Synthesis of novel 4,7-disubstituted quinoline derivatives as autophagy inducing agents via targeting stabilization of ATG5.

A series of new 4,7-disubstituted quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 10c, 10g, 10i, 10j and 10k displayed potent antiproliferative activity with IC50 value of lower than 5.0 µM against human tumor cell lines, and N-(3-nitrophenyl)-7-((3,4,5-trimethoxybenzyl)oxy)quinoline - 4-amine 10k was found to be the most potent antiproliferative agent against HCT-116, HepG2, BCG-823, A549 and A2780 cell lines with IC50 values of 0.35, 1.98, 0.60, 0.39 and 0.67 µM, respectively. The antitumor efficacy of the representative compound 10k in mice was also evaluated, and the results showed that compound 10k effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 10k could inhibit colorectal cancer growth through inducing autophagy via excessively targeting stabilization of ATG5. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.

Bivalent ß-Carbolines Inhibit Colorectal Cancer Growth through Inducing Autophagy.

In this study, a series of alkyl diamine linked bivalent ß-carbolines was synthesized and evaluated as antitumor agent. The results demonstrated that most compounds displayed good antiproliferative activities with IC50 value lower than 10 µM against a panel of human tumor cell lines, and compound 8 was found to be the most potent antiproliferative agent with IC50 value of 1.39, 1.96, 1.42, 1.49, 1.32, 1.96 and 1.63 µM against human breast cancer cell line (MCF-7), human adenocarcinoma cell line (769-P), human malighant melanoma cell line (A375), human ovarian cancer cell line (SK-OV-3), human colon carcinoma cell line (HCT-116), human gastric cancer cell line (BGC-823) and human esophageal squamous carcinoma cell line (Eca-109), respectively. Further investigations on mechanism of action of this class of compound demonstrated that the representative compound 8 inhibited colorectal cancer growth through inducing autophagy.

Pd-catalyzed asymmetric Suzuki-Miyaura coupling reactions for the synthesis of chiral biaryl compounds with a large steric substituent at the 2-position.

Pd-catalyzed asymmetric Suzuki-Miyaura couplings of 3-methyl-2-bromophenylamides, 3-methyl-2-bromo-1-nitrobenzene and 1-naphthaleneboronic acids have been successfully developed and the corresponding axially chiral biaryl compounds were obtained in very high yields (up to 99%) with good enantioselectivities (up to 88% ee) under mild conditions. The chiral-bridged biphenyl monophosphine ligands developed by our group exhibit significant superiority to the naphthyl counterpart MOP in both reactivity and enantioselectivity control. The large steric hindrance from π-conjugated ortho-substituents of the bromobenzene substrates and the Pd···O interaction between carbonyl and palladium seem essential to achieve high enantioselectivity.

Enantioselective synthesis of chiral heterocyclic biaryls via asymmetric Suzuki-Miyaura cross-coupling of 3-bromopyridine derivatives.

A series of chiral heterocyclic biaryls with a pyridyl moiety were prepared in moderate to good yields with up to 92% ee via asymmetric Suzuki-Miyaura coupling. The chiral-bridged biphenyl monophosphine ligand L1 was found to be much more effective in the reaction enantioselection than its counterpart binaphthyl monophosphine ligands.

Design, synthesis and biological evaluation of novel alkyl diamine linked bivalent ß-carbolines as angiogenesis inhibitors.

A series of novel alkyl diamine linked bivalent ß-carbolines was synthesized and evaluated for antiproliferative activity, inhibition of cell migration and tube formation, and anti-angiogenic activity in vivo. The results showed that most bivalent ß-carbolines displayed significant antiproliferative effect against human umbilical vein cell lines EA.HY926. Compound 2s was found to be the most potent antiproliferative agent with IC50 value of 1.06µM against EA.HY926 cell lines. Further investigations on mechanisms of action revealed that compound 2s significantly inhibited EA.HY926 cells migration and tube formation in a dose-dependent manner. Moreover compound 2s exhibited significant angiogenesis inhibitory effects in CAM assay, and the antiangiogenetic potency was comparable with the reference drug Endostar (30µM).

