93493-95-9Relevant academic research and scientific papers
Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs
Balazs, Amber,Barratt, Derek,Bista, Michal,Chuba, Matthew D.,Cosulich, Sabina,Critchlow, Susan E.,Degorce, Sébastien L.,Di Fruscia, Paolo,Edmondson, Scott D.,Embrey, Kevin,Fawell, Stephen,Ghosh, Avipsa,Gill, Sonja J.,Gunnarsson, Anders,Hande, Sudhir M.,Heightman, Tom D.,Hemsley, Paul,Illuzzi, Giuditta,Johannes, Jeffrey W.,Lane, Jordan,Larner, Carrie,Leo, Elisabetta,Liu, Lina,Madin, Andrew,Martin, Scott,McWilliams, Lisa,O'Connor, Mark J.,Orme, Jonathan P.,Pachl, Fiona,Packer, Martin J.,Pei, Xiaohui,Pike, Andrew,Schimpl, Marianne,She, Hongyao,Staniszewska, Anna D.,Talbot, Verity,Underwood, Elizabeth,Varnes, Jeffrey G.,Xue, Lin,Yao, Tieguang,Zhang, Andrew X.,Zhang, Ke,Zheng, Xiaolan
supporting information, p. 14498 - 14512 (2021/10/20)
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application
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Paragraph 0045-0048; 0050; 0052-0053, (2020/11/12)
The invention relates to a compound for inhibiting the activity of Bcl-2/BCL-XL anti-apoptotic protein, a composition containing the compound and application of the compound serving as a synthetic drug, in particular to application of the compound serving as a drug for synthesizing a Bcl-2/BCL-XL anti-apoptotic protein inhibitor and application of the compound to cancer.
NHC-Mediated Synthesis of Tricyclic Spirocarbocycles via an Intramolecular Stetter Reaction of Cyclic Enal-Enones
Hsu, Day-Shin,Liang, Suz-Ping
, p. 1270 - 1278 (2019/12/30)
A general and efficient method for the synthesis of tricyclic spirocarbocycles is described. Various cyclic enal-enones were reacted with an N-heterocyclic carbene, and an intramolecular Stetter reaction proceeded smoothly to give various tricyclic spiro-
Mechanistic Divergence in the Hydrogenative Synthesis of Furans and Butenolides: Ruthenium Carbenes Formed by gem-Hydrogenation or through Carbophilic Activation of Alkynes
Peil, Sebastian,Fürstner, Alois
supporting information, p. 18476 - 18481 (2019/11/14)
Enynes with a tethered carbonyl substituent are converted into substituted furan derivatives upon hydrogenation using [Cp*RuCl]4 as the catalyst. Paradoxically, this transformation can occur along two distinct pathways, each of which proceeds via discrete pianostool ruthenium carbenes. In the first case, hydrogenation and carbene formation are synchronized (“gem-hydrogenation”), whereas the second pathway comprises carbene formation by carbophilic activation of the triple bond, followed by hydrogenative catalyst recycling. Representative carbene intermediates of either route were characterized by X-ray crystallography; the structural data prove that the attack of the carbonyl group on the electrophilic carbene center follows a Bürgi–Dunitz trajectory.
Controlling the Selectivity Patterns of Au-Catalyzed Cyclization-Migration Reactions
Chen, Mo,Su, Naijing,Deng, Tianning,Wink, Donald J.,Zhao, Yingwei,Driver, Tom G.
supporting information, p. 1555 - 1558 (2019/03/20)
As little as 2 mol % of (XPhos)AuNTf2 catalyzes the transformation of a broad range of o-acetylene-substituted styrenes into 1,2-dihydronaphthalenes. Our data suggests that this transformation occurs via a gold-stabilized cyclopropyl carbinyl cation, which triggers either a [1,2] carboxylate shift or a less favorable [1,2] aryl shift. The relative rates of these migrations can be controlled by the identity of the ligand or by stabilizing the mesomeric cation.
Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction
Seefeld, Mark A.,Lin, Hong,Holenz, Joerg,Downie, Dave,Donovan, Brian,Fu, Tingting,Pasikanti, Kishore,Zhen, Wei,Cato, Matthew,Chaudhary, Khuram W.,Brady, Pat,Bakshi, Tania,Morrow, Dwight,Rajagopal, Sridharan,Samanta, Swapan Kumar,Madhyastha, Naveena,Kuppusamy, Bharathi Mohan,Dougherty, Robert W.,Bhamidipati, Ravi,Mohd, Zainuddin,Higgins, Guy A.,Chapman, Mark,Rouget, Céline,Lluel, Philippe,Matsuoka, Yasuji
, p. 3793 - 3797 (2018/10/20)
Neuronal voltage-gated potassium channels, KV7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule KV7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. KV7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual KV7 isoforms was investigated in human detrusor tissue using a panel of KV7 openers with distinct activity profiles among KV7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric KV7.4 did not reduce detrusor contraction. This may suggest that the homomeric KV7.4 channel plays a less significant role in bladder contraction and further investigation is needed.
Achieving Site Selectivity in Metal-Catalyzed Electron-Rich Carbene Transfer Reactions from N-Tosylhydrazones
Su, Naijing,Deng, Tianning,Wink, Donald J.,Driver, Tom G.
supporting information, p. 3990 - 3993 (2017/08/15)
Catalyst control of the site-selectivity of electron-rich alkyl, aryl disubstituted carbenes generated in situ from o-alkenyl-substituted N-tosylhydrazones was achieved in this study. Exposure of these substrates to copper iodide triggered the formation of α-alkoxy 2H-naphthalenones. This investigation established that changing the catalyst to a rhodium(II) carboxylate turned off cyclization and migration of the electron-rich metal carbene with the β-carboxylate and turned on allylic C-H bond functionalization to diastereoselectively afford 1H-indenes. Examination of the scope of this reaction revealed that ethereal, aminomethylene, and unactivated 2° C-H bonds could be functionalized.
A Pd-catalyzed, boron ester-mediated, reductive cross-coupling of two aryl halides to synthesize tricyclic biaryls
Chen, Zhilong,Wang, Xiaodong
supporting information, p. 5790 - 5796 (2017/07/22)
Tricyclic biaryls are important scaffold structures in many natural products and lead compounds in drug discovery. The formation of a biaryl unit is often the key step for the synthesis of tricyclic biaryls. Despite significant progress toward the synthesis of biaryl compounds in recent years, the direct cross-coupling of two different aryl halides is still challenging and robust methods are lacking. Herein we report a direct cross-coupling of two different aryl halides in the presence of a palladium catalyst and boron ester, which provides a new and useful complementary method to synthesize tricyclic biaryls.
Control of the Chemoselectivity of Metal N-Aryl Nitrene Reactivity: C-H Bond Amination versus Electrocyclization
Kong, Chen,Jana, Navendu,Jones, Crystalann,Driver, Tom G.
supporting information, p. 13271 - 13280 (2016/10/22)
A mechanism study to identify the elements that control the chemoselectivity of metal-catalyzed N-atom transfer reactions of styryl azides is presented. Our studies show that the proclivity of the metal N-aryl nitrene to participate in sp3-C-H bond amination or electrocyclization reactions can be controlled by either the substrate or the catalyst. Electrocyclization is favored for mono-β-substituted and sterically noncongested styryl azides, whereas sp3-C-H bond amination through an H-atom abstraction-radical recombination mechanism is preferred when a tertiary allylic reaction center is present. Even when a weakened allylic C-H bond is present, our data suggest that the indole is still formed through an electrocyclization instead of a common allyl radical intermediate. The site selectivity of metal N-aryl nitrenes was found to be controlled by the choice of catalyst: Ir(I)-alkene complexes trigger electrocyclization processes while Fe(III) porphyrin complexes catalyze sp3-C-H bond amination in substrates where Rh2(II) carboxylate catalysts provide both products.
Rh2(II)-catalyzed ester migration to afford 3 H-indoles from trisubstituted styryl azides
Kong, Chen,Driver, Tom G.
supporting information, p. 802 - 805 (2015/04/27)
Rh2(II)-Complexes trigger the formation of 3H-indoles from ortho-alkenyl substituted aryl azides. This reaction occurs through a 4π-electron-5-atom electrocyclization of the rhodium N-aryl nitrene followed by a [1,2]-migration to afford only 3H-indoles. The selectivity of the migration is dependent on the identity of the β-styryl substituent.
