- Dimer ester micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase
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The invention provides dimer ester micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase. The structure of the PROTACs is shown in the specification, wherein in a compound (I), L1 is C1-C30 linear or branched alkyl with or without a substituent group, and any carbon atom in L1 is optionally replaced by heteroatom; R1, R2, R3 and R4 are C1-C30 linear or branched alkyl with orwithout a substituent group, C1-C30 aryl with or a without substituent group, C1-C30 linear or branched alkylaryl with or without a substituent group or C1-C30 linear or branched aryl alkyl with or without a substituent group respectively and independently; X1, X2, X3 and X4 are halogen respectively and independently.
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- Dimer amide micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase
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The invention provides dimer amide micromolecule PROTACs for inducing MDM2 to self-degrade E3 ubiquitin ligase. The structure of the PROTACs is shown in the specification, wherein in a compound (I), L1 is C1-C30 linear or branched alkyl with or without a substituent group, and any carbon atom in L1 is optionally replaced by heteroatom; R1, R2, R3 and R4 are C1-C30 linear or branched alkyl with orwithout a substituent group, C1-C30 aryl with or without a substituent group, C1-C30 linear or branched alkylaryl with or without a substituent group or C1-C30 linear or branched aryl alkyl with or without a substituent group respectively and independently; X1, X2, X3 and X4 are halogen respectively and independently.
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- Design, synthesis and biological evaluation of 2, 4, 5-triphenylimidazole derivatives with preliminary SAR
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A series of N1-substituted 2,4,5-triphenyl imidazole derivatives was designed, synthesized and evaluated for their p53-MDM2 binding inhibitory activities and anti-proliferative activities in vitro against four human cancer cell lines (PC3, KB, A549 and HCT116). Although logical evaluation revealed weak p53-MDM2 binding inhibitory activities, most of the obtained molecules displayed moderate to potent cytotoxicities against tested cell lines. As a potential lead compound for further optimization, compound 9c was evaluated as the most potent compound against four cell lines and could induce cell cycle arrest at G2/M phase. The binding mode of compound 9f and MDM2 was further studied by docking analysis and the unexpected interaction mode revealed that this series of compounds may take part into a different binding modes as the lead compound Such as Nutlin, which could induce a different mechanism in cancer therapy.
- Hu, Chunqi,Shen, Jianfeng,Bian, Kejun,Zhang, Ruoyu,Deng, Liping
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p. 762 - 769
(2014/07/07)
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- ARYL-SUBSTITUTED IMIDAZOLES
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The compounds of the invention are antagonists of MDM2 and MDMX, with excellent specificity for MDM2 and MDMX over other proteins, and with selective binding affinity to MDMX over MDM2. The compounds can therefore regulate p53 activity and treat a variety of cancers. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Page/Page column 55
(2012/04/17)
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- Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53-MDM2 binding inhibitors
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A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53-MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC 50 values in the low micromolar range. Compound 6c exhibited marked p53-MDM2 binding inhibitory activity (IC50 = 0.59 μM) which was eightfold more potent than that of Nutlin-1 (IC50 = 4.78 μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q 2 = 0.645, r2 = 0.979).
- Hu, Chunqi,Dou, Xiaoxue,Wu, Yizhe,Zhang, Lei,Hu, Yongzhou
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scheme or table
p. 1417 - 1424
(2012/04/17)
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- Design, synthesis, and biological evaluation of imidazoline derivatives as p53-MDM2 binding inhibitors
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Three series of novel imidazoline derivatives were designed, synthesized, and evaluated for their p53-MDM2 binding inhibitory activities, and anti-proliferation activities against PC3, A549, KB, and HCT116 cancer cell lines. Five of the tested compounds showed enhanced p53-MDM2 binding inhibitory potency and anti-proliferation activities in comparison with that of Nutlin-1. Flow cytometric analysis indicated that compound 7c, one of the most potent p53-MDM2 binding inhibitors with a Ki value of 0.6 μM, showed its ability to arrest cell cycle progression.
- Hu, Chunqi,Li, Xin,Wang, Weisi,Zhang, Lei,Tao, Lulu,Dong, Xiaowu,Sheng, Rong,Yang, Bo,Hu, Yongzhou
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experimental part
p. 5454 - 5461
(2011/10/30)
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- C-H bond functionalization via hydride transfer: synthesis of dihydrobenzopyrans from ortho-vinylaryl akyl ethers
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The hydride transfer initiated cyclization ("HT-cyclization") of aryl alkyl ethers, which leads to direct coupling of sp3 C-H bonds and activated alkenes, is reported. Readily available salicylaldehyde derived ethers are converted in one step to dihydrobenzopyrans, an important class of heteroarenes frequently found in biologically active compounds. This process has not been previously reported, in contrast to known HTcyclizations of the corresponding fert-amines ("tert-amino effect" reactions).
- McQuaid, Kevin M.,Long, Jonathan Z.,Sames, Dalibor
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supporting information; experimental part
p. 2972 - 2975
(2009/12/05)
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- Chiral Ru-based complexes for asymmetric olefin metathesis: Enhancement of catalyst activity through steric and electronic modifications
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Design, synthesis, characterization, and catalytic activity of six enantiomerically pure Ru-based metathesis catalysts are disclosed (3a-3f). The new chiral catalysts were prepared through steric and electronic alterations of the parent catalyst system (3
- Van Veldhuizen, Joshua J.,Gillingham, Dennis G.,Garber, Steven B.,Kataoka, Osamu,Hoveyda, Amir H.
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p. 12502 - 12508
(2007/10/03)
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- Synthesis of Alkoxybenzenes and Alkoxyvinylbenzenes and Their Chemosterilizing and Toxic Activity on Planococcus citri (Hom., Pseudococcidea)
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Dialkoxy-, trialkoxy-, dialkoxyvinyl-, and trialkoxyvinylbenzenes were investigated for chemosterilant and toxic activity on Planococcus citri.The alkoxyvinylbenzenes were toxic; they reduced the egg production of the test insect.Dialkoxyvinylbenzenes dec
- Belai, I.,Darvas, B.,Matolcsy, G.
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