63126-47-6Relevant academic research and scientific papers
Synthesis of 7-halogenated isatin sulfonamides: Nonradioactive counterparts of caspase-3/-7 inhibitor-based potential radiopharmaceuticals for molecular imaging of apoptosis
Limpachayaporn, Panupun,Wagner, Stefan,Kopka, Klaus,Schober, Otmar,Sch?fers, Michael,Haufe, Günter
, p. 9383 - 9395 (2014)
N-Alkylated (S)-7-halogen-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins were developed as a new group of nonradioactive reference compounds for future radiotracers. Inhibitor potency studies of these compounds suggest that the binding pockets readily accommodate both the 7-halogen substituents and aliphatic side chains (methyl to n-butyl) as well as some ω-fluorinated analogues (3-fluoropropyl and 4-fluorobutyl) at the isatin nitrogen. Indeed, compared to the halogen free parent compounds, some 7-halogenated derivatives exhibited slightly improved inhibitory potencies with IC50 values up to 2.6 nM (caspase-3) and 3.3 nM (caspase-7), respectively. Moreover, the 7-position of isatin, a potential cytochrome P450 hydroxylation site, was substituted by I, Br, Cl, and F to potentially enhance the metabolic stability of isatin sulfonamides. As an example, the radiotracer [18F]39 that was produced by 19F/18F isotope exchange was shown to be stable in human blood serum after incubation at 37 °C for at least 90 min.
Concise Total Synthesis of Peyssonnoside A
Chesnokov, Gleb A.,Gademann, Karl
supporting information, p. 14083 - 14088 (2021/09/13)
Peyssonnoside A is a marine-derived sulfated diterpenoid glucoside with a unique 5/6/3/6 tetracyclic skeleton with a highly substituted cyclopropane ring deeply embedded into the structure. Herein, we report the first total synthesis of this natural product in a concise, efficient, scalable, and highly diastereoselective fashion. The aglucone peyssonnosol was synthesized in 21% overall yield after 15 steps, featuring a Simmons-Smith cyclopropanation and Mukaiyama hydration, fully controlled by the spatial structure of the substrates.
Orthogonal Catalysis for an Enantioselective Domino Inverse-Electron Demand Diels?Alder/Substitution Reaction
Ahles, Sebastian,Beeck, Sebastian,Wegner, Hermann A.
, (2021/12/09)
An enantioselective domino process for the synthesis of substituted 1,2-dihydronaphthalenes has been developed by the combination of chiral amines and a bidentate Lewis acid in an orthogonal catalysis. This new method is based on an inverse electron-demand Diels?Alder and a subsequent group exchange reaction. An enamine is generated in situ from an aldehyde and a chiral secondary amine catalyst that reacts with phthalazine, activated by the coordination to a bidentate Lewis acid catalyst. The absolute configuration of the product is controlled by chiral information provided by the amine. The formed ortho-quinodimethane intermediate is then transformed via a group exchange reaction with thiols. The new method shows a broad scope and tolerates a wide range of functional groups with enantiomeric ratios up to 91 : 9. All-in-all, this enantioselective synthesis tool provides an easy access to complex 1,2-dihydronaphthalenes starting from readily available phthalazine, aldehydes and thiols in a combinatorial way.
Basicities and Nucleophilicities of Pyrrolidines and Imidazolidinones Used as Organocatalysts
An, Feng,Maji, Biplab,Min, Elizabeth,Ofial, Armin R.,Mayr, Herbert
supporting information, p. 1526 - 1547 (2020/02/04)
The Br?nsted basicities pKaH (i.e., pKa of the conjugate acids) of 32 pyrrolidines and imidazolidinones, commonly used in organocatalytic reactions, have been determined photometrically in acetonitrile solution using CH acids as indicators. Most investigated pyrrolidines have basicities in the range 16 aH aH aH 12.6) and the 2-imidazoliummethyl-substituted pyrrolidine A21 (pKaH 11.1) are outside the typical range for pyrrolidines with basicities comparable to those of imidazolidinones. Kinetics of the reactions of these 32 organocatalysts with benzhydrylium ions (Ar2CH+) and structurally related quinone methides, common reference electrophiles for quantifying nucleophilic reactivities, have been measured photometrically. Most reactions followed second-order kinetics, first order in amine and first order in electrophile. More complex kinetics were observed for the reactions of imidazolidinones and several pyrrolidines carrying bulky 2-substituents, due to reversibility of the initial attack of the amines at the electrophiles followed by rate-determining deprotonation of the intermediate ammonium ions. In the presence of 2,4,6-collidine or 2,6-di-tert-butyl-4-methyl-pyridine, the deprotonation of the initial adducts became faster, which allowed the rate of the attack of the amines at the electrophiles to be determined. The resulting second-order rate constants k2 followed the correlation log?k2(20 °C) = sN(N + E), where electrophiles are characterized by one parameter (E) and nucleophiles are characterized by the two solvent-dependent parameters N and sN. In this way, the organocatalysts A1-A32 were integrated in our comprehensive nucleophilicity scale, which compares n-, -, and σ-nucleophiles. The nucleophilic reactivities of the title compounds correlate only poorly with their Br?nsted basicities.
