The reaction conditions for the conversion of 6‐endo‐tosyloxybicyclo[2.2.2]octan‐2‐one ( 7b ) into 6‐exo‐acetoxy ( 8b ) and 6‐exo‐benzoyloxybicyclo[2.2.2]octan‐2‐one ( 8a ), respectively, were improved. Thus known 6‐endo‐tosyloxy‐bicyclo[2.2.2]octan‐2‐ones (+)‐(1RS,6SR,8SR,11RS)‐11‐[(4‐toluenesulfonyl)oxy]tricyclo[6.2.2.01,6]dodecan‐9‐one ( 1a ), 13‐methyl‐15‐oxo‐9β,13b‐ethano‐9β‐podocarpan‐12β‐yl‐4‐toluenesulfonate ( 3a ), and methyl (13R)‐16‐oxo‐13‐[(4‐tolylsulfonyl)oxy]‐17‐noratisan‐18‐oate ( 5 ), were converted,in comparable yields, as previously recorded, but much shorter times, into (+)‐(1RS,6SR,8SR,11SR)‐11‐(benzoyloxy) tricyclo[6.2.2.01,6]dodecan‐9‐one ( 2 ), 13‐methyl‐15‐oxo‐9β,13β‐ethano‐9β‐podocarpan‐12α‐yl benzoate ( 4 ), and methyl (13S)‐13‐(benzoyloxy)‐16‐oxo‐17‐noratisan‐18‐oate ( 6 ), respectively. 相似文献
The benzoxazine scaffolds are of much interest as they are found in a large array of natural products and pharmaceutical drugs with diverse activities. We have developed a palladium‐catalyzed decarboxylative selective mono‐ and bis‐acylation of 4H‐benzo[d][1,3]oxazin‐4‐one derivatives with α‐oxo carboxylic acids via preferential cyclic imine‐N‐directed C−H activation. 2‐Aryl‐4H‐benzo[d][1,3]oxazin‐4‐one was acylated with a variety of substituted phenylglyoxylic acids to produce the corresponding products. It was observed that electron‐donating groups (CH3, OCH3) at any position of the aromatic ring of phenylglyoxylic acid provided good to excellent yields, whereas phenylglyoxylic acids containing electron‐withdrawing groups (COCH3, CN, NO2) gave the products in moderate yields. Interestingly when the reaction was performed with silver triflate (AgOTf) in place of silver nitrate (AgNO3) in the presence of 4 equivalents of glyoxylic acid, the bis‐acylated product was obtained together with a small amount of mono‐acylated product. This is the first report of acylation of 2‐aryl‐4H‐benzo[d][1,3]oxazin‐4‐ones via C−H activation. The notable features of this reaction are acylation with more challenging heteroarene‐oxo carboxylic acids and alkyl oxo carboxylic acids. This new protocol provides an easy and efficient access to a variety of o‐acyl‐4H‐benzo[d][1,3]oxazin‐4‐one derivatives which are of pharmaceutical importance.
By using computer modeling and lead structures from our earlier SAR results, a broad variety of pyrrole‐, indole‐, and pyrazole‐based compounds were evaluated as potential fructose 1,6‐bisphosphatase (FBPase) inhibitors. The docking studies yielded promising structures, and several were selected for synthesis and FBPase inhibition assays: 1‐[4‐(trifluoromethyl)benzoyl]‐1H‐indole‐5‐carboxamide, 1‐(α‐naphthalen‐1‐ylsulfonyl)‐7‐nitro‐1H‐indole, 5‐(4‐carboxyphenyl)‐3‐phenyl‐1‐[3‐(trifluoromethyl)phenyl]‐1H‐pyrazole, 1‐(4‐carboxyphenylsulfonyl)‐1H‐pyrrole, and 1‐(4‐carbomethoxyphenylsulfonyl)‐1H‐pyrrole were synthesized and tested for inhibition of FBPase. The IC50 values were determined to be 0.991 and 1.34 μM , and 575, 135, and 32 nM , respectively. The tested compounds were significantly more potent than the natural inhibitor AMP (4.0 μM ) by an order of magnitude; indeed, the best inhibitor showed an IC50 value toward FBPase more than two orders of magnitude better than that of AMP. This level of activity is virtually the same as that of the best currently known FBPase inhibitors. This work shows that such indole derivatives are promising candidates for drug development in the treatment of type II diabetes.相似文献
SnCl4 reacts with [1,2‐(N,N‐dimethylaminomethyl) ferrocenyl]lithium (FcNLi) under formation of the organo tin compounds of the four valued tin (FcN)n SnCl 4‐n [n = 1( 1 ), 2( 2 ), 3( 3 ), 4( 4 )]. The heterobimetallic chelate complex bis[1,2‐(N,N‐dimethylaminomethyl)ferrocenyl]tin(II) (FcN)2 Sn ( 5 ) is formed at the reaction of SnCl2 with two equivalents of FcNLi. The heterobimetallic tin compounds 1 — 5 were characterized by 1H NMR‐, 13C‐NMR and mass spectroscopy, single crystal x‐ray analyses ( 1,3,4,5 ), 57 Fe‐Moessbauer spectroscopy ( 1, 3, 4, 5 ), respectively cyclic voltammetry. 相似文献