Synthesis and photophysical properties of europium(III)-ß-diketonate complexes applied in LEDs.

Six ß-diketonate ligands were used to prepare the corresponding antenna europium(III) ternary complexes using 1,10-phenanthroline as an ancillary ligand. All the complexes exhibited high decomposition temperatures. Photophysical properties such as FT-IR spectra, UV-Vis absorption spectra, excitation and emission spectra, relative luminescent intensity ratios, luminescence decay curves and quantum yields based on the complexes were systematically studied and compared with each other. The energy-transfer mechanism was proposed as a ligand-sensitized luminescence process. Bright red light-emitting diodes (LEDs) were then fabricated by coating the complexes onto 395 nm-emitting InGaN chips. The light emission from the InGaN chips could be completely absorbed in the spectra of LEDs. The Commission International de I'Eclairage (CIE) chromaticity coordinates are close to the National Television Standard Committee (NTSC) standard value for the red color. All these findings indicate that these Eu(III) complexes are promising red phosphors for fabrication of near UV-based white LEDs.

[Simultaneous determination of four N-lauryl amino acid surfactants in facial cleansers by high performance liquid chromatography-ultraviolet detection].

Significant developments have recently been achieved in the field of N-lauryl amino acid (NLAA) surfactants derived from renewable resources. Compared with conventional surfactants, NLAAs exhibit remarkable surfactant properties, exceptional biodegradability, good biocompatibility, and high safety profiles. These attributes have led to the widespread use of NLAAs in personal-care products. The detection methods employed for NLAAs include two-phase titration (TT), spectrophotometric analysis (SA), and high performance liquid chromatography (HPLC). However, because both TT and SA measure the total concentration of anionic active matter, identifying and quantifying individual compounds in a sample containing multiple anionic surfactants is impossible. The presence of cationic surfactants in the sample also introduces interferences, which lead to significant errors. Compared with TT and SA, HPLC offers direct and rapid testing procedures. However, compounds with no or weak UV-visible light absorption exhibit low sensitivity when detected by UV, necessitating the use of detectors such as differential refractive index detectors (RIDs), evaporative light scattering detectors (ELSDs), or charged aerosol detectors (CADs). Most HPLC users consider UV light as the fundamental configuration of the instrument, and other detectors are less commonly employed. Therefore, establishing a new HPLC method suitable for the UV detection of NLAAs is of practical significance. In this study, a novel HPLC-UV method was developed for the simultaneous detection of N-lauryl glutamine (LG), N-lauryl glycine (LC), N-lauryl alanine (LA), and N-lauryl sarcosine (LS) by optimizing the mobile-phase composition and selecting an appropriate chromatographic column and detection wavelength. The samples were mixed with acetonitrile-0.10% H3PO4 aqueous solution (60∶40, v/v) and sonicated for 10 min, then stayed at room temperature for 5 min. Subsequently, the mixture was filtered through a 0.22 µm filter membrane and separated on an Agilent Eclipse Plus C18 column (150 mm×4.6 mm, 5 µm). The mobile phase used for separation consisted of acetonitrile-0.10% H3PO4 aqueous solution at a flow rate of 1.0 mL/min. The detection wavelength was set at 205 nm, and the injection volume was 10 µL. The results demonstrated that the four NLAAs exhibited good linearity in the range of 2.0-800.0 mg/L, with correlation coefficients (r)≥0.9995. The limits of detection (LODs) ranged from 0.17 to 0.49 mg/L, and limits of quantification (LOQs) ranged from 0.57 to 1.63 mg/L. The relative standard deviations (RSDs) for precision, repeatability, and stability over 24 h were all below 2.0%. Using this method, the NLAA contents of five facial-cleanser products were determined. The results demonstrated that all five samples contained one or more NLAAs, and the total NLAA contents ranged from 64.58 to 97.01 mg/g. The five spiked-sample recoveries of the NLAAs at four different spiked levels (0.60, 4.50, 15.00, 24.00 mg/g) ranged from 94.3% to 107.4%, indicating satisfactory accuracy. However, the actual NLAA composition and label for one facial-cleanser product were not consistent with our test results. This finding demonstrates the necessity of strengthening market monitoring through testing. The proposed method has the advantages of simple pretreatment, rapid testing, good precision, high accuracy, and appropriate stability. Thus, it is suitable for the determination of NLAA contents in facial cleansers and provides an effective technical reference for the raw-material purity assessment, synthetic yield detection, and product quality control of this type of surfactant.

