- Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
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The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
- Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
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p. 14895 - 14911
(2021/10/12)
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- A Solid-Phase Assisted Flow Approach to In Situ Wittig-Type Olefination Coupling
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Described herein is the development of a continuous flow, solid-phase triphenylphosphine (PS-PPh3) assisted protocol to facilitate the in situ coupling of reciprocal pairs of halogen and carbonyl functionalised molecular pairs by a Wittig olefination within 15 mins. The protocol entails injecting a single solution (1 : 1 CHCl3 : EtOH) containing the halogenated and carbonyl-based substrates into a continuously flowing stream of CHCl3 : EtOH (1 : 1), passed through a fixed bed of K2CO3 and PS-PPh3. With advancement to the previous PS-PPh3 coupling procedures, the method employs a traditional polystyrene-based immobilisation matrix, the substrate scope of the protocol extended to substituted ketones, secondary alkyl chlorides, and an unprotected maleimide scaffold.
- Aldrich-Wright, Janice R.,Dankers, Christian,Gordon, Christopher P.,Polyzos, Anastasios,Tadros, Joseph
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supporting information
p. 4184 - 4194
(2021/08/24)
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- Synthesis and biological evaluation of 2-(2'/3'/4'/6'-substituted phenyl)-1hindoles
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Objective: Indole derivatives were reported to a wide range of biological activities. Thus it was our aim to synthesize a series of 2-(2'/3'/4'/6'- substituted phenyl) -1H-indoles using clayzic catalyst and screen for their in vitro anti-inflammatory, antioxidant and antimicrobial activities. Methods: Various substituted acetophenones were reacted with phenylhydrazine in the presence of modified clayzic catalyst and obtained 2- (2'/3'/4'/6'-substituted phenyl)-1H-indoles in a one pot reaction. The cyclized compounds were characterized by FT-IR, NMR, UV-Vis and mass spectral analyses and screened for anti-inflammatory activity against cytokines tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) by measuring cytokine production by performing sandwich ELISA model, antioxidant activity by DPPH assay method and antimicrobial activity by well-diffusion method. Results: An eco-friendly route with better yields for the synthesis of 2-(2'/3'/4'/6'-substituted phenyl)-1H-indoles in the presence of clayzic catalyst was achieved. The biological activity results suggested that compounds (2d, 2e and 2i) have excellent anti-inflammatory activity, compounds (2a-2d and 2j) possessing better antioxidant property and compounds (2b, 2i, 2k and 2m) have promising antibacterial and antifungal activities when compared to the standard drugs. Conclusion: Synthesis of 2-(2'/3'/4'/6'-substituted phenyl)-1H-indoles was successfully achieved in the presence of clayzic catalyst. Compounds bearing amino, methyl, methoxy, hydroxyl and fluoro groups have shown better anti-inflammatory, antioxidant and antimicrobial activities when compared to the other compounds and 1H-indole.
- Sravanthi,Rani,Manju
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p. 268 - 273
(2015/11/17)
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- Palladium-catalyzed direct arylation of (hetero) arenes with aryl boronic acids
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(Chemical Equation Presented) No compass required: A method is described for forming biaryl C-C bonds by a PdII-catalyzed cross-coupling of aryl C-H bonds with aryl boronic acids under mild conditions without the presence of directing groups. Different substituents on both (hetero)arenes and aryl boronic acids are compatible with the reaction conditions, and the homocoupling of boronic acids is highly inhibited. Dioxygen was applied as the final oxidant.
- Yang, Shang-Dong,Sun, Chang-Liang,Fang, Zhao,Li, Bi-Jie,Li, Yi-Zhou,Shi, Zhang-Jie
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p. 1473 - 1476
(2008/12/22)
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