- Facile syntheses of disubstituted bis(vinylquinolinium)benzene derivatives as G-quadruplex DNA binders
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Abstract A series of disubstituted bis(vinylquinolinium)benzene derivatives were designed, which were prepared through a facile three-component one-pot reaction in good yield. FRET results showed that 1,3-disubstituted benzene derivatives had much stronger stabilization effect on G-quadruplex DNA than that of 1,4-disubstituted benzene derivatives. The introduction of substituted amine side chain at quinolinium obviously increased the binding affinity of compounds to G-quadruplex DNA. It was also found that 1,3-disubstituted benzene derivatives and 1,4-disubstituted benzene derivatives had different effects on the conformation of G-quadruplex DNA by CD spectroscopy analysis. The differences for the interactions of these two classes of compounds with G-quadruplex were further studied and elaborated through molecular modeling experiments.
- Liu, Zhen-Quan,Zhuo, Shi-Tian,Tan, Jia-Heng,Ou, Tian-Miao,Li, Ding,Gu, Lian-Quan,Huang, Zhi-Shu
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- Development of a light-up fluorescent probe for HRAS G-quadruplex DNA
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The development of small-molecule G-quadruplex DNA probes has attracted significant attention in recent years. However, G-quadruplexes can display a wide variety of topologies, which process different structures and functions. Therefore, selective discrimination one G-quadruplex structure over another is promising. Herein, we reported the design, synthesis and biological evaluation of a long-chain fatty amine functionalized triphenylamine-quinolinium conjugate 1b. Significant enhancement of the fluorescence intensity (over 180 fold) was observed when 1b bound with HRAS G-quadruplex DNA, while much weaker enhancements were presented in the presence of other G-quadruplexes (45–90-fold) and single/double-stranded DNAs (less than 20-fold), indicating 1b had an excellent selectivity to HRAS. The details of the interactions were investigated by UV–Vis, FID and CD analysis. The results show 1b could interact and stabilize HRAS structure mainly by π-π stacking binding mode. The introduced amine chain of the structure core was found to be better in the terms of inducing selectivity toward G-quadruplex structure. In addition, the application of 1b as a fluorescent agent for living cell imaging was also demonstrated.
- Wang, Ming-Qi,Wang, Zi-Yu,Yang, Yi-Fan,Ren, Gui-Ying,Liu, Xiao-Ning,Li, Shuo,Wei, Jian-Wei,Zhang, Lan
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- A triphenylamine derivative as a naked-eye and light-up fluorescent probe for G-quadruplex DNA
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G-quadruplex (G4) DNAs have attracted considerable interest because of their important biological functions and medical applications. Searching for highly specific binding molecules is important for the basic research of G4 DNA, as well as the design of novel anticancer drugs. Previous, we have developed a quinolone-substituted triphenylamine probe (TPA-2b) with selectivity to G4 DNAs. Herein, we further designed and synthesized a hydroxyethyl functionalized derivative (TPA-3) and investigated the interactions with G4 DNAs and living cells. TPA-3 was found to express significant fluorescence enhancement upon its interaction with G4 DNAs while shows almost no response to non-quadruplex DNAs. The distinction can even be easily distinguished by the naked eye under UV light. The spectral analysis showed TPA-3 bound to G4 DNAs mainly through intercalative binding mode. CD study results indicated TPA-3 did not disturb the conformation of G4 structure. Cellular uptake assay suggested that TPA-3 could pass through membrane and enter living cells. Our results suggested the side chain of core structure could change the binding affinity to G4 DNAs, as well as the interaction with living cells. Thus, this study gives some clues to design new G4 DNA probes with high selectivity, sensitivity, and biological imaging applications.
- Wang, Ming-Qi,Gao, Lie-Xiong,Yang, Yi-Fan,Xiong, Xian-Ning,Zheng, Zhao-Yi,Li, Shuo,Wu, Yuan,Ma, Lu-Lu
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- Development of an engineered carbazole/thiazole orange conjugating probe for G-quadruplexes
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The development of selective and sensitive probes for sensing G-quadruplexes either in vitro or in cellulo has been the focus of investigation for a long time. Of those investigated, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is a promising fluorescent probe utilized in many studies investigating G-quadruplex structures. However, its shortcomings, including similar fluorescence responses for G-quadruplex and duplex DNA and green but not red fluorescent emission, might restrict the further application of BMVC. In this study, in order to improve the selectivity and optical properties of BMVC, we engineered a new probe (TO-CZ) by incorporating thiazole orange (TO) into the structure of BMVC. We next found that TO-CZ can act as a colorimetric and red-emitting fluorescent dual probe selective for G-quadruplexes without affecting the G-quadruplex topology. Further experiments showed that a 2:1 binding model involving the external binding of TO-CZ to both ends of the G-quadruplex is the most possible binding mode. Furthermore, we applied TO-CZ in sensing G-quadruplexes both in vitro and in cellulo, and found that TO-CZ can selectively and sensitively visualize G-quadruplexes. Notably, TO-CZ might be used to map DNA and RNA G-quadruplexes in cellulo, showing its great potential in investigating intracellular G-quadruplex structures.
