- A New Synthesis of 3-Fluorophthalic Anhydride
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A high yield, one pot synthesis of 3-fluorophthalic anhydride from the easily accessible 3-nitrophthaloyl dichloride is described.The mechanistic implications of the fluorodenitration process are also discussed.
- Passudetti, Margherita,Prato, Maurizio,Quintily, Ugo,Scorrano, Gianfranco
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Read Online
- Design, synthesis, and biological evaluation of proteolysis targeting chimeras (PRoTACS) for the dual degradation of IGF-1R and SrC
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A focused PROTAC library was developed to degrade both IGF-1R and Src proteins, which are associated with various cancers. PROTACs with IGF-1R and Src degradation potentials were synthesized by tethering different inhibitor warhead units and the E3 ligase (CRBN) recruiting-pomalidomide with various linkers. The designed PROTACs 12a–b inhibited the proliferation and migration of MCF7 and A549 cancer cells with low micromolar potency (1–5 μM) in various cellular assays.
- Lee, Jeeyeon,Lee, Na Keum,Manda, Sudhakar,Oh, Dong-Chan
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supporting information
(2020/04/29)
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- Simultaneous Inhibition of SIRT2 Deacetylase and Defatty-Acylase Activities via a PROTAC Strategy
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As a member of the sirtuin family of enzymes, SIRT2 promotes tumor growth and regulates various biological pathways through lysine deacetylation and defatty-acylation. In the past few years, many SIRT2-selective small molecule inhibitors have been developed, but none have demonstrated simultaneous inhibition of both SIRT2 activities in cells. To further scrutinize the physiological importance and significance of SIRT2 deacetylase and defatty-acylase activities, small molecules that can selectively inhibit both activities of SIRT2 in living cells are needed. Here, we have applied the Proteolysis Targeting Chimera (PROTAC) strategy and synthesized a new SIRT2 inhibitor (TM-P4-Thal) to degrade SIRT2 selectively, which led to simultaneous inhibition of its deacetylase and defatty-acylase activities in living cells. Additionally, this compound exemplifies the advantage of the PROTAC strategy that allows complete eradication of an enzyme and its activity in biological settings.
- Hong, Jun Young,Jing, Hui,Price, Ian Robert,Cao, Ji,Bai, Jessica Jingyi,Lin, Hening
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p. 2305 - 2311
(2020/12/17)
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- Protein degradation targeting chimeric compound, application and preparation method thereof
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The invention provides a novel protein degradation targeting chimeric compound, application and a preparation method thereof. The protein degradation targeting chimeric compound is 2-(2, 6-dioxo-piperidine-3-yl)-4-fluoro-isoindole-1, 3-dione. The preparation method comprises the following steps: S1, carrying out a fluorination reaction on 3-chlorophthalic anhydride to generate 3-fluorophthalic anhydride; and step S2, carrying out a condensation reaction on the 3-fluorophthalic anhydride and 3-amino-2, 6-piperidinedione hydrochloride so as to obtain the 2-(2, 6-dioxo-piperidine-3-yl)-4-fluoro-isoindole-1, 3-dione. According to the protein degradation targeting chimeric body, the compound is moderate in molecular size, good in fluorine leaving performance, small in molecular weight and stable in performance, target protein and E3 ubiquitin enzyme can be effectively close to each other, and the protein degradation targeting chimeric body can be effectively used for preparing targeting drugs. And the preparation method is simple and convenient, less in three wastes and low in raw material price, so that the preparation cost is low, and the method is suitable for industrial large-scaleproduction.
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Paragraph 0058-0060; 0065-0067; 0072-0074; 0079-0081; 0086
(2020/07/21)
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- IMIDE-BASED MODULATORS OF PROTEOLYSIS AND METHODS OF USE
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The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Page/Page column 158; 161; 162
(2019/08/12)
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- SMALL MOLECULES
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Compounds having the general structure A - L - B are presented wherein A and B are independently an E3 ubiquitin ligase protein binding ligand compound of formula 1A or 1 B. Pharmaceutical compositions comprising these compounds and methods of use are also presented.
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Page/Page column 17
(2018/11/10)
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- RAF-DEGRADING CONJUGATE COMPOUNDS
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The present disclosure provides, inter alia, RAF-Degrading Conjugate Compounds that are useful in the treatment of cancer and other RAF related diseases. Also provided are, pharmaceutical compositions, methods of treatment, and kits comprising a RAF- Degrading Conjugate Compound.
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Paragraph 0209; 0246
(2018/11/22)
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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 0016; 0023; 0024; 0025
(2018/10/19)
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- IMIDE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Page/Page column 108
(2015/11/09)
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- Dual fluorescent N-Aryl-2,3-naphthalimides: Applications in ratiometric DNA detection and white organic light-emitting devices
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A ten element matrix of 5- and 6-substituted-(2,3)-naphthalimides was prepared for the appropriate placement of substituents necessary to promote dual fluorescence (DF). As prescribed by our balanced seesaw photophysical model this matrix yielded nine new DF dyes out of a possible ten compounds. From this set of nine DF dyes, 4-fluoronaphthalic amide (37) was selected as a probe for ratiometric detection of DNA and demonstration of panchromatic emission.
