Development of an (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114] carba analogue inhibitor for murine γ-aminobutyric acid transporter type 4

A series of GABA uptake inhibitors related to (S)-1-{2-[tris(4-methoxyphenyl)methoxy]ethyl}piperidine-3-carboxylic acid [(S)-SNAP-5114], the most potent mGAT4 inhibitor known so far, were synthesized and biologically evaluated for their inhibitory potency at the four GABA uptake transporters mGAT1-4 stably expressed in HEK-293 cell lines. New analogues were developed with potencies that are similar to or slightly higher than those of current mGAT4 inhibitors, but with distinctly improved chemical stability. (S)-Nipecotic acid derivatives possessing a 2-[1-(4-methoxy-2-methylphenyl)-1,1-bis(4-methoxyphenyl)methoxy]ethyl (DDPM-859) or a 4,4,4-tris(4-methoxyphenyl)but-2-en-1-yl moiety (DDPM-1457) were found to exhibit pIC(50) values of 5.78 and 5.87, respectively. Thus, as mGAT4 inhibitors, these compounds compare well with (S)-SNAP-5114 (pIC(50) =5.71), but are far more stable than the latter. Moreover, DDPM-859 displays a more favorable subtype selectivity for mGAT4 versus mGAT3 than does (S)-SNAP-5114.     

Synthesis and Biological Evaluation of Nipecotic Acid and Guvacine Derived 1,3-Disubstituted Allenes as Inhibitors of Murine GABA Transporter mGAT1

A new class of nipecotic acid and guvacine derivatives has been synthesized and characterized for their inhibitory potency at mGAT1–4 and binding affinity for mGAT1. Compounds of the described class are defined by a four-carbon-atom allenyl spacer connecting the nitrogen atom of the nipecotic acid or guvacine head with an aromatic residue. Among the compounds investigated, the mixture of nipecotic acid derivatives rac-{(R_a)-1-[4-([1,1′:2′,1′′-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic acid} and rac-{(S_a)-1-[4-([1,1′:2′,1′′-terphenyl]-2-yl)buta-2,3-dien-1-yl](3R)-piperidine-3-carboxylic acid} ( 21 p ), possessing an o-terphenyl residue, was identified as highly selective and the most potent mGAT1 inhibitor in this study. For the (R)-nipecotic acid derived form of 21 p , the inhibitory potency in [³H]GABA uptake assays was determined as pIC₅₀=6.78±0.08, and the binding affinity in MS Binding Assays as pK_i=7.10±0.12. The synthesis of the designed compounds was carried out by a two-step procedure, generating the allene moiety via allenylation of terminal alkynes which allows broad variation of the terminal phenyl and biphenyl subunit.     

MS-Based Screening of 5-Substituted Nipecotic Acid Derived Hydrazone Libraries as Ligands of the GABA Transporter 1

A screening of compound libraries based on nipecotic acid derivatives with lipophilic residues attached to the scarcely explored 5-position of the core structure was used for the search of new inhibitors of the γ-aminobutyric acid (GABA) transporter 1 (mGAT1). The generated compound libraries, which were based on hydrazone chemistry commonly used in dynamic combinatorial chemistry but rendered pseudostatic, were screened for their binding affinities toward mGAT1 by means of MS Binding Assays. With nipecotic acid derived hydrazone rac- 16 h [rac-(3R,5S)-{5-[(E)-2-{[5-(2-phenylethynyl)thiophen-2-yl]methylidene}hydrazin-1-yl]piperidine-3-carboxylic acid}-sodium chloride (1/2)], one hit was found and evaluated displaying sub-micromolar potency (pK_i=6.62±0.04) and a noncompetitive interaction mode at mGAT1. By bearing a 5-(2-phenylethynyl)thiophen-2-yl residue attached to the 5-position of nipecotic acid via a three-atom spacer, compound rac- 16 h contains a structural moiety so far unprecedented for these kinds of bioactive molecules, and complements novel 5-substituted nipecotic acid derived ligands of mGAT1 revealed in a recently published screening campaign. This new class of ligands, with an inhibition mode distinct from that of benchmark mGAT1 inhibitors, could serve as research tools for investigations of mGAT1-mediated GABA transport.     

