- Linker Immolation Determines Cell Killing Activity of Disulfide-Linked Pyrrolobenzodiazepine Antibody-Drug Conjugates
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Disulfide bonds could be valuable linkers for a variety of therapeutic applications requiring tunable cleavage between two parts of a molecule (e.g., antibody-drug conjugates). The in vitro linker immolation of β-mercaptoethyl-carbamate disulfides and DNA alkylation properties of associated payloads were investigated to understand the determinant of cell killing potency of anti-CD22 linked pyrrolobenzodiazepine (PBD-dimer) conjugates. Efficient immolation and release of a PBD-dimer with strong DNA alkylation properties were observed following disulfide cleavage of methyl- and cyclobutyl-substituted disulfide linkers. However, the analogous cyclopropyl-containing linker did not immolate, and the associated thiol-containing product was a poor DNA alkylator. As predicted from these in vitro assessments, the related anti-CD22 ADCs showed different target-dependent cell killing activities in WSU-DLCL2 and BJAB cell lines. These results demonstrate how the in vitro immolation models can be used to help design efficacious ADCs.
- Zhang, Donglu,Pillow, Thomas H.,Ma, Yong,Cruz-Chuh, Josefa Dela,Kozak, Katherine R.,Sadowsky, Jack D.,Lewis Phillips, Gail D.,Guo, Jun,Darwish, Martine,Fan, Peter,Chen, Jingtian,He, Changrong,Wang, Tao,Yao, Hui,Xu, Zijin,Chen, Jinhua,Wai, John,Pei, Zhonghua,Hop, Cornelis E. C. A.,Khojasteh, S. Cyrus,Dragovich, Peter S.
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- SULFONYLCYCLOALKYL CARBOXAMIDE COMPOUNDS AS TRPA1 MODULATORS
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The invention is concerned with the compounds of formula (I): and pharmaceutically acceptable salts thereof. In addition, the present invention relates to methods of manufacturing and methods of using the compounds of formula I as well as pharmaceutical compositions containing such compounds. The compounds may be useful in treating diseases and conditions mediated by TRPA1, such as pain.
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Paragraph 0165; 0166; 0167; 0168; 0169; 0170
(2018/02/28)
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- Design, synthesis, and conformational analysis of 3-: Cyclo -butylcarbamoyl hydantoins as novel hydrogen bond driven universal peptidomimetics
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A collection of systematically substituted 3-cyclo-butylcarbamoyl hydantoins was synthesized by a regioselective multicomponent domino process followed by easy coupling reactions. Calculations, NMR studies and X-ray analysis show that these scaffolds are able to project their side chains similar to common secondary structures, such as the α-helix and β-turn, with favourable enthalpic and entropic profiles.
- Bellucci,Frigerio,Castellano,Meneghetti,Sacchetti,Volonterio
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supporting information
p. 521 - 525
(2018/02/07)
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- HINDERED DISULFIDE DRUG CONJUGATES
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The invention relates generally to disulfide drug conjugates wherein a linker comprising a sulfur-bearing carbon atom substituted with at least one hydrocarbyl or substituted hydrocarbyl is conjugated by a disulfide bond to a cysteine sulfur atom of a targeting carrier, and wherein the linker is further conjugated to a drug moiety. The invention further relates to activated linker-drug conjugates suitable for conjugation to a targeting carrier by a disulfide bond. The invention further relates to methods for preparing hindered disulfide drug conjugates.
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Page/Page column 119; 124; 125
(2017/05/02)
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- PROCESS FOR THE PREPARATION OF ORGANIC BROMIDES
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The present invention provides a process for the preparation of organic bromides, by a radical bromodecarboxylation of carboxylic acids with a bromoisocyanurate.
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Paragraph 00169; 00171; 00194
(2017/07/28)
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- Cu-Catalyzed Alkynylation of Unactivated C(sp3)-X Bonds with Terminal Alkynes through Directing Strategy
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In this letter, we report an efficient and concise protocol for Cu-catalyzed cross-coupling of unactivated alkyl halides/peusudohalides with terminal alkynes to afford internal alkynes with the assistance of various amides as directing groups. Different alkyl halides/pseudohalides exhibited excellent reactivities, and the inactivated alkyl chlorides and sulfonates showed better reactivity than bromides/iodides. This is the first successful example to apply alkyl chlorides and sulfonates directly in cross-coupling with terminal alkynes in the absence of any additives. A Cu catalyst was found to be more effective than other transition metal catalysts. This reaction also exhibited a broad substrate scope with respect to terminal alkynes.
- Luo, Fei-Xian,Xu, Xing,Wang, Ding,Cao, Zhi-Chao,Zhang, Yun-Fei,Shi, Zhang-Jie
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supporting information
p. 2040 - 2043
(2016/06/01)
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- Synthesis of chiral cyclobutanes via rhodium/diene-catalyzed asymmetric 1,4-addition: A dramatic ligand effect on the diastereoselectivity
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A highly diastereo- and enantioselective rhodium-catalyzed arylation of cyclobutenes for the efficient synthesis of chiral cyclobutanes has been developed. Chiral diene ligands exhibited excellent capability for the reaction diastereoselectivity control.
- Chen, Ya-Jing,Hu, Tian-Jiao,Feng, Chen-Guo,Lin, Guo-Qiang
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supporting information
p. 8773 - 8776
(2015/05/20)
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- NOVEL COMPOUNDS
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Disclosed are novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORγ.
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Page/Page column 59
(2015/12/17)
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- Synthesis of the 1-monoester of 2-ketoalkanedioic acids, for example, octyl α-ketoglutarate
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Oxidative cleavage of cycloalkene-1-carboxylates, made from the corresponding carboxylic acids, and subsequent oxidation of the resulting ketoaldehyde afforded the important 1-monoesters of 2-ketoalkanedioic acids. Thus ozonolysis of octyl cyclobutene-1-carboxylate followed by sodium chlorite oxidation afforded the 1-monooctyl 2-ketoglutarate. This is a cell-permeable prodrug form of α-ketoglutarate, an important intermediate in the tricarboxylic acid (TCA, Krebs) cycle and a promising therapeutic agent in its own right.
- Jung, Michael E.,Deng, Gang
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p. 11002 - 11005
(2013/02/22)
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- 7 2-(Aminocarbonylalkoxyimino)acetamido! derivatives of cephalosporin
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Cephalosporin antibiotics in which the 7β-acylamido group has the structure STR1 (WHERE R is phenyl, thienyl or furyl; Ra and Rb are each selected from hydrogen, C1-4 alkyl, C2-4 alkenyl, C3-7 cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, C2-5 alkoxycarbonyl, aminocarbonyl, N-substituted aminocarbonyl and cyano, or Ra and Rb together with the carbon atom to which they are attached form a C3-7 cycloalkylidene or cycloalkenylidene group; Rc is hydrogen or C1-4 alkyl; and m and n are each 0 or 1 such that the sum of m and n is 0 or 1) exhibit broad spectrum antibiotic activity characterized by particularly high activity against gram negative microorganisms, including those which produce β-lactamases. The compounds, which are syn isomers or exist as mixtures of syn and anti isomers containing at least 90% of the syn isomer, have particularly good activity against Proteus organisms including indole positive strains and, especially when both Ra and Rb are other than hydrogen, against Pseudomonas organisms.
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