- Hu, Ming-Hao,Guo, Rui-Jun,Chen, Shuo-Bin,Huang, Zhi-Shu,Tan, Jia-Heng
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- Preparation of 4-flexible amino-2-arylethenyl-quinoline derivatives as multi-target agents for the treatment of Alzheimer’s disease
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Alzheimer’s disease (AD) is a complex and multifactorial neurodegenerative disorder of aged people. The development of multitarget-directed ligands (MTDLs) to act as multifunctional agents to treat this disease is the mainstream of current research. As a continuation of our previous studies, a series of 4-flexible amino-2-arylethenylquinoline derivatives as multi-target agents was efficiently synthesized and evaluated for the treatment of AD. Among these synthesized derivatives, some compounds exhibited strong self-induced Aβ1–42 aggregation inhibition and antioxidant activity. The structure-activity relationship was summarized, which confirmed that the introduction of a flexible amino group featuring a N,N-dimethylaminoalkylamino moiety at the 4-position increased the Aβ1–42 aggregation inhibition activity, with an inhibition ratio of 95.3% at 20 μM concentration. Compound 6b1, the optimal compound, was able to selectively chelate copper (II), and inhibit Cu2+-induced Aβ aggregation effectively. It also could disassemble the self-induced Aβ1–42 aggregation fibrils with a ratio of 64.3% at 20 μM concentration. Moreover, compound 6b1 showed low toxicity and a good neuroprotective effect against Aβ1–42-induced toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated compound 6b1 significantly reversed scopolamine-induced memory deficit in mice. Taken together, these results suggested that compound 6b1 was a promising multi-target compound worthy of further study for AD.
- Wang, Xiao-Qin,Zhao, Chu-Ping,Zhong, Long-Cheng,Zhu, De-Ling,Mai, De-Hao,Liang, Mei-Gui,He, Ming-Hua
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- Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines
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There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline UCF501 as a promising antimalarial compound. To optimize UCF501, we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar antiplasmodial compounds against a Plasmodium falciparum CQ-resistant Dd2 strain, with excellent selectivity profiles (resistance index 200). Several metabolically stable 2-arylvinylquinolines are identified as fast-acting agents that kill asexual blood-stage parasites at the trophozoite phase, and the most promising compound 24 also demonstrates transmission blocking potential. Additionally, the monophosphate salt of 24 exhibits excellent in vivo antimalarial efficacy in the murine model without noticeable toxicity. Thus, the 2-arylvinylquinolines represent a promising class of antimalarial drug leads.
- Huang, Guang,Murillo Solano, Claribel,Melendez, Joel,Shaw, Justin,Collins, Jennifer,Banks, Robert,Arshadi, Arash Keshavarzi,Boonhok, Rachasak,Min, Hui,Miao, Jun,Chakrabarti, Debopam,Yuan, Yu
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p. 11756 - 11785
(2020/11/26)
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- Discovery of 4-anilinoquinolinylchalcone derivatives as potential NRF2 activators
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Activation of nuclear factor erythroid-2-related factor 2 (NRF2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent NRF2 activator and cancer chemopreventive agent. In this study, we have synthesized a series of 4-anilinoquinolinylchalcone derivatives, and used a NRF2 promoter-driven firefly luciferase reporter stable cell line, the HaCaT/ARE cells, to screen a panel of these compounds. Among them, (E)-3-{4-[(4-acetylphenyl)amino]quinolin-2-yl}-1-(4-fluorophenyl)prop-2-en-1-one (13b) significantly increased NRF2 activity in the HaCaT cell with a half maximal effective concentration (EC50) value of 1.95 μM. Treatment of compound 13b upregulated HaCaT cell NRF2 expression at the protein level. Moreover, the mRNA level of NRF2 target genes, heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glucose-6-phosphate dehydrogenase (G6PD) were significantly increased in HaCaT cells upon the compound 13b treatment. The molecular docking results exhibited that the small molecule 13b is well accommodated by the bound region of Kelch-like ECH-associated protein 1 (Keap1)-Kelch and NRF2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. Compound 13b has been identified as the lead compound for further structural optimization.
