- CYCLIC PEPTIDE ANALOGS OF MELANOCORTIN AND AMANITIN AND METHODS OF MAKING SUCH
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The invention described herein is based in part on the discovery of a protein/peptide crosslink, which introduces fluorescent properties, and which has been applied to synthesize analogues of melanocortin and amanitin as choice peptides to be explored in the context of isoindole peptides. Without limitation, it is expected that those trained in the art of peptide synthesis and stapling would appreciate the consequences of this invention such that other peptides of varied length can be similarly constrained by isoindole staples as featured herein.
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Paragraph 0114-0115; 0119
(2021/01/29)
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- Fluorescent Isoindole Crosslink (FlICk) Chemistry: A Rapid, User-friendly Stapling Reaction
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The stabilization of peptide secondary structure via stapling is a ubiquitous goal for creating new probes, imaging agents, and drugs. Inspired by indole-derived crosslinks found in natural peptide toxins, we employed ortho-phthalaldehydes to create isoindole staples, thus transforming inactive linear and monocyclic precursors into bioactive monocyclic and bicyclic products. Mild, metal-free conditions give an array of macrocyclic α-melanocyte-stimulating hormone (α-MSH) derivatives, of which several isoindole-stapled α-MSH analogues (Ki≈1 nm) are found to be as potent as α-MSH. Analogously, late-stage intra-annular isoindole stapling furnished a bicyclic peptide mimic of α-amanitin that is cytotoxic to CHO cells (IC50=70 μm). Given its user-friendliness, we have termed this approach FlICk (fluorescent isoindole crosslink) chemistry.
- Todorovic, Mihajlo,Schwab, Katerina D.,Zeisler, Jutta,Zhang, Chengcheng,Bénard, Francois,Perrin, David M.
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supporting information
p. 14120 - 14124
(2019/07/31)
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- A 3 - phthalic acid synthetic method (by machine translation)
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The invention discloses a 3 - phthalic acid synthetic method, the raw material 3 - nitrophthalic acid is dissolved by acetyl chloride solvent dehydration is carried out, after the dehydration by the fluorination potassium [...], then adding thionyl chloride to remove the by-product generated in the process of fluoro, purification to obtain the target compound 3 - phthalic acid. The invention relates to 3 - nitrophthalic acid as the synthetic 3 - phthalic acid raw material, the raw material is cheap, simple process, high yield; by adjusting the PH of the method, the product from the sulfolane solvent in very good separation out, solves the high boiling point of the solvent is not easily evaporated difficult; using acetyl chloride as dehydration solvent, not only replacing the drug control acetic anhydride, but also reduces the acetic anhydride in the dehydration process of the acetic acid by-product, mild reaction conditions after processing is simple and convenient. (by machine translation)
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Paragraph 0023; 0024; 0025; 0029
(2018/10/19)
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- A concise, regio and stereoselective route to fluorinated protoberberines via tandem addition-cyclisation reactions of phthalide anions with 3,4-dihydroisoquinolines
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A series of fluorinated protoberberines have been prepared by condensing fluorinated phthalide anions with 6,7-dimethoxydihydroisoquinoline. The spectroscopy and stereochemistry of the products are discussed and the stereochemical outcome of the reactions rationalised.
- Warrener, Ronald N.,Liu, Ligong,Russell, Richard A.
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p. 7485 - 7496
(2007/10/03)
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- On the regioselectivity of metal hydride reductions of 3-substituted phthalic anhydrides
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A problem of 3-methoxyphthalide reduction by metal hydrides was reinvestigated. Various effects controlling selectivity of reductions in 3-substituted phthalides were studied, and a qualitative interpretation of the results is now proposed. Methods for obtaining enhanced yields of one or the other lactonic product were developed.
- Soucy,Favreau,Kayser
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p. 129 - 134
(2007/10/02)
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- Regioselectivity of metal hydride reductions of unsymmetrically substituted cyclic anhydrides. Systems where "steric hindrance along the preferred reaction path" rationalization is not applicable
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Metal hydride reductions of planar cyclic anhydrides such as methylmaleic or 3-substituted phthalic anhydrides occur preferentially at the sterically more hindered carbonyl function.This regioselectivity cannot be rationalized in terms of "the most favourable pathway for non-perpendicular attack by a nucleophile" since both carbonyl groups present are equally accessible to non-perpendicular approach.A study which takes into account the alkaline cation and inductive, mesomeric, and steric effects has been conducted for the reduction of several conjugated and aromatic anhydrides.A qualitative interpretation for the regioselectivities observed in these reductions (as well as in reductions already reported in the literature) is suggested.An early transition state for the catalyzed versus late transition state for the non-catalyzed process is proposed.
- Kayser, Margaret M.,Morand, Peter
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p. 2484 - 2490
(2007/10/02)
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