- Synthesis of highly functionalized oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups
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α-Helix proteomimetics represent an emerging class of ligands that can be used to inhibit an array of helix mediated protein-protein interactions. Within this class of inhibitor, aromatic oligobenzamide foldamers have been widely and successfully used. This manuscript describes alternative syntheses of these compounds that can be used to access mimetics that are challenging to synthesize using previously described methodologies, permitting access to compounds functionalized with multiple sensitive side chains and accelerated library assembly through late stage derivatisation.
- Burslem, George M.,Kyle, Hannah F.,Prabhakaran, Panchami,Breeze, Alexander L.,Edwards, Thomas A.,Warriner, Stuart L.,Nelson, Adam,Wilson, Andrew J.
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- Oligocarbonate molecular transporters: Oligomerization-based syntheses and cell-penetrating studies
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(Chemical Equation Presented) A new family of guanidinium-rich molecular transporters featuring a novel oligocarbonate backbone with 1,7-side chain spacing is described. Conjugates can be rapidly assembled irrespective of length in a one-step oligomerization strategy that can proceed with concomitant introduction of probes (or by analogy drugs). The new transporters exhibit excellent cellular entry as determined by flow cytometry and fluorescence microscopy, and the functionality of their drug delivery capabilities was confirmed by the delivery of the bioluminescent small molecule probe luciferin and turnover by its intracellular target enzyme.
- Cooley, Christina B.,Trantow, Brian M.,Nederberg, Fredrik,Kiesewetter, Matthew K.,Hedrick, James L.,Waymouth, Robert M.,Wender, Paul A.
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- Conjugation of Indoles to Antibodies through a Novel Self-Immolating Linker
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A novel strategy to attach indole-containing payloads to antibodies through a carbamate moiety and a self-immolating, disulfide-based linker is described. This new strategy was employed to connect a selective estrogen receptor down-regulator (SERD) to various antibodies in a site-selective manner. The resulting conjugates displayed potent, antigen-dependent down-regulation of estrogen receptor levels in MCF7-neo/HER2 and MCF7-hB7H4 cells. They also exhibited similar antigen-dependent modulation of the estrogen receptor in tumors when administered intravenously to mice bearing MCF7-neo/HER2 tumor xenografts. The indole-carbamate moiety present in the new linker was stable in whole blood from various species and also exhibited good in vivo stability properties in mice.
- Dragovich, Peter S.,Blake, Robert A.,Chen, Chunjiao,Chen, Jinhua,Chuh, Josefa,den Besten, Willem,Fan, Fang,Fourie, Aimee,Hartman, Steven J.,He, Changrong,He, Jintang,Ingalla, Ellen Rei,Kozak, Katherine R.,Leong, Steven R.,Lu, Jiawei,Ma, Yong,Meng, Lingyao,Nannini, Michelle,Oeh, Jason,Ohri, Rachana,Lewis Phillips, Gail,Pillow, Thomas H.,Rowntree, Rebecca K.,Sampath, Deepak,Vandlen, Richard,Vollmar, Breanna,Wai, John,Wertz, Ingrid E.,Xu, Keyang,Xu, Zijin,Zhang, Donglu
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- Tuning the molecular weight of polymeric amphiphiles as a tool to access micelles with a wide range of enzymatic degradation rates
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Enyzme-responsive polymeric assemblies hold great potential for biomedical applications due to the over-expression of disease-associated enzymes, which can be utilized to activate such systems only in afflicted tissues. Herein we demonstrate that the overall molecular weight of polymeric amphiphiles, which have the same hydrophilic/hydrophobic ratio, can be tuned to create polymeric micelles with an extreme range of degradation rates. This approach expands the available set of molecular parameters that can be adjusted to tune the degradation rate of polymeric assemblies, paving new possibilities for rational design of polymeric systems with controlled degradation rates.
- Slor, Gadi,Papo, Nitsan,Hananel, Uri,Amir, Roey J.
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supporting information
p. 6875 - 6878
(2018/06/26)
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- METHODS FOR PREPARING ANTIBODY DRUG CONJUGATES
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The subject matter described herein is directed to methods of preparing certain antibody-drug conjugates (ADCs) wherein the antibody is linked to the drug through a linker, wherein the drug contains a heteroaryl group having a secondary nitrogen, and the linker is attached to the drug via the secondary nitrogen. The resulting conjugates are useful in treating various diseases and conditions.