- Chen, Yeh-Long,Chen, Yi-Siao,Kao, Yu-Tse,Lee, Jin-Ching,Tang, Kai-Wei,Tseng, Chih-Hua,Tzeng, Cherng-Chyi,Yen, Chia-Hung
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- A ortho position alkylation method of organic compound containg pyridine
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A process for introducing alkyl at ortho positions of organic compounds containing pyridine. The method is not affected by the kind of substituent bonded to the pyridine and can be alkylated with high positional selectivity and high yield at N-based ortho-position of pyridine without being affected by the kind of substituent introduced to pyridine ortho position (pyridine N-based) can be advantageously used for the preparation of a compound containing an alkyl-introduced pyridine structure.
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Paragraph 0108-0116
(2020/12/05)
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- Syntheses and evaluation of new Quinoline derivatives for inhibition of hnRNP K in regulating oncogene c-myc transcription
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Aberrant overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key feature in oncogenesis and progression of many human cancers. hnRNP K has been found to be a transcriptional activator to up-regulate c-myc gene transcription, a critical proto-oncogene for regulation of cell growth and differentiation. Therefore, down-regulation of c-myc transcription by inhibiting hnRNP K through disrupting its binding to c-myc gene promoter is a potential approach for cancer therapy. In the present study, we synthesized and screened a series of Quinoline derivatives and evaluated their binding affinity for hnRNP K. Among these derivatives, (E)-1-(4-methoxyphenyl)-3-(4-morpholino-6-nitroquinolin-2-yl)prop-2-en-1-one (compound 25) was determined to be the first-reported hnRNP K binding ligand with its KD values of 4.6 and 2.6 μM measured with SPR and MST, respectively. Subsequent evaluation showed that the binding of compound 25 to hnRNP K could disrupt its unfolding of c-myc promoter i-motif, resulting in down-regulation of c-myc transcription. Compound 25 showed a selective anti-proliferative effect on human cancer cell lines with IC50 values ranged from 1.36 to 3.59 μM. Compound 25 exhibited good tumor growth inhibition in a Hela xenograft tumor model, which might be related to its binding with hnRNP K. These findings illustrated that inhibition of DNA-binding protein hnRNP K by compound 25 could be a new and selective strategy of regulating oncogene transcription instead of targeting promoter DNA secondary structures such as G-quadruplexes or i-motifs.
- Shu, Bing,Zeng, Ping,Kang, Shuangshuang,Li, Peng-Hui,Hu, Dexuan,Kuang, Guotao,Cao, Jiaojiao,Li, Xiaoya,Zhang, Meiling,An, Lin-Kun,Huang, Zhi-Shu,Li, Ding
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- Triphenylamine - quinoline derivatives and adopts its modification for detecting the oncogene related G - quadruplex optical fiber sensor
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The invention belongs to the field of molecular biology, in particular to triphenylamine - quinoline derivatives and adopts its modification for detecting the oncogene related G - quadruplex optical fiber sensor, the present invention provides a new structure of the triphenylamine - quinoline derivatives, the quinoline derivative by the method of the present invention modified with activated hydroxyl of the surface layer of the optical fiber sensor of the optical fiber, the optical fiber sensor can be quickly specific detection HRAS G - quadruplex and HTG - 21 G - quadruplex, makes up for the optical fiber DNA sensor detecting G4 - DNA vacancies of the chain, since many of the cancer disease is due to the initiation of the cells in vivo G4 - DNA over-expression of the chain, the invention is specific detection G4 DNA offers a high-efficient and swift sensor, the sensor is expected to be applied to the biological and clinical analysis.
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- Design, synthesis, biological evaluation, and molecular modeling studies of quinoline-ferulic acid hybrids as cholinesterase inhibitors
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A series of quinoline-ferulic acid hybrids has been designed, synthesized, and evaluated as cholinesterase inhibitors. Most of the compounds showed good inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 10f was found to be the most potent inhibitor against AChE (IC50 = 0.62 ± 0.17 μM), and 14 was the most potent inhibitor against BChE (IC50 = 0.10 ± 0.01 μM). Representative compounds, such as 10f and 12g, act in a competitive manner when they inhibit AChE or BChE. Molecular docking and dynamic simulation revealed that the synthesized compounds bind to the target by simultaneously interacting with the catalytic active site (CAS) and the peripheral anionic site (PAS) of both AChE and BChE. The U-shaped confirmation was preferred when 12g bound to BChE, which was different from the linear conformation of 10f bound to AChE. Cell-based assays have confirmed the moderate neuroprotective effects of compounds 10f and 12g against H2O2-induced oxidative damage towards PC12 cells. Moreover, the hepatotoxicity of 12g was lower than that of tacrine, indicating its potential safety as an anti-Alzheimer's agent. In summary, we report a new chemotype of multifunctional hybrid, which may be further modified to develop new anti-Alzheimer's agents.
