- Structure-based design, synthesis, and evaluation of inhibitors with high selectivity for PARP-1 over PARP-2
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The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors have lower selectivity to PARP-1 than to PARP-2, so they will inevitably have side effects. Based on the different catalytic domains of PARP-1 and PARP-2, we developed a strategy to design and synthesize highly selective PARP-1 inhibitors. Compounds Y17, Y29, Y31 and Y49 showed excellent PARP-1 inhibition, and their IC50 values were 0.61, 0.66, 0.41 and 0.96 nM, respectively. Then, Y49 (PARP-1 IC50 = 0.96 nM, PARP-2 IC50 = 61.90 nM, selectivity PARP-2/PARP-1 = 64.5) was proved to be the most selective inhibitor of PARP-1. Compounds Y29 and Y49 showed stronger inhibitory effect on proliferation in BRCA1 mutant MX-1 cells than in other cancer cells. In the MDA-MB-436 xenotransplantation model, Y49 was well tolerated and showed remarkable single dose activity. The design strategy proposed in this paper is of far-reaching significance for the further construction of the next generation of selective PARP-1 inhibitors.
- Yu, Jiang,Luo, Lingling,Hu, Tong,Cui, Yating,Sun, Xiao,Gou, Wenfeng,Hou, Wenbin,Li, Yiliang,Sun, Tiemin
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- Chemoselective, Scalable Nickel-Electrocatalytic O-Arylation of Alcohols
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The formation of aryl-alkyl ether bonds through cross coupling of alcohols with aryl halides represents a useful strategic departure from classical SN2 methods. Numerous tactics relying on Pd-, Cu-, and Ni-based catalytic systems have emerged over the past several years. Herein we disclose a Ni-catalyzed electrochemically driven protocol to achieve this useful transformation with a broad substrate scope in an operationally simple way. This electrochemical method does not require strong base, exogenous expensive transition metal catalysts (e.g., Ir, Ru), and can easily be scaled up in either a batch or flow setting. Interestingly, e-etherification exhibits an enhanced substrate scope over the mechanistically related photochemical variant as it tolerates tertiary amine functional groups in the alcohol nucleophile.
- Baran, Phil S.,Chen, Longrui,Edwards, Jacob T.,Kawamata, Yu,Oderinde, Martins S.,Zhang, Hai-Jun
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supporting information
p. 20700 - 20705
(2021/08/17)
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- Convergent Total Synthesis of Lamellarins and Their Congeners
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A convergent total synthesis of lamellarins S and Z is described. The synthesis features a halogen dance of an easily accessible α,β-dibromopyrrole promoted by an ester moiety. The resultant β,β′-dibromopyrrole undergoes a ligand-controlled Suzuki-Miyaura coupling to provide a range of diarylated pyrrole derivatives. The established synthetic method was also applicable to the synthesis of ningalin B and lukianols A and B.
- Morikawa, Daiki,Morii, Kazuki,Yasuda, Yuto,Mori, Atsunori,Okano, Kentaro
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p. 8603 - 8617
(2020/07/16)
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- Development and Mechanistic Studies of Iron-Catalyzed Construction of Csp2-B Bonds via C-O Bond Activation
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Herein we describe an iron-catalyzed borylation of alkenyl and aryl carbamates through the activation of a C-O bond. This protocol exhibits high efficiency, a broad substrate scope, and the late-stage borylation of biorelevant compounds, thus providing potential applications in medicinal chemistry. Moreover, this method enables orthogonal transformations of phenol derivatives and also offers good opportunities for the synthesis of multisubstituted arenes. Preliminary mechanistic studies suggest that a FeII/FeIII catalytic cycle via a radical pathway might be involved in the reaction.
- Geng, Shasha,Zhang, Juan,Chen, Shuo,Liu, Zhengli,Zeng, Xiaoqin,He, Yun,Feng, Zhang
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p. 5582 - 5588
(2020/07/08)
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- Iron-Catalyzed Borylation of Aryl Ethers via Cleavage of C-O Bonds
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Herein, we report the iron-catalyzed borylation of aryl ethers and aryl amines via cleavage of C-O and C-N bonds. This protocol does not require the use of Grignard reagents and displays a broad substrate scope, which allows the late-stage borylation. It also provides facile access to multisubstituted arenes through C-H functionalization using 2-pyridyloxy as the directing group.