Sphingosine‐1‐phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure–activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five‐membered heterocycles, and the use of diverse 2,2′‐disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N‐methyl‐N‐(4‐{5‐[2‐methyl‐2′‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 45 ), and a dual S1P1,5 agonist, N‐methyl‐N‐(3‐{5‐[2′‐methyl‐2‐(trifluoromethyl)biphenyl‐4‐yl]‐1,2,4‐oxadiazol‐3‐yl}benzyl)glycine ( 49 ), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head‐to‐head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan‐S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1‐selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS. 相似文献
The development of drug resistance remains a critical problem for current HIV‐1 antiviral therapies, creating a need for new inhibitors of HIV‐1 replication. We previously reported on a novel anti‐HIV‐1 compound, N2‐(phenoxyacetyl)‐N‐[4‐(1‐piperidinylcarbonyl)benzyl]glycinamide ( 14 ), that binds to the highly conserved phosphatidylinositol (4,5)‐bisphosphate (PI(4,5)P2) binding pocket of the HIV‐1 matrix (MA) protein. In this study, we re‐evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV‐1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2‐(4‐{[3‐(4‐fluorophenyl)‐1,2,4‐oxadiazol‐5‐yl]methyl})‐1‐piperazinyl)‐N‐(4‐methylphenyl)acetamide ( 7 ), 3‐(2‐ethoxyphenyl)‐5‐[[4‐(4‐nitrophenyl)piperazin‐1‐yl]methyl]‐1,2,4‐oxadiazole ( 17 ), and N‐[4‐ethoxy‐3‐(1‐piperidinylsulfonyl)phenyl]‐2‐(imidazo[2,1‐b][1,3]thiazol‐6‐yl)acetamide ( 18 ), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV‐1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P2 for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P2 binding site of MA decreased the antiviral effect of compound 7 . Additionally, compound 7 displays a broadly neutralizing anti‐HIV activity, with IC50 values of 7.5–15.6 μM for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti‐HIV‐1 therapeutics. 相似文献
4‐Amino‐2,5‐dihydro‐3‐thiophenecarbonitriles 1 reacted with dimethyl diazomalonate in the presence of rhodium(II) acetate to give regioselectively 4‐cyano‐2H‐thio‐pyrans 2 (C 2— S insertion), and 5‐cyano‐2H‐thiopyrans (C 5— S insertion) were not isolated. Similar insertion was also observed in the reaction of 1 with methyl diazoacetoacetate and ethyl diazobenzoylacetate. The starting compounds 1 were synthesized by the reaction of tetrahydro‐4‐oxo‐3‐thiophene‐carbonitrile with morpholine, piperidine, and pyrrolidine in the presence of formic acid in ethanol. 相似文献
The binding behavior of green fluorescent ligands, derivatives of 7‐nitrobenzo‐2‐oxa‐1,3‐diazole (NBD), with DNA duplexes containing an abasic (AP) site is studied by thermal denaturation and fluorescence experiments. Among NBD derivatives, N1‐(7‐nitrobenzo[c][1,2,5]oxadiazol‐4‐yl)propane‐1,3‐diamine (NBD‐NH2) is found to bind selectively to the thymine base opposite an AP site in a DNA duplex with a binding affinity of 1.52×106 M ?1. From molecular modeling studies, it is suggested that the NBD moiety binds to thymine at the AP site and a protonated amino group tethered to the NBD moiety interacts with the guanine base flanking the AP site. Green fluorescent NBD‐NH2 is successfully applied for simultaneous G>T genotyping of PCR amplification products in a single cuvette in combination with a blue fluorescent ligand, 2‐amino‐6,7‐dimethyl‐4‐hydroxypteridine (diMe‐pteridine).相似文献
The monometallic species {Salen}AlX (X=Me, 2a , b ; X=Cl, 4a , b ; O‐i‐Pr, 5a,b ) and open bimetallic species {Salen}[AlMe2]2 ( 3a , b ) that result from binary combinations between an aluminum precursor [trimethylaluminum, dimethylaluminum chloride, aluminum tris(isopropoxide)] and a diprotio {Salen}H2 pro‐ligand 1a , b ( a =1R,2R‐cyclohexyl‐salen; b =1R,2R‐diphenylethylene‐salen) have been isolated. The crystal structures of 3b , 4b and of μ‐oxo species [{diphenylethylene‐salen}Al]2O ( 6b ) are reported. The discrete species 2 – 5a,b have been individually evaluated in the asymmetric cyanosilylation of acetophenone. It is shown that, in several cases, these discrete catalysts display dramatically different performances than the catalyst systems in situ‐generated from the binary combinations. The influence of the achiral ligand X on both the enantioselectivity and activity of the cyanosilylation reaction has been investigated, resulting in the definition of a highly active and productive hexafluoro‐2‐propoxide‐based catalyst for a variety of aryl alkyl ketones (TON up to 470, TOF up to 140 h−1 at −20 °C for acetophenone). 相似文献