Iridium-Catalyzed Intramolecular Asymmetric Allylic Etherification of Pyrimidinemethanols: Enantioselective Construction of Multifunctionalized Pyrimidine-Fused Oxazepines.

An iridium-catalyzed intramolecular asymmetric allylic etherification of pyrimidinemethanols is described. In the presence of chiral-bridged biphenyl phosphoramidite ligand L3 and triethylborane, this process provided a class of novel pyrimidine-fused oxazepanes in up to 99% yield with 99.5% enantiomeric excess. The work addresses the challenge of insufficient nucleophilicity of aliphatic alcohols for allyl substitution and indicates the vital value of chiral-bridged biphenyl phosphoramidites. Various multifunctionalized transformations of the products further demonstrate the robust synthetic utility of this methodology.

Design, synthesis and pharmacological evaluation of ß-carboline derivatives as potential antitumor agent via targeting autophagy.

A series of novel ß-carboline derivatives was designed, synthesized and evaluated as potential anticancer agents. Among them, compound 6g showed the most potent antiproliferative activity against the 786-0, HT-29 and 22RV1 cell lines with IC50 values of 2.71, 2.02, and 3.86 µM, respectively. The antitumor efficiency of compound 6gin vivo was also evaluated, and the results revealed that compound 6g significantly suppressed tumor development and reduced tumor weight in a mouse colorectal cancer homograft model. Further investigation on mechanisms of action demonstrated that compound 6g inhibited HCT116 cell growth by stimulating the ATG5/ATG7-dependent autophagic pathway. These molecules might be served as candidates for further development of colorectal cancer therapy agent.

Design, synthesis and mechanism of action of novel 1,9-disubstituted ß-carboline derivatives as antitumor agents.

A range of novel 1,9-disubstituted ß-carboline derivatives was designed, synthesized and evaluated as potential anticancer agents. The preliminary study suggested that compounds 6a, 6b, 6c, 6d, 6e, 6f, 6g, and 6h tested in this study exerted potent antiproliferative effects on ten selected human tumor cell lines, with compound 6e being the most effective antiproliferative agent against the BGC-823, A375 and HT-29 cell lines, with IC50 values of 23.9, 9.3, and 3.6 µM, respectively. In addition, the antitumor capability of compound 6e was also evaluated in vivo, which demonstrated that compound 6e distinctly inhibited colorectal tumor growth in syngeneic BALB/c mice. Further research into the fundamental mechanism revealed that compound 6e inhibited colorectal cancer growth through the ATG5 (autophagy-related-5)/ATG7 (autophagy-related-7)-dependent autophagy pathway. This research can contribute to further clinical application of ß-carboline derivatives as new antitumor drugs.

Synthesis of 4-[(diethylamino)methyl]-phenol derivatives as novel cholinesterase inhibitors with selectivity towards butyrylcholinesterase.

A series of novel cholinesterase inhibitors, being composed of 4-[(diethylamino)methyl]-phenoxy and secondary amine which were linked with a different length alkyl chain, were designed and synthesized from the starting material p-hydroxybenzaldehyde. These compounds were evaluated as acetylcholinesterase and butyrylcholinesterase (AChE/BChE) inhibitors. Compounds 25-31 having a secondary amine moiety connected to the phenyl ring via eight CH(2) units spacer were found to be the most potent inhibitors with IC(50) value lower than 220nM and 48nM against AChE and BChE, respectively. Interestingly, these inhibitors showed a surprising selectively toward BChE, and compounds 26, 27, and 30 displayed 12.5, 18.6, and 18.8-fold higher affinity to BChE. The inhibition kinetics analyzed by Linewear-Burk plots revealed that such compounds were mix-type inhibitors.