Aromatic Acids of Carnauba Wax

Cinnamic acid withpara-hydroxy andpara-methoxy substitution has been isolated from carnauba wax in a yield of about 5%. Thepara-hydroxycinnamic acid accounts for approximately 75% of the total aromatic acids. These hitherto unreported aromatic acids occur predominantly as part of a polymerizable diester of approximate average molecular weight 1025. Certain properties of carnauba wax are believed to be due to the presence of about 30% of these diesters. Except for trace amounts, no significant quantities of these aromatic acids could be isolated in the free state from the whole wax.     

Conformation analysis of aspartame-based sweeteners by NMR spectroscopy, molecular dynamics simulations, and X-ray diffraction studies

We report here the synthesis and the conformation analysis by 1H NMR spectroscopy and computer simulations of six potent sweet molecules, N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-S-tert-butyl-L-cysteine 1-methylester (1; 70 000 times more potent than sucrose), N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-beta-cyclohexyl-L-alanine 1-methylester (2; 50 000 times more potent than sucrose), N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-4-cyan-L-phenylalanine 1-methylester (3; 2 000 times more potent than sucrose), N-[3,3-dimethylbutyl]-alpha-L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide (4; 5500 times more potent than sucrose), N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-alpha-L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide (5; 15 000 times more potent than sucrose), and N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-alpha-L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide (6; 15 000 times more potent than sucrose). The "L-shaped" structure, which we believe to be responsible for sweet taste, is accessible to all six molecules in solution. This structure is characterized by a zwitterionic ring formed by the AH- and B-containing moieties located along the +y axis and by the hydrophobic group X pointing into the +x axis. Extended conformations with the AH- and B-containing moieties along the +y axis and the hydrophobic group X pointing into the -y axis were observed for all six sweeteners. For compound 5, the crystal-state conformation was also determined by an X-ray diffraction study. The result indicates that compound 5 adopts an L-shaped structure even in the crystalline state. The extraordinary potency of the N-arylalkylated or N-alkylated compounds 1-6, as compared with that of the unsubstituted aspartame-based sweet taste ligands, can be explained by the effect of a second hydrophobic binding domain in addition to interactions arising from the L-shaped structure. In our examination of the unexplored D zone of the Tinti-Nofre model, we discovered a sweet-potency-enhancing effect of arylalkyl substitution on dipeptide ligands, which reveals the importance of hydrophobic (aromatic)-hydrophobic (aromatic) interactions in maintaining high potency.     

Development of Isatin-Based Schiff Bases Targeting VEGFR-2 Inhibition: Synthesis,Characterization, Antiproliferative Properties,and QSAR Studies

Three sets of isatin-based Schiff bases were synthesized utilizing the molecular hybridization approach. Some of the synthesized Schiff bases show significant to moderate antiproliferative properties against MCF7 (breast), HCT116 (colon), and PaCa2 (pancreatic) cancer cell lines with potency compared to reference drugs 5-fluorouracil (5-FU) and Sunitinib. Among all, compound 17 f (3-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino)-1-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-methylindolin-2-one) exhibits promising antiproliferative properties against the MCF7 cancer cell line with 2.1-fold more potency than Sunitinib. However, among all the synthesized compounds, three (5-methylisatin derivatives) were the most effective against HCT116 in comparison to 5-FU. Compound 17 f exhibited the highest anti-angiogenic effect on the vasculature as it significantly reduced BV from 43 mm to 2 mm in comparison to 5.7 mm for Sunitinib and flow cytometry supports the arrest of the cell cycle at G1/S phases. In addition, compound 17 f also showed high VEGFR-2 inhibition properties against breast cancer cell lines. Robust 2D-QSAR studies supported the biological data.     

Synthesis and lyotropic behavior of mesogen‐linked cellulose acetates

Three aromatic (p‐carboxyl phenyl) esters, 4‐(benzoyloxy) benzoic acid, 4‐(4′‐methylbenzoyloxy) benzoic acid, and 4‐(4′‐chlorobenzoyloxy) benzoic acid, were synthesized and they showed nematic monotropic or thermotropic behavior. The mesogen‐linked cellulose acetates were first prepared by the reaction of aromatic (p‐carboxyl phenyl) esters with cellulose acetate through esterification in the presence of N,N‐dicyclohexylcarbodiimide (DCC) and 4‐dimethylaminopyridine (DMAP). Their degrees of mesogenic unit substitution (DS_‐meso) were between 0.27 and 0.41. It was found that they can form cholesteric lyotropic phases in dichloroacetic acid and their critical concentration was about 25 wt %. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 2693–2697, 2004     

