- CONJUGATES COMPRISING SELF-IMMOLATIVE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and an active agent. The antibody-drug conjugate may comprise a self- immolative group. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 134; 135
(2017/06/27)
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- CONJUGATES COMPRISING PEPTIDE GROUPS AND METHODS RELATED THERETO
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In some aspects, the invention relates to an antibody-drug conjugate, comprising an antibody; a linker; and at least two active agents. In preferred embodiments, the linker comprises a peptide sequence of a plurality of amino acids, and at least two of the active agents are covalently coupled to side chains of the amino acids. The antibody-drug conjugate may comprise a self-immolative group, preferably two-self-immolative groups. The linker may comprise an O-substituted oxime, e.g., wherein the oxygen atom of the oxime is substituted with a group that covalently links the oxime to the active agent; and the carbon atom of the oxime is substituted with a group that covalently links the oxime to the antibody.
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Page/Page column 144; 145
(2017/08/08)
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- Stereoselective approach to cis -2,3-disubstituted piperidines via reduction of N -acyliminium ion intermediate: Enantioselective synthesis of (+)-(2 S,3 S)-CP-99,994
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A very simple and efficient stereoselective approach to cis-2,3-disubstituted piperidines via the reduction of N-acyliminium ion intermediates is described. Application of this methodology is exemplified by the enantioselective total synthesis of (+)-(2S,3S)-CP-99,994.
- Sultane, Prakash R.,Bhat, Ramakrishna G.
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p. 11349 - 11354
(2013/02/23)
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- α-Helix nucleation constant in copolypeptides of alanine and ornithine or lysine
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The α-helix is one of a small number of fundamental structural motifs of the peptide backbone that are abundant in native proteins. The forces responsible for its stability have attracted a great deal of theoretical and experimental attention. Helix formation can naturally be considered in terms of two processes, initial nucleation of a helix from a sequence of disordered residues and propagation or growth of helical structure from such a nucleus. Data from a variety of short peptide and polypeptide models have revealed more details about the propagation of helix structure than about helix nucleation. To investigate helix nucleation, we have synthesized two series of high molecular weight polypeptides containing differing ratios of alanine and one of the basic side chains, ornithine or lysine; poly L-alanine is insoluble in water. The CD signals of these copolymers have been analyzed by a program that evaluates the helix content in terms of the experimental chain-length distribution and composition, with the helix nucleation constant (σ value) and the propagation constants (s values) for the amino acids involved. Fitting the CD data allows the determination of the propagation constants for Orn (s = 0.45) and Lys (s = 0.8) in addition to that of the helix nucleation constant once the s value for Ala is specified. The value of σ is sensitive to the dependence of the CD signal on helix length; using the Yang equation, [θ]222 = -41000(n - x)/n, with x = 2.5, the nucleation constant value is σ = 0.004 ± 0.002 at 4 °C in the presence of 1 M salt. This value is consistent with earlier estimates based on analysis of the helix-coil transition in poly(Lys), poly(Glu), and shorter Ala-rich peptides. However, if x is taken to be zero, the resulting σ value is 0.02, considerably larger than the above estimates.
- Yang, Jianxin,Zhao, Kang,Gong, Youxiang,Vologodskii, Alexander,Kallenbach, Neville R.
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p. 10646 - 10652
(2007/10/03)
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- Differentiation Among the Four Diastereomers of Benzyloxycarbonyl-protected γ-Hydroxyornithine in Negative-ion Fast Atom Bombardment Mass Spectrometry
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Discrimination among the four γ-hydroxyornithine diastereomers was studied by fast atom bombardment mass spectrometry (FABMS).It is impossible to distinguish among the four diastereomers of this amino acid by positive- and negative-ion FAB and collisionally activated dissociation MS, but benzyloxycarbonyl group protection of the α- and δ-amino groups in γ-hydroxyornithine allows differentiation among the diastereomers in negative-ion FABMS.The negative-ion mass spectra of benzyloxycarbonyl-protected γ-hydroxyornithine diastereomers showed differences among the abundances of the molecule ion (-), the dehydrated ion (-) due to the loss of the γ-hydroxyl group and the fragment ions formed from both (-) and (-) ions.On the other hand, no difference was found between the fragmentations of the benzyloxycarbonyl-protected enantiomers of ornithine in negative-ion FABMS.These results indicate that the orientation of the γ-hydroxyl group and the existence of two benzene rings in the benzyloxycarbonyl group are important factors which are responsible for the fragmentations of the four benzyloxycarbonyl-protected γ-hydroxyornithine diastereomers in negative-ion FABMS.These studies also showed that the negative-ion FABMS for benzyloxycarbonyl-protected γ-hydroxyornithine diastereomers is a useful method for determining the configuration of each diastereomer of γ-hydroxyornithine.
- Tsunematsu, Hideaki,Isobe, Ryuichi,Mizusaki, Koichi,Makisumi, Satoru,Yamamoto, Magobei
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p. 260 - 265
(2007/10/02)
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- Asymmetric Syntheses of the Naturally Ocurring β-Amino Acids, β-Lysine, β-Leucine and β-Phenyl-β-alanine via Nitrone Cycloaddition
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A general asymmetric synthesis of β-amino acids is based on the dipolar cycloaddition of nitrones 7 (R* chiral) with vinyl acetate 8a, ketene acetals 8b or α-chloroacrylonitrile 8c.The cycloadducts 9 are converted either directly (9b) or via the isoxazolidones 10 (9a, 9c) into the free β-amino acids 11.Diastereoselectivity at C-3 in the adducts 9 ranges between 2:1 and 11:1.The natural β-amino acids, β-lysine, β-leucine and β-phenyl-β-alanine, have been prepared in this way.
- Keirs, David,Moffat, David,Overton, Karl,Tomanek, Richard
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p. 1041 - 1051
(2007/10/02)
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