- Zeng, Xiaoqin,Zhang, Yuxuan,Liu, Zhengli,Geng, Shasha,He, Yun,Feng, Zhang
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p. 2950 - 2955
(2020/04/15)
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- Nickel-catalysed decarbonylative borylation of aroyl fluorides
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The first Ni(cod)2/PPh3 catalyst system has been established for decarbonylative borylation of aroyl fluorides with bis(pinacolato)diboron. A wide range of functional groups in the substrates were well tolerated. The ease of access of the starting aroyl fluorides indicates that these results might become an alternative to the existing decarbonylation events.
- Wang, Zhenhua,Wang, Xiu,Nishihara, Yasushi
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supporting information
p. 13969 - 13972
(2019/01/03)
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- Metal-Free and Redox-Neutral Conversion of Organotrifluoroborates into Radicals Enabled by Visible Light
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Converting organoboron compounds into the corresponding radicals has broad synthetic applications in organic chemistry. To achieve these transformations, various strong oxidants such as Mn(OAc)3, AgNO3/K2S2O8, and Cu(OAc)2, in stoichiometric amounts are required, proceeding by a single-electron transfer mechanism. Established herein is a distinct strategy for generating both aryl and alkyl radicals from organotrifluoroborates through an SH2 process. This strategy is enabled by using water as the solvent, visible light as the energy input, and diacetyl as the promoter in the absence of any metal catalyst or redox reagent, thereby eliminating metal waste. To demonstrate its synthetic utility, an efficient acetylation to prepare valuable aryl (alkyl) methyl ketones is described and applications to construct C?C, C?I, C?Br, and C?S bonds are also feasible. Experimental evidence suggests that triplet diacetyl serves as the key intermediate in this process.
- Liu, Wenbo,Liu, Peng,Lv, Leiyang,Li, Chao-Jun
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supporting information
p. 13499 - 13503
(2018/09/25)
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- METHODS OF MANUFACTURING OF BORON COMPOUND WITHOUT TRANSITION METALS
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The present invention refers to aryl boron compound number bath method relates to search, more particularly transition metal catalyst to a tank without the use of boron compounds number is given to the aryl organic halo [ceyn [ceyn] freight method are disclosed to boron. (by machine translation)
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Paragraph 0065; 0066; 0071; 0072; 0076
(2018/05/03)
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- NOVEL HYDRAZIDE CONTAINING COMPOUNDS AS BTK INHIBITORS
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The present invention relates to novel hydrazide containing compounds as Bruton tyrosine kinase inhibitors, process of preparation thereof, and to the use of the compounds in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders involving mediation of Bruton tyrosine kinase in humans.
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- Chemoselective coupling of 1,1-bis[(pinacolato)boryl]alkanes for the transition-metal-frec borylation of aryl and vinyl halides: A combined experimental and theoretical investigation
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A new transition-metal-frec borylation of aryl and vinyl halides using l,l-bis[(pinacolato)boryl]alkanes as boron sources is described. In this transformation one of the boron groups from 1,1-bis[(pinacolato)boryl]alkanes is selectively transferred to aryl and vinyl halides in the presence of sodium tert-butoxide as the only activator to form organoboronate esters. Under the developed borylation conditions, a broad range of organohalides are borylated with excellent chemo-selectivity and functional group compatibility, thus offering a rare example of a transition-metal-frec borylation protocol. Experimental and theoretical studies have becn performed to elucidate the reaction mechanism, revealing the unusual formation of Lewis acid/base adduct betwecn organohalides and α-borylcarbanion, generated in situ from the reaction of l,l-bis[(pinacolato)boryl]alkanes with an alkoxide base, to facilitate the borylation reactions.
- Lee, Yeosan,Baek, Seung-Yeol,Park, Jinyoung,Kim, Seoung-Tae,Tussupbayev, Samat,Kim, Jeongho,Baik, Mu-Hyun,Cho, Seung Hwan
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p. 975 - 984
(2017/05/16)
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- Rhodium-Catalyzed Decarbonylative Borylation of Aromatic Thioesters for Facile Diversification of Aromatic Carboxylic Acids
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Transformation of aromatic thioesters into arylboronic esters was achieved efficiently using a rhodium catalyst. The broad functional-group tolerance and mild conditions of the method have allowed for the two-step decarboxylative borylation of a wide range of aromatic carboxylic acids, including commercially available drugs.