- Nandhikonda, Premchendar,Heagy, Michael D.
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supporting information; experimental part
p. 4796 - 4799
(2011/01/03)
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- Sarcosine based indandione hGlyT1 inhibitors
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A series of sarcosine based indandione hGlyT1 inhibitors has been developed. Optimization of substitution around the indandione and sarcosine moieties has led to highly potent inhibitors at hGlyT1, which show selectivity over a number of other receptors.
- Thomson, Christopher G.,Duncan, Karen,Fletcher, Stephen R.,Huscroft, Ian T.,Pillai, Gopalan,Raubo, Piotr,Smith, Alison J.,Stead, Darren
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p. 1388 - 1391
(2007/10/03)
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- Auxin transport inhibitor compounds
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The invention relates to the compounds of Formula XA STR1 wherein X and Y represent independently hydrogen, fluorine or chlorine, Z1 is fluorine or chlorine and M is hydrogen or a salt forming moiety and Z2 ' is chlorine or fluorine; and the corresponding herbicidal composition and methods of use. The compounds of the invention are useful as auxin transport inhibitors (i.e. useful as herbicides) and useful as potentiators or enhancers of herbicides.
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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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- Potentiating herbicidal compositions
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The use of certain herbicidal semicarbazones and salts thereof as potentiators or enhancers of herbicidal and/or plant growth regulating substances.
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- Compositions containing semicarbazones
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The use of certain herbicidal semicarbazones and salts thereof as potentiators or enhancers of herbicidal and/or plant growth regulating substances.
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- Compositions containing semicarbazones
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The use of certain herbicidal semicarbazones and salts thereof as potentiators or enhancers of herbicidal and/or plant growth regulating substances.
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- Novel compositions containing an auxin transport inhibitor and another herbicide
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The use of certain herbicidal semicarbazones and salts thereof as potentiators or enhancers of herbicidal and/or plant growth regulating substances.
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- Nuclear spin-spin coupling via nonbonded interactions. 6. F-F coupling through an Intervening Phenyl Group
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Evidence is presented for a novel type of "through-space" nuclear spin-spin coupling involving two fluorine atoms that are intramolecularly crowded against opposite sides of an intervening group X. The first example of this new phenomenon of F-X-F coupling involves the interaction of F-1 and F-8 through the intervening C-9 phenyl group in 1,5,8-trifluoro-9,10-diphenylanthracene (1) with a coupling constant of J1,8 = 6.4 Hz. The "through-bond" component of this coupling is estimated as 1.1 Hz on the basis that J1,8 = 1.1 Hz for 1,5,8-trifluoroanthracene (2). The fact that the magnitude of J1,8 is significantly larger in 1 than in 2 is attributed to a novel coupling mechanism in 1 involving overlap interactions between the in-plane 2p lone-pair orbitals on the two fluorine atoms and the nearly isoenergetic lowest energy π molecular orbital on the C-9 phenyl group. To rationalize the small value of J1,8 = 0.8 Hz for 1,5,8-trifluoroanthraquinone (3), it is argued that the in-plane 2p lone-pair orbital on the oxygen atom of the C-9 carbonyl group, which would be the relevant intervening orbital for F-X-F coupling, is much higher in energy than the fluorine in-plane 2p lone-pair orbitals, and this energy mismatch allows only a weak interaction between these two types of orbital.
- Mallory, Frank B.,Mallory, Clelia W.,Baker, Mary B.
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p. 2577 - 2581
(2007/10/02)
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- Preparation of fluoroaromatic compounds in dispersion of potassium fluoride
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An improved process is disclosed for preparing fluoroaromatic compounds (such as fluoronitrobenzene compounds) wherein chloroaromatic compounds (such as chloronitrobenzene compounds) are reacted with potassium fluoride in a solvent dispersion thereof prepared from a mixture including the solvent, the fluoride, methanol and an aromatic compound.
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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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- AN IMPROVED PROCEDURE FOR THE SYNTHESIS OF 3-FLUOROANTHRANILIC ACID
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3-Ffluoroanthranilic acid is derived in four steps from 3-nitrophthalic acid in 53percent overall yield.
- Milner, David J.
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p. 485 - 490
(2007/10/02)
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- Method for the preparation of fluoroaniline
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A process for the preparation of fluoroaniline compounds comprises the steps of (A) reacting an ammonium fluorophthalamate or a fluorophthalamic acid of the formula STR1 where n is 1 or 2 with an alkali or an alkali earth metal hypochlorite to form the corresponding fluoroanthranilic acid; and (B) decarboxylating the fluoroanthranilic acid by reaction with a mineral acid to form the corresponding fluoroaniline of the formula STR2 where n is as previously defined.
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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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