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Page/Page column 38; 125; 126
(2018/04/21)
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- Templated Chromophore Assembly by Dynamic Covalent Bonds
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Through the simultaneous use of three orthogonal dynamic covalent reactions, namely disulfide, boronate, and acyl hydrazone formation, we conceived a facile and versatile protocol to spatially organize tailored chromophores, which absorb in the blue, red, and yellow regions, on a preprogrammed α-helix peptide. This approach allowed the assembly of the dyes in the desired ratio and spacing, as dictated by both the relative positioning and distribution of the recognition units on the peptide scaffold. Steady-state UV/Vis absorption and emission studies suggest an energy transfer from the yellow and red donors to the blue acceptor. A molecular dynamics simulation supports the experimental findings that the helical structure is maintained after the assembly and the three dyes are confined in defined conformational spaces.
- Rocard, Lou,Berezin, Andrey,De Leo, Federica,Bonifazi, Davide
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supporting information
p. 15739 - 15743
(2016/01/29)
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- NOVEL CELL-PERMEABLE SUCCINATE COMPOUNDS
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The present invention provides novel cell-permeable succinates and cell permeable precursors of succinate aimed at increasing ATP-production in mitochondria. The main part of ATP produced and utilized in the eukaryotic cell originates from mitochondrial oxidative phosphorylation, a process to which high-energy electrons are provided by the Kreb's cycle. Not all Kreb's cycle intermediates are readily permeable to the cellular membrane, one of them being succinate. The provision of the novel cell permeable succinates is envisaged to allow passage over the cellular membrane and thus the cell permeable succinates can be used to enhance mitochondrial ATP-output.
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Page/Page column 71
(2015/11/03)
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- COMPOUND FOR USE IN PEPTIDE SYNTHESIS
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The present invention generally relates to processes and methods of peptide and protein synthesis. The present invention also relates to specific compounds for use in such processes and methods. It is shown herein that peptides with a C-terminal tertiary N,N-bis(2-mercaptoethyl)-amide (BMEA) undergo N-to-S acyl transfer at weakly acidic pH to form a transient thioester which can be captured for direct ligation with a cysteinyl peptide. These C-terminal BMEA peptides are easily prepared with standard Fmoc solid-phase synthesis protocols, thus giving a very convenient access to the thioester components for native chemical ligation.
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Page/Page column 24
(2012/02/01)
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- Tandem thiol switch synthesis of peptide thioesters via N-S acyl shift on thiazolidine
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An efficient "thiol switch" approach for the synthesis of peptide thioesters via an acid-catalyzed N-S acyl shift and a thioester exchange reaction in tandem with concurrent removal of protecting groups is described. This method employs novel 2-(thiomethyl)thiazolidine (TMT)-anchored resins and is fully compatible with Fmoc chemistry.
- Sharma, Rohit K.,Tam, James P.
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supporting information; experimental part
p. 5176 - 5179
(2011/12/15)
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- Peptide ligation assisted by an auxiliary attached to amidyl nitrogen
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New thiol-containing auxiliaries were developed for peptide ligation. They were placed at the amidyl N-atom in the second amino acid residue of a peptide fragment. With the new auxiliaries, peptide ligation could be conducted at non-Cys and non-Gly sites. Compared to other recently developed auxiliaries, an important feature of the present design was that the new auxiliaries were generally applicable and readily removable.
- Li, Juan,Cui, Hong-Kui,Liu, Lei
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scheme or table
p. 1793 - 1796
(2010/06/13)
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- Label-free detection of protein-protein interactions on biochips
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(Figure Presented) Eliminating the middle-man: The combination of MALDI-TOF mass spectrometry and self-assembled monolayers on gold (SAMDI) offers a new detection method for protein-ligand (shown) and protein-protein interactions. Proteins and protein complexes are selectively bound to biochips and then directly analyzed by MALDI-TOF MS without the need for labels.