Synthesis of novel beta-carbolines with efficient DNA-binding capacity and potent cytotoxicity.

A series of water-soluble beta-carbolines, bearing a flexible amino side chain, was prepared and evaluated in vitro against a panel of human tumor cell lines. The N(9)-arylated alkyl substituted beta-carbolines represented the most interesting cytotoxic activities, and compound 7b was found to be the most potent antitumor agent with IC(50) values lower than 10microM against eight human tumor cell lines. The results confirmed that the N(9)-arylated alkyl substituents of beta-carboline nucleus played an important role in the modulation of the cytotoxic potencies. In addition, these compounds were found to exhibit significant DNA-binding affinity.

Design, synthesis and evaluation of difunctionalized 4-hydroxybenzaldehyde derivatives as novel cholinesterase inhibitors.

A series of difunctionalized 4-hydroxybenzaldehyde derivatives were designed, synthesized and evaluated as cholinesterase (acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)) inhibitors. The results demonstrated that all the compounds had more potent AChE and BChE inhibitory activities than galanthamine-HBr, one of the best cholinesterase inhibitors known so far. The inhibition mechanism revealed that the best active compound 4e displayed a mix-type mode of AChE and BChE by its dual-site interactions with the catalytic triad active center and the peripheral anionic site (PAS) of enzyme. All these data suggested that further development of such compounds may be of interest.

Synthesis and biological evaluation of novel beta-carbolines as potent cytotoxic and DNA intercalating agents.

A series of novel water-soluble beta-carbolines bearing a flexible amino side chain was designed, synthesized and evaluated as potent cytotoxic and DNA intercatalating agents. The N(9)-arylated alkyl substituted beta-carbolines represented the most interesting cytotoxic activities. The results suggested that (1) the N(9)-arylated alkyl substituents of beta-carboline nucleus played a very important role in the modulation of the cytotoxic potencies; (2) the length of the alkylamino side chain significantly affected their cytotoxic potency, and N,N-dimethylaminopropylamino substituent were more favorable. In addition, these compounds were found to exhibit significant DNA intercalating potencies.

Rational design and synthesis of 4-o-substituted phenylmethylenethiosemicarbazones as novel tyrosinase inhibitors.

In continuing our program aimed to search for tyrosinase inhibitors, a series of novel 4-O-substituted phenylmethylenethiosemicarbazones were rational designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were also evaluated. A fair number of compounds were found to have significant tyrosinase inhibitiory activity. Particularly, the IC(50) values of compounds 3a-g, 3j and 3s were of the same magnitude as tropolone, one of the best tyrosinase inhibitors known so far. Furthermore, the structure-activity relationships of these compounds were also investigated. All these data suggested that these molecules might be utilized for the development of new candidate for the treatment of dermatological disorders, and further development of such compounds may be of interest.

Discovery of 4-functionalized phenyl-O-beta-D-glycosides as a new class of mushroom tyrosinase inhibitors.

A series of 4-functionalized phenyl-O-beta-D-glycosides were designed, synthesized and evaluated as a new class of mushroom tyrosinase inhibitors. The results demonstrated that compounds 6a-13a bearing a thiosemicarbazide moiety exhibited potent activities with IC50 values range from 0.31 to 52.8 microM. Particularly, compound 9a containing acetylated glucose moiety was found to be the most active molecule with an IC50 value of 0.31 microM. SARs analysis suggested that (1) the thiosemicarbazide moiety remarkably contributed to the increase of inhibitory effects on tyrosinase; (2) the configuration and bond type of sugar moiety also played a very important role in determining their inhibitory activities. The inhibition kinetics and inhibition mechanism study revealed that compound 9a was reversible and competitive type inhibitor, whereas compound 13a was reversible and competitive-uncompetitive mixed-II type inhibitor.