- Ochiai, Hidenori,Uetake, Yuta,Niwa, Takashi,Hosoya, Takamitsu
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p. 2482 - 2486
(2017/02/23)
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- Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode
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On the basis of Ibrutinib’s core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del
- Wang, Aoli,Li, Xixiang,Wu, Hong,Zou, Fengming,Yan, Xiao-E,Chen, Cheng,Hu, Chen,Yu, Kailin,Wang, Wenchao,Zhao, Peng,Wu, Jiaxin,Qi, Ziping,Wang, Wei,Wang, Beilei,Wang, Li,Ren, Tao,Zhang, Shanchun,Yun, Cai-Hong,Liu, Jing,Liu, Qingsong
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p. 2944 - 2962
(2017/04/21)
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- Rhodium-Catalyzed ipso-Borylation of Alkylthioarenes via C-S Bond Cleavage
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Rhodium-catalyzed transformation of alkyl aryl sulfides into arylboronic acid pinacol esters via C-S bond cleavage is reported. In combination with transition-metal-catalyzed sulfanyl group-guided regioselective C-H borylation reactions of alkylthioarenes, this method allows the synthesis of a diverse range of multisubstituted arenes.
- Uetake, Yuta,Niwa, Takashi,Hosoya, Takamitsu
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p. 2758 - 2761
(2016/06/15)
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- Palladium-Catalyzed ipso-Borylation of Aryl Sulfides with Diborons
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A catalytic Miyaura-type ipso-borylation of aryl sulfides with diboron reagents has been achieved, providing arylboronate esters of synthetic use. The key conditions to transform inherently reluctant C-S bonds into C-B bonds include a palladium-NHC (N-heterocyclic carbene) precatalyst, bis(pinacolato)diboron, and lithium hexamethyldisilazide. This protocol is applicable to a reasonable range of aryl alkyl sulfides. Twofold borylation was observed in the reaction of diphenyl sulfide.
- Bhanuchandra,Baralle, Alexandre,Otsuka, Shinya,Nogi, Keisuke,Yorimitsu, Hideki,Osuka, Atsuhiro
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p. 2966 - 2969
(2016/07/06)
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- Design, synthesis and evaluation of potent G-protein coupled receptor 40 agonists
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GPR40 has emerged as an attractive drug target for the treatment of type 2 diabetes due to its role in the enhancement of insulin secretion with glucose dependency. With the aim to improve the metabolic and safety profiles, a series of novel phenylpropionic acid derivatives were synthesized. Extensive structural optimization led to identification of compounds 22g and 23e as potent GPR40 agonists with moderate liver microsomal stability. All the discovery supported further exploration surrounding this scaffold.
- Huang, Jing,Guo, Bin,Chu, Wen-Jing,Xie, Xin,Yang, Yu-She,Zhou, Xian-Li
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supporting information
p. 159 - 162
(2016/01/26)
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- SUBSTITUTED 4,5,6,7-TETRAHYDRO-PYRAZOLO[1,5-a]PYRAZINE DERIVATIVES AND 5,6,7,8-TETRAHYDRO-4H-PYRAZOLO[1,5-a][1,4]DIAZEPINE DERIVATIVES AS ROS1 INHIBITORS
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The present invention relates to substituted 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine derivatives and 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine derivatives of formula (I) wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as ROS 1 inhibitors. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
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Page/Page column 233
(2015/12/08)
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- Solid-Supported Iodonium Salts for Fluorinations
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Solid-supported iodonium salt precursors have been prepared and used for the production of fluoroarenes. The importance of the resin functionality for the attachment of the iodonium salt moieties has been demonstrated. Furthermore, the production of new i
- Edwards, Richard,De Vries, Wilke,Westwell, Andrew D.,Daniels, Stephen,Wirth, Thomas
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p. 6909 - 6916
(2015/11/02)
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- Palladium-Catalyzed Monofluoromethylation of Arylboronic Esters with Fluoromethyl Iodide
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The first palladium-catalyzed direct monofluoromethylation of arylboronic esters to produce monofluoromethyl arenes is reported. The reaction is typically carried out at room temperature within 4 h and has a good functional group tolerance. The monofluoromethylating agent, CH2FI, was readily prepared via a halogen-exchange process.
- Hu, Jingyu,Gao, Bing,Li, Lingchun,Ni, Chuanfa,Hu, Jinbo
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supporting information
p. 3086 - 3089
(2015/06/30)
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- Synthesis of dictyomedins using phosphazene base catalyzed diaryl ether formation
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Dictyomedins isolated from dictyostelium cellular slime molds were synthesized by using diaryl ether derivatives as key intermediates for the cyclization to dibenzofuran followed by palladium catalyzed intramolecular biaryl formation.
- Ebisawa, Masaru,Ueno, Masahiro,Oshima, Yoshiteru,Kondo, Yoshinori
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p. 8918 - 8921
(2008/03/14)
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