- Yeo, Woon-Seok,Min, Dal-Hee,Hsieh, Robert W.,Greene, Geoffrey L.,Mrksich, Milan
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p. 5480 - 5483
(2007/10/03)
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- Synthesis of polylactide with thiol end groups
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Four synthetic routes to poly(L-lactide) with thiol end groups based on ring-opening polymerization of L-lactide (LA) catalysed with tin(II) 2-ethylhexanoate (Sn(Oct)2) are reported. The following alcohols were used as co-initiators of polymerization: 2-sulfanylethan-1-ol, 2-[(2,4-dinitrophenyl)sulfanyl]ethan-1-ol, 2-(tritylsulfanyl)ethan-1-ol and allyl alcohol. End groups introduced into polymers by co-initiators were transformed to thiol groups by a subsequent modification reaction. The efficiencies of the used synthetic methods were evaluated and discussed. The best results were obtained with co-initiator 2-(tritylsulfanyl)ethan-1-ol.
- Popelka, Stepan,Rypacek, Frantisek
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p. 1131 - 1140
(2007/10/03)
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- Reductive demercuration in deprotection of trityl thioethers, trityl amines, and trityl ethers
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A room-temperature deprotection method of trityl amines, -ethers, and -thioethers is presented, based on coupling of metal acid catalysis (HgX2, with X- = Cl- or OAc-) and sodium borohydride reduction. The results of its application to monotritylated compounds (ethanethiol, ethanol, and piperidine) and to mono- and ditritylated 1,2-bifunctional compounds (mercaptoethanol, aminoethanethiol, and ethanolamine) are compared with those obtained with early methods based on the use of strong Bronsted acids (pure TFA and MeCN solutions of HCl). Trityl thioethers of simple thiols and amino and hydroxy thiols are promptly cleaved by reductive detritylation, and one-pot procedures can be employed to produce free thiols. In contrast, dilution with water of these same compounds in solutions of strong Bronsted acids leaves them unaffected. O-Tr and N-Tr bonds are broken by this latter treatment. However, trityl ethers are rapidly cleaved by even dilute HCl solutions, while cleaving of trityl amines is modulated by HCl concentration. Addition of NaBH4 to solutions of monofunctional trityl ethers in HgCl2/MeCN leads to complete deprotection. Monofunctional trityl amines are partially deprotected only if the complexation reaction is allowed to reach equilibrium. Combination of H+- with HgX+-catalyzed detritylation methods allows selective deprotection of pertritylated amino and hydroxy thiols. The results appear to be due to the strong difference in the affinity of the donor atoms present in the pertritylated substrates for H+ and HgX+. Catalysis based on Bronsted acids leads to cleaving of the N- and O-trityl bonds with recovering of the S-trityl group; that based on mercury salts allows recovering of N- and O-trityl groups with deprotection of the -SH function. Selectivity in deprotection of pertritylated amino alcohols seems to be severely hampered by similarity in the affinity of N- and O-atoms for H+ and HgX+, and, taking advantage of the lower HgX+-complexation rate of the N-trityl with respect to the O-trityl group, only preservation of the N-trityl bond has been achieved.
- Maltese
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p. 7615 - 7625
(2007/10/03)
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- A one-pot multistep approach to α-azido-phosphonate and phosphonothioate diesters: Key intermediates in the synthesis of haptens for the generation of antibody ligases
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A four-step, one-pot synthesis of mixed α-azido-phosphonates and phosphonothioates 12a-d is described. This chemistry has provided a facile route to haptens 6a-b and 7 that have been employed for the elicitation of antibody ligases. Five hapten-specific antibodies have been identified as modest catalysts of a model peptide ligation reaction between thioester 1b and thiol 2 to give the amide product 5. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Harwig, Curtis W.,Hoffman, Timothy Z.,Wentworth, Anita D.,Janda, Kim D.
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p. 915 - 918
(2007/10/03)
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- Carbapenem antibiotics
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Disclosed are novel carbapenem derivatives characterized by a 2-substituent of the formula STR1 in which A represents cyclopentylene, cyclohexylene or C2 -C6 alkylene optionally substituted by one or more C1 -C4 alkyl groups and STR2 represents a quaternized nitrogen-containing aromatic heterocycle. Such derivatives are useful as potent antibacterial agents. Also disclosed are processes for the preparation of such derivatives and novel intermediates utilized in these processes.
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