- Mo, Jun,Yang, Hongyu,Chen, Tingkai,Li, Qihang,Lin, Hongzhi,Feng, Feng,Liu, Wenyuan,Qu, Wei,Guo, Qinglong,Chi, Heng,Chen, Yao,Sun, Haopeng
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- Reductive C2-Alkylation of Pyridine and Quinoline N-Oxides Using Wittig Reagents
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The ability to alkylate pyridines and quinolines is important for their further development as pharmaceuticals and agrochemicals, and for other purposes. Herein we describe the unprecedented reductive alkylation of pyridine and quinoline N-oxides using Wittig reagents. A wide range of pyridine and quinoline N-oxides were converted into C2-alkylated pyridines and quinolines with excellent site selectivity and functional-group compatibility. Sequential C?H functionalization reactions of pyridine and quinoline N-oxides highlight the utility of the developed method. Detailed labeling experiments were performed to elucidate the mechanism of this process.
- Han, Sangil,Chakrasali, Prashant,Park, Jihye,Oh, Hyunjung,Kim, Saegun,Kim, Kyuneun,Pandey, Ashok Kumar,Han, Sang Hoon,Han, Soo Bong,Kim, In Su
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supporting information
p. 12737 - 12740
(2018/09/20)
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- DMSO as a Switchable Alkylating Agent in Heteroarene C?H Functionalization
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Herein, we report a novel strategy for the activation of DMSO to act as a versatile alkylating agent in heteroarene C?H functionalization. This direct, simple, and mild switch between methylation/trideuteromethylation and methylthiomethylation of heteroarenes was achieved under reagent-controlled photoredox catalysis conditions. The proposed mechanism is supported by both experimental and computational studies.
- Garza-Sanchez, R. Aleyda,Patra, Tuhin,Tlahuext-Aca, Adrian,Strieth-Kalthoff, Felix,Glorius, Frank
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supporting information
p. 10064 - 10068
(2018/07/29)
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- Design, synthesis and anti-HIV-1 activity of modified styrylquinolines
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Background: Drug resistance and reservoirs of latent viral infection have prevented total eradication of the HIV-virus which underlines the need for continuous efforts in the discovery of new anti-HIV agents. The present study deals with the synthesis of novel compounds based on naturally occurring scaffolds and their evaluation as potential anti-HIV agents. Objective: Design and synthesis of styrylquinoline scaffold based new molecules and evaluation of their anti-HIV-1 activity. Methods: A series of forty three new styrylquinolines (SQLs) was designed and synthesized. The newly synthesized compounds were tested for anti-HIV-1 activity against HIV-1VB59 and HIV-1UG070 primary isolates in TZM-bl cell lines. Results: The most active compounds 9 and 34 (IC50 = 0.5-4.0 μM), also exhibited significant inhibition activity against HIV-1VB51 primary isolate in PBMCs (IC50 = 7.3 μM). Compounds 9 and 34 were also found to inhibit HIV-1 entry into host cells and fusion inhibitory activities. The study encourages further exploration of SQL nucleus to design anti-HIV-1 agents. Conclusion: The study encourages further exploration of SQL nucleus to design anti-HIV-1 agents.
- Mahajan, Shivani,Gupta, Shiv,Jariwala, Nisha,Bhadane, Deepali,Bhutani, Late K.K.,Kulkarni, Smita,Singh, Inder Pal
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p. 937 - 944
(2018/08/17)
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- NEW TARGETED CYTOTOXIC ISOCOMBRETAQUINOLINE DERIVATIVES AND CONJUGATES THEREOF
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The present invention is directed to novel natural product-derived combretastatin- based compounds useful as payloads in drug-conjugates constructs with cell target binding moieties (CTBM) and payload-linker compounds useful in connection with drug conjugates. The present invention further relates to new isoNH2CombretaQuinoline compositions including the aforementioned payloads, payload-linkers and drug conjugates, and methods for using these payloads, payload-linkers and drug conjugates, to treat pathological conditions including cancer.
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- Design, synthesis and evaluation of 2-arylethenyl-N-methylquinolinium derivatives as effective multifunctional agents for Alzheimer's disease treatment
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A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349–361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12?HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier.