Relay Catalysis: Enantioselective Synthesis of Cyclic Benzo‐Fused Homoallylic Alcohols by Chiral Brønsted Acid‐Catalyzed Allylboration/Ring Closing Metathesis

Six‐ and seven‐membered benzo‐fused cyclic homoallylic alcohols can be readily synthesized by a tandem chiral Brønsted acid‐catalyzed allyl (crotyl)boration/ring closing metathesis sequence performed under orthogonal relay catalysis conditions. Excellent enantio‐ and diastereoselectivities are obtained in most of the cases. In addition, the parent crotylboration/RCM process is also described. The required substrates, ortho‐vinylbenzaldehydes, are readily available in one step from commercially available starting materials. Both catalysts and reactants are also available from commercial suppliers. The reaction shows broad functional group compatibility and is also suitable for heteroaromatic substrates. Substitution at any position of the aromatic ring is tolerated; however, substitution at position 6 results in a substantial drop in enantioselectivity.     

Co-Immobilization of a Multi-Enzyme Cascade: (S)-Selective Amine Transaminases,l-Amino Acid Oxidase and Catalase

An enzyme cascade was established previously consisting of a recycling system with an l -amino acid oxidase (hcLAAO4) and a catalase (hCAT) for different α-keto acid co-substrates of (S)-selective amine transaminases (ATAs) in kinetic resolutions of racemic amines. Only 1 mol % of the co-substrate was required and l -amino acids instead of α-keto acids could be applied. However, soluble enzymes cannot be reused easily. Immobilization of hcLAAO4, hCAT and the (S)-selective ATA from Vibrio fluvialis (ATA-Vfl) was addressed here. Immobilization of the enzymes together rather than on separate beads showed higher reaction rates most likely due to fast co-substrate channeling between ATA-Vfl and hcLAAO4 due to their close proximity. Co-immobilization allowed further reduction of the co-substrate amount to 0.1 mol % most likely due to a more efficient H₂O₂-removal caused by the stabilized hCAT and its proximity to hcLAAO4. Finally, the co-immobilized enzyme cascade was reused in 3 cycles of preparative kinetic resolutions to produce (R)-1-PEA with high enantiomeric purity (97.3 %ee). Further recycling was inefficient due to the instability of ATA-Vfl, while hcLAAO4 and hCAT revealed high stability. An engineered ATA-Vfl-8M was used in the co-immobilized enzyme cascade to produce (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine, an apremilast-intermediate, with a 1,000 fold lower input of the co-substrate.     

Discovery of Biased Mu-Opioid Receptor Agonists for the Treatment of Pain

G protein-biased mu-opioid receptor (MOR) agonists have been developed as promising new potent analgesic drugs with fewer adverse side effects than standard MOR agonists. PZM21 represents a unique chemotype unrelated to known opioids, which makes it a desirable lead for modification to find analgesics with new chemical entities. In the present study, we synthesized and tested novel PZM21 derivatives as potent biased MOR agonists by introducing a benzodioxolane group to replace the hydroxybenzene of PZM21. The new compounds displayed more potent analgesic activities in vivo and greater bias toward G protein signaling in vitro than did PZM21. These results suggest that the benzodioxolane group is essential for the maintenance of bias. Compounds 7 i ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-phenethylurea) and 7 j ((S)-1-(3-(benzo[d][1,3]dioxol-4-yl)-2-(dimethylamino)propyl)-3-benzylurea) could serve as new leads for further modifications to find novel biased MOR agonists with greater G protein signaling potency and less β-arrestin-2 recruitment.     

Synthesis and Structure-Activity Relationships of 3-Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors

Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3-arylisoquinolones 3 h [3-(4-(benzyloxy)-3-methoxyphenyl)-7,8-dimethoxyisoquinolin-1(2H)-one] and 4 a [3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-dimethoxyisoquinolin-1(2H)-one] were found to have potent inhibitory effects on hCES2A (IC₅₀=0.68 μΜ, K_i=0.36 μΜ) and excellent specificity (more than 147.05-fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h , with an IC₅₀ value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure−activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.     

