- Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody-Drug Conjugates
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Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody-drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.
- Staben, Leanna R.,Chen, Jinhua,Cruz-Chuh, Josefa dela,Del Rosario, Geoff,Go, Mary Ann,Guo, Jun,Khojasteh, S. Cyrus,Kozak, Katherine R.,Li, Guangmin,Ng, Carl,Lewis Phillips, Gail D.,Pillow, Thomas H.,Rowntree, Rebecca K.,Wai, John,Wei, BinQing,Xu, Keyang,Xu, Zijin,Yu, Shang-Fan,Zhang, Donglu,Dragovich, Peter S.
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p. 9603 - 9622
(2020/10/19)
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- Corresponding amine nitrile and method of manufacturing thereof
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The invention relates to a manufacturing method of nitrile. Compared with the prior art, the manufacturing method has the characteristics of significantly reduced using amount of an ammonia source, low environmental pressure, low energy consumption, low production cost, high purity and yield of a nitrile product and the like, and nitrile with a more complex structure can be obtained. The invention also relates to a method for manufacturing corresponding amine from nitrile.
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- Structure and Mechanism Revision of a Catalyzed Cyclization of Benzaldehyde Bearing Alkyne-Nitrile
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Pt(II)-catalyzed carbocyclization of benzaldehyde containing a keto-nitrile functionality resulted in the formation, respectively, of isochromenes and spiro-lactones instead of fused lactams and spiro-lactams as was previously reported. The reaction mecha
- ?afá?, Peter,Marchalín, ?tefan,?oral, Michal,Moncol, Ján,Da?ch, Adam
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supporting information
p. 4742 - 4745
(2017/09/25)
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- OXAZOLIDINONE HYDROXAMIC ACID COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS
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This invention pertains generally to treating bacterial infections using organic compounds of Formula I. In certain aspects, the invention pertains to treating infections caused by Gram-negative bacteria. (I) wherein X, Y, R1, R2, R3, R4 and R5 and defined herein.
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Page/Page column 99
(2015/05/19)
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- HETEROCYCLIC INHIBITORS OF GLUTAMINASE
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The invention relates to the heterocyclic compounds of Formula (I) as defined further herein, and pharmaceutical preparations thereof. The invention further relates to methods of treating cancer, immunological or neurological diseases using the heterocyclic compounds of the invention.
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Page/Page column 81; 82
(2013/06/06)
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- Chemoselectivities in the platinum-catalyzed hydrative carbocyclizations of oxo-alkyne-nitrile functionalities
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Two new hydrative carbocyclizations of oxa-alkyne-nitrile functionalities are reported to produce distinct nitrogen-containing heterocycles. Protracted heating of oxoalkynyl nitrile substrates with PtCl2/CO/H2O in hot 1,4-dioxane gave 2,3-dihydro-1H-pyrido[1.2-b]-isoquinolin-4(6H)-ones. In this hydration reaction, dicarbonyl nitrile intermediates were isolated efficiently after a brief period, and they were subjected to an NHC-based crossed benzoin coupling to give spiro alcohols that further reacted with TfOH to give spiro[indene-2,2′-piperidine]-1,6′(3H)-diones.
- Mukherjee, Anupam,Liu, Rai-Shung
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supporting information; experimental part
p. 660 - 663
(2011/05/03)
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- Synthesis of (E,Z)-5-bromo-1,1-dimethoxy-5-trimethylsilyl-4-pentene, an upper chain allenic prostaglandin building block
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This work explores the synthetic route to allenic prostaglandins. In a search for more efficient and reliable methods for the introduction of the allene moiety into the side chains of prostaglandins, the synthons, the (E) and (Z) isomers of 1-bromo-5,5-dimethoxy-1-trimethylsilyl-1-pentene (13a) and (13b), have been prepared and converted to R,S-1,1-dimethoxy-6-phenyl-4,5-hexadiene (16), a prostaglandin analog.
- Guzman-Duran, Antonio,Guzman, Esther,Pannell, Keith H.,Lloyd, Winston D.
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p. 3271 - 3283
(2007/10/03)
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- Synthesis and biological characterization of 1,4,5,6- tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine derivatives as selective m1 agonists
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Previous studies identified several novel tetrahydropyrimidine derivatives exhibiting muscarinic agonist activity in rat brain. Such compounds might be useful in treating cognitive and memory deficits associated with low acetylcholine levels, as found in Alzheimer's disease. To determine the molecular features of ligands important for binding and activity at muscarinic receptor subtypes, the series of tetrahydropyrimidines was extended. Several active compounds were examined further for functional selectivity through biochemical studies of muscarinic receptor activity using receptor subtypes expressed in cell lines. Several amidine derivatives displayed high efficacy at m1 receptors and lower activity at m3 receptors coupled to phosphoinositide (PI) metabolism in A9 L cells. Four ligands, including 1b, 1f, 2b, and 7b, exhibited marked functional selectivity for m1 vs m3 receptors. Compound 1f also exhibited low activity at m2 receptors coupled to the inhibition of adenylyl cyclase in A9 L cells. Molecular modeling studies also were initiated to help understand the nature of the interaction of muscarinic agonists with the m1 receptor using a nine amino model of the m1 receptor. Several important interactions were identified, including interactions between the ester moiety and Thr192. Additional interactions were found for oxadiazoles and alkynyl derivatives with Asn382, suggesting that enhanced potency and selectivity may be achieved by maximizing interactions with Asp105, Thr192, and Ash382. Taken together, the data indicate that several amidine derivatives display functional selectivity for m1 muscarinic receptors, warranting further evaluation as therapeutic agents for the treatment of Alzheimer's disease. In addition, several amino acid residues were identified as potential binding sites for m1 agonists. These data may be useful in directing efforts to develop even more selective m1 agonists.
- Messer Jr., William S.,Abuh, Yahaya F.,Liu, Yang,Periyasamy, Sumudra,Ngur, Dan O.,Edgar, Michael A. N.,El-Assadi, Afif A.,Sbeih, Sbeih,Dunbar, Philip G.,Roknich, Scott,Rho, Taikyun,Fang, Zheng,Ojo, Babatunde,Zhang, Hao,Huzl III, James J.,Nagy, Peter I.
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p. 1230 - 1246
(2007/10/03)
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- Intramolecular aminopalladation and cross coupling of acetylenic amines
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Stereodefined 2-alkylidene-pyrrolidines and -piperidine were synthesized by treatment of an acetylenic amines with n-BuLi followed by addition of catalytic amount of Pd(OAc)2 and PPh3 in THF and 3 equiv of an organic halide.
- Luo, Fen-Tair,Wang, Ren-Tzong
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p. 6835 - 6838
(2007/10/02)
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