- Xia, Chun-Li,Wang, Ning,Guo, Qian-Liang,Liu, Zhen-Quan,Wu, Jia-Qiang,Huang, Shi-Liang,Ou, Tian-Miao,Tan, Jia-Heng,Wang, Hong-Gen,Li, Ding,Huang, Zhi-Shu
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p. 139 - 153
(2017/03/02)
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- Design, synthesis and biological evaluation of 4-anilinoquinoline derivatives as novel potent tubulin depolymerization agents
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A series of novel 4-anilinoquinoline derivatives were synthesized and evaluated for their antiproliferative activities. Among them, 14h exhibited the most potent cytotoxic activity with IC50 values ranging from 1.5 to 3.9 nM against all tested cancer cell lines, and showed promising efficacy in multidrug resistant cancer cells. Flow cytometry assay, immune-fluorescence staining, microtubule dynamics assays and competition assays with EBI identified that 14h was a novel tubulin depolymerization agent by binding to the colchicine site. Importantly, in vivo efficacy evaluation of HCT116 xenograft model, 14h showed efficient antitumor activity without significant loss in body weight. All the results indicated that 14h could be a promising candidate for the treatment of cancer.
- Zhou, Yuanyuan,Yan, Wei,Cao, Dong,Shao, Mingfeng,Li, Dan,Wang, Fang,Yang, Zhuang,Chen, Yong,He, Linhong,Wang, Taijin,Shen, Mingsheng,Chen, Lijuan
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supporting information
p. 1114 - 1125
(2017/08/02)
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- G-quadruplex DNA fluorescence sensing by a bis-amine-substituted styrylquinolinium dye
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Searching for specific G-quadruplex DNA probes is important for study of the function of G-rich gene sequence, as well as design of novel effective anticancer drugs. In this paper, a novel bis-amine-substituted styrylquinolinium dye (BSAQ) was designed and synthesized to enhance the performance for the application as a G-quadruplex DNA probe. The studies on BSAQ with different DNA forms showed that it could be used as a colorimetric and red-emitting ?uorescent probe for G-quadruplex DNA. The limits of detection of BASQ with various G-quadruplex DNAs were found to below 1 nM. CD spectroscopy analysis revealed that BSAQ did not induce the G-rich sequence folding into G-quadruplex structure. These results of this study gave some crucial factors on developing of effective probes for G-quadrupex DNA applications.
- Wang, Ming-Qi,Wu, Yuan,Wang, Zi-Yu,Chen, Qiu-Yun,Xiao, Fu-Yan,Jiang, Yu-Chi,Sang, Amy
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- Photoredox-mediated Minisci C-H alkylation of N-heteroarenes using boronic acids and hypervalent iodine
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A photoredox-mediated Minisci C-H alkylation reaction of N-heteroarenes with alkyl boronic acids is reported. A broad range of primary and secondary alkyl groups can be efficiently incorporated into various N-heteroarenes using [Ru(bpy)3]Cl2 as photocatalyst and acetoxybenziodoxole as oxidant under mild conditions. The reaction exhibits excellent substrate scope and functional group tolerance, and offers a broadly applicable method for late-stage functionalization of complex substrates. Mechanistic experiments and computational studies suggest that an intramolecularly stabilized ortho-iodobenzoyloxy radical intermediate might play a key role in this reaction system.
- Li, Guo-Xing,Morales-Rivera, Christian A.,Wang, Yaxin,Gao, Fang,He, Gang,Liu, Peng,Chen, Gong
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p. 6407 - 6412
(2016/09/28)
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- A double-quinoline derivatives and method for preparing the same and the application of the preparation of anticancer drugs
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The invention relates to a field of medicament and chemical, and concretely to a biquinoline derivative, a preparation method thereof and an application thereof in preparing anticancer medicament. The biquinoline derivative has a structure as shown in a formula I or formula II which is as shown in specification, wherein R is H, aliphatic diamine or saturated heterocyclic amines. The biquinoline derivative provided by the invention has a strong interacting with guanine-rich telomeric DNA and c-kitDNA, is good in inhibitory activity for telomerase in cancer cells, thereby being substantial in inhibitory effect on cancer cell strains; and thus the biquinoline derivative is quite high in medical values and broad in market prospects.
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- Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor
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Abstract A practical and efficient synthesis of a complex chiral atropisomeric HIV integrase inhibitor has been accomplished. The combination of a copper-catalyzed acylation along with the implementation of the BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical. Furthermore, the overall synthesis was conducted in an asymmetric and diastereoselective fashion with respect to the imbedded atropisomer. Atropselective: An efficient asymmetric synthesis of an atropisomeric HIV inhibitor has been accomplished. The combination of a copper-catalyzed acylation with the implementation of BI-DIME ligands for a ligand-controlled Suzuki cross-coupling and an unprecedented bis(trifluoromethane)sulfonamide-catalyzed tert-butylation renders the synthesis of this complex molecule robust, safe, and economical.