Synthesis and evaluation of 5-benzylidene(thio)barbiturate-beta-D-glycosides as mushroom tyrosinase inhibitors.

A series of 5-benzylidene(thio)barbiturate-beta-d-glycosides were designed, synthesized and evaluated as a new class of mushroom tyrosinase inhibitors. The results demonstrated that most of compounds had more potent inhibitory activities than arbutin (IC(50) 8.4mmol/L). Compound 12b was found to be the most potent inhibitor with IC(50) value of 0.05mmol/L. SARs analysis suggested that (1) 5-benzylidenethiobarbiturate substructures were efficacious for the inhibitory activity; (2) the lipophilic property of acetylated sugar moiety facilitated the inhibitory potency; (3) the hydroxyl group of 3'-configuration contributed to the increase of inhibitory effects. In addition, the inhibition mechanism study revealed that 5-benzylidene(thio)barbiturate-beta-d-glycosides were irreversible inhibitors.

Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted phenylmethylenethiosemicarbazones as tyrosinase inhibitors.

A series of hydroxy- or methoxy-substituted phenylmethylenethiosemicarbazones were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. The results demonstrated that most of target compounds had remarkable inhibitory activities on mushroom tyrosinase. Interestingly, compound 2h was found to be the most potent tyrosinase inhibitor with IC50 value of 0.18 microM. The possible interaction mode between compound 2h and tyrosinase was proposed. In addition, the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities of select compounds (IC50<10.0 microM) were also investigated. Compounds 2d, 2e, 2h, 2i and 2l exhibited more potent DPPH radical scavenging activity than well-known antioxidants ascorbic acid (Vc) and tertiary butyl hydroquinone (TBHQ). These results suggested that such compounds might be utilized for the development of new candidate for treatment of dermatological disorders.

Design, synthesis and biological evaluation of new quinoline derivatives as potential antitumor agents.

A series of new quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 11p, 11s, 11v, 11x and 11y exhibited potent antiproliferative activity with IC50 value of lower than 10 µM against seven human tumor cell lines, and N-(3-methoxyphenyl)-7- (3-phenylpropoxy)quinolin-4-amine 11x was found to be the most potent antiproliferative agent against HCT-116, RKO, A2780 and Hela cell lines with an IC50 value of 2.56, 3.67, 3.46 and 2.71 µM, respectively. The antitumor efficacy of the representative compound 11x in mice was also evaluated, and the results showed that compound 11x effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 11x could inhibit colorectal cancer growth through ATG5-depenent autophagy pathway. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.

Design, synthesis, structure-activity relationships and mechanism of action of new quinoline derivatives as potential antitumor agents.

A series of new quinoline derivatives was designed, synthesized and evaluated as potential antitumor agents. The results indicated that most compounds exhibited potent antiproliferative activity, and 7-(4-fluorobenzyloxy)N-(2-(dimethylamino)- ethyl)quinolin-4-amine 10g was found to be the most potent antiproliferative agent against human tumor cell lines with an IC50 value of less than 1.0 µM. Preliminary structure-activity relationships analysis suggested that (1) the large and bulky alkoxy substituent in position-7 might be a beneficial pharmacophoric group for antiproliferative activity; (2) the amino side chain substituents in position-4 facilitated the antiproliferative activity of this class of compounds; and (3) the length of the alkylamino side chain moiety affected the antiproliferative potency, with two CH2 units being the most favorable. Further investigation of the mechanism of action of this class of compounds demonstrated that the representative compound 10g triggered p53/Bax-dependent colorectal cancer cell apoptosis by activating p53 transcriptional activity. Moreover, the results showed that compound 10g effectively inhibited tumor growth in a colorectal cancer xenograft model in nude mice. Thus, these quinoline derivatives might serve as candidates for the development of new antitumor drugs.