesized and evaluated a new spirocyclic piperidine derivative 3 , containing a 4‐fluorobutyl side chain, as a PET radioligand for neuroimaging of σ₁ receptors. In vitro, compound 3 displayed high affinity for σ₁ receptors (K_i=1.2 nM ) as well as high selectivity. [¹⁸F] 3 radiosynthesis was performed from the corresponding tosylate precursor, with high radiochemical yield (45–51 %), purity (>98 %), and specific activity (>201 GBq μmol^?1). Metabolic stability of [¹⁸F] 3 in the brain of CD‐1 mice was verified, and no penetration of peripheral radiometabolites into the cerebral tissue was observed. Results of ex vivo autoradiography revealed that the distribution of [¹⁸F] 3 in the brain corresponded to regions with high σ₁ receptor density. The highest region‐specific total‐to‐nonspecific ratio was determined in the facial nucleus (4.00). Biodistribution studies indicated rapid and high levels in brain uptake of [¹⁸F] 3 (2.2 % ID per gram at 5 min p.i.). Pre‐administration of haloperidol significantly inhibited [¹⁸F] 3 uptake into the brain and σ₁ receptor‐expressing organs, further confirming in vivo target specificity.