- Fandrick, Keith R.,Li, Wenjie,Zhang, Yongda,Tang, Wenjun,Gao, Joe,Rodriguez, Sonia,Patel, Nitinchandra D.,Reeves, Diana C.,Wu, Jiang-Ping,Sanyal, Sanjit,Gonnella, Nina,Qu, Bo,Haddad, Nizar,Lorenz, Jon C.,Sidhu, Kanwar,Wang, June,Ma, Shengli,Grinberg, Nelu,Lee, Heewon,Tsantrizos, Youla,Poupart, Marc-André,Busacca, Carl A.,Yee, Nathan K.,Lu, Bruce Z.,Senanayake, Chris H.
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p. 7144 - 7148
(2015/06/16)
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- Design, synthesis, and biological evaluation of 2-arylethenylquinoline derivatives as multifunctional agents for the treatment of Alzheimer's disease
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A series of new 2-arylethenylquinoline derivatives (4a1-4a12, 4b1-4b8, 4c1-4c4, 4d1-4d3 and 4e1-4e9) were designed, synthesized, and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro studies showed that these synthetic compounds inhibited self-induced Aβ1-42 aggregation effectively ranged from 23.6% to 83.9% at the concentration of 20 μM, and acted as potential antioxidants and biometal chelators. Their structure-activity relationships were obtained and discussed. In particular, compound 4b1, the most active compound, displayed strong inhibitory activity with an IC50 value of 9.7 μM for self-induced Aβ1-42 aggregation, good antioxidative activity with a value of 3.9-fold of Trolox, potent inhibitory activity for cholinesterase with IC50 values of 0.2 μM and 64.1 μM against butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE), respectively. Besides, 4b1 was also capable of disassembling the self-induced Aβ1-42 aggregation fibrils with a ratio of 59.8% at 20 μM concentration, and had a good metal chelating activity. Taken together, these results suggest that compound 4b1 might be a promising lead compound for AD treatment.
- Wang, Xiao-Qin,Xia, Chun-Li,Chen, Shuo-Bin,Tan, Jia-Heng,Ou, Tian-Miao,Huang, Shi-Liang,Li, Ding,Gu, Lian-Quan,Huang, Zhi-Shu
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p. 349 - 361
(2015/05/06)
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- Discovery of small molecules for up-regulating the translation of antiamyloidogenic secretase, a disintegrin and metalloproteinase 10 (ADAM10), by binding to the G-quadruplex-forming sequence in the 5' untranslated region (UTR) of its mRNA
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Up-regulation of a disintegrin and metalloproteinase 10 (ADAM10) to prevent the formation of β-amyloid (Aβ) peptides might be a promising strategy to treat Alzheimer's disease (AD). RNA G-quadruplex motif within the 5′-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus, mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by surface plasmon resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10 and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPPα, consequently decreasing the Aβ40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.
- Dai, Jie,Liu, Zhen-Quan,Wang, Xiao-Qin,Lin, Jing,Yao, Pei-Fen,Huang, Shi-Liang,Ou, Tian-Miao,Tan, Jia-Heng,Li, Ding,Gu, Lian-Quan,Huang, Zhi-Shu
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p. 3875 - 3891
(2015/05/27)
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- A triphenylamine-based colorimetric and fluorescent probe with donor-bridge-acceptor structure for detection of G-quadruplex DNA
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In this Letter, three triphenylamine-based dyes (TPA-1, TPA-2a and TPA-2b) with donor-bridge-acceptor (D-π-A) structure were designed and synthesized for the purpose of G-quadruplexes recognition. In aqueous conditions, the interactions of the dyes with G-quadruplexes were studied with the aim to establish the influence of the geometry of the dyes on their binding and probing properties. Results indicate that TPA-2b displays significant selective colorimetric and fluorescent changes upon binding of G-quadruplex DNA. More importantly, its distinct color change enables visual detection and differentiation of G-quadruplexes from single and duplex DNA structures. CD titration date reveals that TPA-2b could induce and stabilize the formation of G-quadruplex structure. All these remarkable properties of TPA-2b suggest that it should have promising application in the field of G-quadruplexes research.
- Wang, Ming-Qi,Zhu, Wen-Xiang,Song, Zhuan-Zhuan,Li, Shuo,Zhang, Yong-Zhao
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supporting information
p. 5672 - 5676
(2015/11/24)
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- A practical and mild chlorination of fused heterocyclic N-oxides
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Fused azine N-oxides were selectively chlorinated at C2 in moderate to excellent yields, employing Vilsmeier reagent as both the activating agent and the nucleophilic chloride source. Remarkable features of the method include simple operation, mild reaction conditions, a wide substrate scope, and the use of only stoichiometric amount of POCl3. The potential extension of this method to a one-pot oxidation/chlorination sequence that obviates the need for isolation of the N-oxide intermediates is also validated.