Structure-activity relationships among aromatic analogs of trail-following pheromone of subterranean termites

A series of 12 substituted (Z)-4-phenyl-3-buten-l-ol (PBO) derivatives were synthesized and evaluated for trail-following activity in five species of subterranean termites in the generaCoptotermes, Prorhinotermes, Reticulitermes, andSchedorhinotermes (Isoptera: Rhinotermitidae). The unsubstituted parent PBO was the most active for all species, and electron-withdrawing and electron-donating groups both reduced potency. Sensitivity to substitution in the ortho position suggests steric inhibition of binding by the 2-substituted analogs. Different sensitivities to these pheromone analogs were found among the five species, withR.flavipes andS. lamanianus showing the highest level of trail-following activity for the PBO analogs.Fellow of the Alfred P. Sloan Foundation (1981–85) and Camille and Henry Dreyfus Teacher-Scholar (1981–86).     

Synthesis of poly(phenylene oxide) — aromatic polyester multiblock copolymers

Summary Poly(phenylene oxide) (PPO) — aromatic polyester multiblock copolymers were synthesized by polycondensation of bisphenol-A / isophthalic acid or m- and p-hydroxybenzoic acids in the presence of PPO having a carboxylic acid at one end and a phenolic hydroxy group at the other using triphenylphosphine / hexachloroethane as coupling agent. TG analysis showed that the multiblock copolymer showed relatively high thermal stability. Received: 5 January 1998/Accepted: 4 February 1998     

4-甲氧基-α-[(3-甲氧基苯基)硫代]苯乙酮的制备及工艺改进

以苯甲醚和3-甲氧基苯硫酚为主要原料,通过三步反应,合成4-甲氧基-α-[(3-甲氧基苯基)硫代]苯乙酮。讨论了各步反应工艺条件,在最适合工艺条件下,产品总收率从39.4%提高到78.6%。     

Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E2 Production: Increasing Aqueous Solubility

Water solubility is one of the key features of potential therapeutic agents. In order to enhance the low water solubility of the parent 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine, a potent inhibitor of prostaglandin E₂ (PGE₂) production, we synthesized and evaluated a new series of derivatives in which the butyl group at the C5 position of the pyrimidine ring was replaced with a less lipophilic substituent, preferably with a hydrophilic aliphatic moiety. Except for the 5-cyanopyrimidine derivative, all target compounds exhibited increased (2.7–87-fold) water solubility relative to the parent compound. Although nontoxic in mouse peritoneal cells, the prepared compounds were either equipotent or weaker inhibitors of PGE₂ production than the parent compound. The most promising compound from the series was found to be the 5-(2,5,8,11-tetraoxadodecyl)pyrimidine derivative (with three polyethylene glycol units at the C5 position), which exhibited 32-fold higher water solubility and only slightly weaker inhibitory activity (22 % of remaining PGE₂ production) compared with the parent compound (15 % of remaining PGE₂ production).     

S-(4-Methoxyphenyl)-4-methoxybenzenesulfonothioate as a Promising Lead Compound for the Development of a Renal Carcinoma Agent

Organosulfur compounds show cytotoxic potential towards many tumor cell lines. Disulfides and thiosulfonates act through apoptotic processes, inducing proteins associated with apoptosis, endoplasmic reticulum stress, and the unfolded protein response. Three p-substituted symmetric diaryl disulfides and three diaryl thiosulfonates were synthesized and analyzed for inhibition of tubulin polymerization and for human cancer cell cytotoxic activity against seven tumor cell lines and a non-tumor cell line. S-(4-methoxyphenyl)-4-methoxybenzenesulfonothioate ( 6 ) exhibited inhibition of tubulin polymerization and showed the best antiproliferative potential, especially against the 786-0 cell line, being six times more selective as compared with the non-tumor cell line. In addition, compound 6 was able to activate caspase-3 after 24 and 48 h treatments of the 786-0 cell line and induced cell-cycle arrest in the G2/M stage at the highest concentration evaluated at 24 and 48 h. Compound 6 was able to cause complete inhibition of proliferation, inducing the death of 786-0 cells, by increasing the number of cells at G2/M and greater activation of caspase-3.     