Non‐cationic and amphipathic indoloazepinone‐constrained (Aia) oligomers have been synthesized as new vectors for intracellular delivery. The conformational preferences of the [l ‐Aia‐Xxx]n oligomers were investigated by circular dichroism (CD) and NMR spectroscopy. Whereas Boc‐[l ‐Aia‐Gly]2,4‐OBn oligomers 12 and 13 and Boc‐[l ‐Aia‐β3‐h‐l ‐Ala]2,4‐OBn oligomers 16 and 17 were totally or partially disordered, Boc‐[l ‐Aia‐l ‐Ala]2‐OBn ( 14 ) induced a typical turn stabilized by C5‐ and C7‐membered H‐bond pseudo‐cycles and aromatic interactions. Boc‐[l ‐Aia‐l ‐Ala]4‐OBn ( 15 ) exhibited a unique structure with remarkable T‐shaped π‐stacking interactions involving the indole rings of the four l ‐Aia residues forming a dense hydrophobic cluster. All of the proposed FITC‐6‐Ahx‐[l ‐Aia‐Xxx]4‐NH2 oligomers 19 – 23 , with the exception of FITC‐6‐Ahx‐[l ‐Aia‐Gly]4‐NH2 ( 18 ), were internalized by MDA‐MB‐231 cells with higher efficiency than the positive references penetratin and Arg8. In parallel, the compounds of this series were successfully explored in an in vitro blood–brain barrier (BBB) permeation assay. Although no passive diffusion permeability was observed for any of the tested Ac‐[l ‐Aia‐Xxx]4‐NH2 oligomers in the PAMPA model, Ac‐[l ‐Aia‐l ‐Arg]4‐NH2 ( 26 ) showed significant permeation in the in vitro cell‐based human model of the BBB, suggesting an active mechanism of cell penetration. 相似文献
Given their high neuroprotective potential, ligands that block GluN2B‐containing N‐methyl‐D ‐aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B‐selective NMDA receptor antagonists with the benzo[7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N‐(2‐methoxy‐5‐oxo‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐yl)acetamide ( 11 ), was obtained by cyclization of 3‐acetamido‐5‐(3‐methoxyphenyl)pentanoic acid ( 10 b ). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis‐ and trans‐configured 7‐(ω‐phenylalkylamino)benzo[7]annulen‐5‐ols. High GluN2B affinity was observed with cis‐configured γ‐amino alcohols substituted with a 3‐phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2‐methoxy‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 20 a , Ki=10 nM ) and 2‐methoxy‐N‐methyl‐N‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5H‐benzo[7]annulen‐7‐amine ( 23 a , Ki=7.9 nM ). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ1 and σ2 receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo[7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit‐containing NMDA receptors was not inhibited by the new ligands. 相似文献
A library of 5‐methylindolo[3,2‐c]quinolones (IQc) with various substitution patterns of alkyldiamine side chains were evaluated for G‐quadruplex (G4) binding mode and efficiency. Fluorescence resonance energy transfer melting assays showed that IQcs with a positive charge in the heteroaromatic nucleus and two weakly basic side chains are potent and selective human telomeric (HT) and gene promoter G4 stabilizers. Spectroscopic studies with HT G4 as a model showed that an IQc stabilizing complex involves the binding of two IQc molecules (2,9‐bis{[3‐(diethylamino)propyl]amino}‐5‐methyl‐11H‐indolo[3,2‐c]quinolin‐5‐ium chloride, 3 d ) per G4 unit, in two non‐independent but equivalent binding sites. Molecular dynamics studies suggest that end‐stacking of 3 d induces a conformational rearrangement in the G4 structure, driving the binding of a second 3 d ligand to a G4 groove. Modeling studies also suggest that 3 d , with two three‐carbon side chains, has the appropriate geometry to participate in direct or water‐mediated hydrogen bonding to the phosphate backbone and/or G4 loops, assisted by the terminal nitrogen atoms of the side chains. Additionally, antiproliferative studies showed that IQc compounds 2 d (2‐{[3‐(diethylamino)propyl]amino}‐5‐methyl‐11H‐indolo[3,2‐c]quinolin‐5‐ium chloride) and 3 d are 7‐ to 12‐fold more selective for human malignant cell lines than for nonmalignant fibroblasts. 相似文献