- Wang, Dong,Jia, Hailing,Wang, Wuchang,Wang, Zhe
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supporting information
p. 7130 - 7132
(2015/02/02)
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- N1-{4-[(10S)-Dihydroartemisinin-10-oxyl]}phenylmethylene-N 2-(2-methylquinoline-4-yl)hydrazine derivatives as antiplasmodial falcipain-2 inhibitors
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A series of N1-{4-[(10S)-dihydroartemisinin- 10-oxyl]}phenylmethylene-N2-(2-methylquinoline-4-yl) hydrazine derivatives 9a-9n possessing 4-quinolylhydrazone and artemisinin cores were herein synthesized and evaluated for their activities against cysteine protease falcipain- 2 of Plasmodium falciparum. The structures were clearly confirmed by elemental analysis, 1H NMR, and mass spectra. The pharmacological results indicated that all compounds showed excellent activity against recombinant falcipain-2 (IC50 = 0.15-2.28 μM). The best one of this series was compound 9d (IC50 = 0.15 μM). The molecular docking results showed that the compound 9d made close contact with the key active site of cysteine protease falcipain-2.
- Luo, Wei,Liu, Yang,Wang, Jian,Guo, Chun,Lu, Wei-Qiang,Cui, Kun-Qiang
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p. 3073 - 3079,7
(2020/08/20)
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- ANILINE OR PHENOL MUSTARDS LINKED TO DNA-AFFINIC MOLECULES OR WATER-SOLUBLE AROMATIC RINGS AND THEIR USE AS CANCER THERAPEUTIC AGENTS
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New aniline or phenol N-mustards linked to DNA-affinity carriers (such as 9-anilinoacridines, acridines andquinolines), aminobenzamides or aminophenol ethers by a urea, carbamic acid, carbanic acid ester, hydxazine urea, hydrazine carbamic acid ester, phenoxyurea, phenoxycarbamic acid ester linkage with improved chemical stability and anti-tumor therapeutic efficacy are provided.
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Page/Page column 19-20
(2008/12/06)
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- Synthesis, antimicrobial activities and cytogenetic studies of newer diazepino quinoline derivatives via Vilsmeier-Haack reaction
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The study of the Vilsmeier-Haack reagent on 4-hydroxyquinaldines resulted in a new versatile intermediate 4-chloro-3-formyl-2-(2-hydroxy-ethene-1-yl)quinolines, which on further treatment with hydrazine hydrate yielded the desired diazepino quinoline derivatives. All the synthesized diazepino quinoline derivatives are screened for their antibacterial and antifungal activities. Cytogenetic analysis of the samples is also reported.
- Nandhakumar,Suresh,Jude, A.L. Calistus,Rajesh kannan,Mohan
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p. 1128 - 1136
(2008/03/12)
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- A novel approach to 12-chloro-3-thio-4H-quino[3,2-e][1,3]diazocines via Vilsmeier Haack reaction
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The Vilsmeier Haack reaction on 4-hydroxyquinaldines lead to potential intermediate 4-chloro-3-formyl-2-(2-hydroxyethene-1-yl)quinolines. The intermediate is further utilized to prepare quino[3,2-e][1,3]diazocines on treatment with thiourea. The structures of the new compounds are determined by the analytical and spectroscopic data.
- Kumar, R. Nandha,Suresh,Dhanabal,Mohan
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p. 995 - 1000
(2008/09/18)
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- Heteroatom directed photoannulation: synthesis of indoloquinoline alkaloids: cryptolepine, cryptotackieine, cryptosanguinolentine, and their methyl derivatives
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A three-step synthesis of indoloquinoline alkaloids is described. The reaction of 2,3 and 4-substituted haloquinolines with anilines afforded the respective anilinoquinolines, which upon photocyclization gave the indoloquinolines. By regioselective methylation on quinoline nitrogen, furnished the alkaloids cryptotackieine, cryptosanguinolentine, cryptolepine, and the synthetic isomer isoneocryptolepine. Their methyl derivatives were also synthesized in search of new antiplasmodial drugs and DNA intercalating agents.
- Dhanabal,Sangeetha,Mohan
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p. 6258 - 6263
(2007/10/03)
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- Synthesis of 6-methylbenzo-[b]pyrido[3,2-f][1,6]naphthyridines from 4-chloro-2-methylquinoline
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4-Chloro-2-methylquinolines in reaction with 3-aminopyridine yielded 4-quinolinamines, which upon cyclisation under Vilsmeier-Haak conditions afforded the title compounds. 2005 Springer Science+Business Media, Inc.
- Suresh,Nandha Kumar,Mohan
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p. 778 - 781
(2007/10/03)
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- Utility of Vilsmeier Haack reagent in the synthesis of 3-amino-12-chloroquino[3,2-e][1,3]diazocines
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Application of Vilsmeier condition on 4-hydroxyquinaldines gives a potential intermediate 4-chloro-3-formyl-2-(2-hydroxy-ethene-1-yl)quinolines which is utilized to prepare quino[3,2-e][1,3]diazocines on treatment with guanidine nitrate. All the synthesized compounds are characterized by the analytical and spectroscopic data.