Stereoselective Reduction of 1‐O‐Isopropyloxygenipin Enhances Its Neuroprotective Activity in Neuronal Cells from Apoptosis Induced by Sodium Nitroprusside

Genipin is a Chinese herbal medicine with both neuroprotective and neuritogenic activity. Because of its unstable nature, efforts have been to develop more stable genipin derivatives with improved biological activities. Among the new compounds reported in the literature, (1R)‐isopropyloxygenipin (IPRG001) is a more stable but less active compound compared with the parent, genipin. Here, two new IPRG001 derivatives generated by stereoselective reduction of the C₆=C₇ double bond were synthesized. The 1R and 1S isomers of (4aS,7S,7aS)‐methyl‐7‐(hydroxymethyl)‐1‐isopropoxy‐1,4a,5,6,7,7a‐hexahydrocyclopenta[c]pyran‐4‐carboxylate ( CHR20 and CHR21 ) were shown to be very stable both in high‐glucose cell culture medium and in mice serum at 37 °C. Evaluation using an MTT assay and Hoechst staining showed that CHR20 and CHR21 promote the survival of rat adrenal pheochromocytoma (PC12) and retinal neuronal (RGC‐5) cells from injury induced by sodium nitroprusside (SNP). The neuroprotective effects of CHR20 and CHR21 were greater than both isomers of IPRG001, the parent compounds. These results indicate that reduction of 1‐O‐isopropyloxygenipin enhances its neuroprotective activity without affecting its stability.     

Synthesis and photo-induced transformation of helical aromatic polyamides consisting of axially dissymmetric biphenylene joints and azobenzene segments in the backbone

Wholly aromatic polyamides having a novel helical structure were prepared by the reaction of axially dissymmetric (R)- or (S)-6,6′-dimethylbiphenyl-2,2′-dicarbonyl chloride with aromatic diamines, which are soluble in common solvents such as tetrahydrofuran and N,N-dimethylformamide. Photo-irradiation of a tetrahydrofuran solution of the polymer obtained with 4,4′-diaminoazobenzene induced a change of the helical conformation because of the trans–cis isomerization of the azobenzene units in the polymer chain. No change in the specific rotation of the polymer was observed on heating at 100°C for 4h, indicating thermal stability of its helical structure. CD spectra showed that the helical conformation was maintained in methanesulphonic acid. © 1998 SCI.     

Integrated synthetic, pharmacological, and computational investigation of cis-2-(3,5-dichlorophenylcarbamoyl)cyclohexanecarboxylic acid enantiomers as positive allosteric modulators of metabotropic glutamate receptor subtype 4

2‐(3,5‐Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid ( 1 ) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol. Pharmacol. 2008 , 74, 1345–1358). In the present study, the asymmetric synthesis of each of the cis enantiomers was performed, and their activities were compared with that of the racemic trans. In our assays, the cis enantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemic trans. High‐level quantum chemical calculations were carried out to characterize the structures of minimum energy in all‐isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of 1 that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R,2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R,2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work.     

Long-chain phenols: XX. Synthesis of oxidative degradation products from the methylated component phenols ofAnacardium occidentale and other phenolic lipids: Confirmation of the structure of the parent phenols and of a related material

A general procedure for the determination of the first double bond position in the side-chain of a phenolic lipid has been investigated and, in the first place, the phenols of natural cashew nut-shell liquid (Anacardium occidentale) have been examined. An improved oxidative degradation procedure has been applied consisting of methylation by the phase transfer procedure, hydroxylation with performic acid and oxidation of the mixture of vicinal diols with periodic acid (Malaprade reaction) followed by reduction of the aldehyde fragments with sodium borohydride. The aromatic moieties from the 15∶1, 15∶2 and 15∶3 constituents of cardanol methyl ether, cardol dimethyl ether and dimethyl anacardate were shown to be 8-(3-methoxyphenyl)octan-1-ol, 8-(3,5-dimethoxyphenyl)octan-1-ol and 6-(8-hydroxyocyl)salicylate methyl ether, respectively. The first two octanols were identical to synthetic materials, thus confirming the 8-position for the first double bond in the side-chain of cardanol methyl ether and cardol dimethyl ether constituents. Methyl 6-(8-hydroxyoctyl)salicylate relationship in a series of synthetic reference materials of log (retention time) to the methylene chain length. The synthetic acids 8-(3-methoxyphenyl)octanoic acid, 8-(3,5-dimethoxyphenyl)octanoic acid and 6-(7-carboxyheptyl)salicylic acid methyl ether have been obtained pure for the first time and correspond to the oxidation products of the aromatic aldehyde fragments from the Malaprade reaction stage. The unsaturation in peladjauol, 17∶1-bishomocardanol methyl ether, fromPentaspadon officinalis was confirmed to be at the 8-position by the identity of the anilides of synthetic 8-(3-methoxyphenyl) octanoic acid and of the oxidative degradation product. For part XIX, see ref. 1.