- Kumar, R. Nandha,Suresh,Dhanabal,Mohan
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p. 846 - 851
(2007/10/03)
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- Synthesis of 12-ethoxy-3-oxo-4-phenylquino[3,2-c][1,3]diazocines via Vilsmeier-Haack reaction
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Application of Vilsmeier condition on 4-hydroxyquinaldines give potentially useful intermediates 4-chloro-3-formyl-2-(2-hydroxyethene-1-yl)quinolines, which are utilized to prepare quino[3,2-c][1,3]diazocines on treatment with N-phenylurea.
- Kumar, Nandha,Suresh,Dhanabal,Mohan
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p. 598 - 601
(2007/10/03)
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- PROLINE DERIVATIVES AND USE THEREOF AS DRUGS
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The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.
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- Vilsmeier-Haack reaction on quinaldines
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The study of the Vilsmeier-Haack reaction on 4-hydroxyquinaldines resulted with the preparation of rarely existing 4-chloro-3-formyl-2(vinyl-1-ol)-quinolines.
- Nandha Kumar,Suresh,Mohan
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p. 2069 - 2073
(2007/10/03)
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- Use of highly active palladium-phosphinous acid catalysts in Stille, Heck, amination, and thiation reactions of chloroquinolines
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An efficient synthetic route toward a variety of 2,4-disubstituted quinolines has been developed. Alkylation and arylation of 4-chloroquinoline using organolithium reagents proceed with high regioselectivity in position 2 under cryogenic conditions. The intermediate 1,2-dihydro-4-chloro-quinoline derivatives are unstable to air and are easily oxidized to the corresponding 2-substituted 4-chloroquinolines in high yields. Highly active palladium-phosphinous acid catalysts POPd, POPd1, and POPd2 have been employed in Stille cross-couplings of quinaldine with arylstannanes and in Heck additions of various 2-substituted 4-chloroquinolines to tert-butyl acrylate. In particular, POPd combines high catalytic activity for cross-coupling reactions with simplicity of use due to its stability to air. Utilizing CsF in POPd-catalyzed Stille couplings further increased the reactivity of arylstannanes, which was attributed to the fluorophilicity of organotin compounds. Basic additives were found to exhibit a significant effect on the yields of the POPd-promoted Heck reactions. In general, dicyclohexylmethylamine affords superior results than NaOAc, Cs2CO3, or t-BuOK. POPd was also found to tolerate amine and thiol substrates and proved to promote carbon-heteroatom bond formation of chloroquinoline derivatives with aliphatic and aromatic amines and thiols, respectively.
- Wolf, Christian,Lerebours, Rachel
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p. 7077 - 7084
(2007/10/03)
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- A preparative and preliminary spectroscopic study of analogues of a Zinquin-related fluorophore
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The syntheses of the 4- and 5-methoxy isomers of 4-N-(6-methoxy-2-methyl-8-quinolyl)-4-methylbenzenesulfonamide and of N-(2-methoxy-8-quinolyl)-4-methylbenzenesulfonamide are described. The 6-methoxy compound is a precursor of Zinquin ester, a specific fluorophore for Zn(II). The 2-methoxy analogue was synthesized by nitration of 2-chloroquinoline and subsequent functional group manipulation. The 4-methoxy isomer was synthesized from a 4-quinolone derivative, and the 5-methoxy isomer was synthesized by a standard Skraup quinoline synthesis. The structures of the 4- and 5-methoxy isomers were determined by single-crystal X-ray analysis. All of these compounds showed a bathochromic shift in their ultraviolet/visible spectra upon addition of Zn(II) to the solution. These compounds are all weakly or non-fluorescent in solution. All form fluorescent complexes with Zn(II) except the 5-methoxy compound. The 4-methoxy compound forms a significantly more fluorescent complex than those of the 6-methoxy compound and Zinquin ester and has a higher quantum yield than the others.
- Kimber, Marc C.,Geue, Jason P.,Lincoln, Stephen F.,Ward, A. David,Tiekink, Edward R.T.
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- A facile approach to dibenzo [b,f] [1,6] naphthyridines using Vilsmeier conditions
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A series of 1,6-naphthyridines have been synthesized. When 4-chloro 2-methyl quinoline 1a on reaction with aniline yielded 4-quinolinamine 2a which upon cyclisation afforded the titled compounds 3a using Vilsmeier conditions.
- Suresh,Kumar, R. Nandha,Mohan
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