A New Class of C2-Symmetric Chiral Cyclopentadienyl Ligand Derived from Ferrocene Scaffold: Design, Synthesis and Application
Liang, Hao,Vasamsetty, Laxmaiah,Li, Teng,Jiang, Jijun,Pang, Xingying,Wang, Jun
supporting information, p. 14546 - 14550 (2020/10/15)
A new class of C2-symmetric, chiral cyclopentadienyl ligand based on planar chiral ferrocene backbone was developed. A series of its corresponding rhodium(I), iridium(I), and ruthenium(II) complexes were prepared as well. In addition, the rhodium(I) complexes were evaluated in the asymmetric catalytic intramolecular amidoarylation of olefin-tethered benzamides via C?H activation.
Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis
Waldmann, Christopher M.,Hermann, Sven,Faust, Andreas,Riemann, Burkhard,Schober, Otmar,Sch?fers, Michael,Haufe, Günter,Kopka, Klaus
supporting information, p. 5734 - 5739 (2015/11/11)
The programmed type I cell death, defined as apoptosis, is induced by complex regulated signaling pathways that trigger the intracellular activation of executioner caspases-3, -6 and -7. Once activated, these enzymes initiate cellular death through cleavage of proteins which are responsible for DNA repair, signaling and cell maintenance. Several radiofluorinated inhibitors of caspases-3 and -7, comprising a moderate lipophilic 5-(1-pyrrolidinylsulfonyl)isatin lead structure, are currently being investigated for imaging apoptosis in vivo by us and others. The purpose of this study was to increase the intrinsic hydrophilicity of the aforementioned lead structure to alter the pharmacokinetic behavior of the resulting caspase-3 and -7 targeted radiotracer. Therefore, fluorinated and non-fluorinated derivatives of 5-(1-pyrrolidinylsulfonyl)-7-azaisatin were synthesized and tested for their inhibitory properties against recombinant caspases-3 and -7. Fluorine-18 has been introduced by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) of an alkyne precursor with 2-[18F]fluoroethylazide. Using dynamic micro-PET biodistribution studies in vivo the kinetic behavior of one promising PET-compatible 5-pyrrolidinylsulfonyl 7-azaisatin derivative has been compared to a previously described isatin based radiotracer.
Stereoselective alkylations of chiral nitro imine and nitro hydrazone dianions. Synthesis of enantiomerically enriched 3-substituted 1-nitrocyclohexenes
Denmark, Scott E.,Ares, Jeffrey J.
scheme or table, p. 9647 - 9656 (2009/04/11)
(Chemical Equation Presented) Dianions of chiral nitro imines (generated by a combination of LDA and s-BuLi) underwent diastereoselective alkylation with methyl, butyl, isopropyl, allyl, and methallyl iodides. In contrast to the behavior of simple metalloenamines, the most selective auxiliary contained no coordinating groups but did possess a large steric difference between the two substituents. The yield and selectivity of the alkylations were improved by the addition of HMPA or DMPU. The use of (S)-1-naphthylethylamine as the auxiliary afforded the R absolute configuration of the alkylation products. This stereochemical outcome could be rationalized by simple steric approach controlled alkylation in a conformationally fixed, internally coordinated dianion. A SAMP nitro hydrazone gave poorer yields and selectivities.
5-Pyrrolidinylsulfonyl isatins as a potential tool for the molecular imaging of caspases in apoptosis
Kopka, Klaus,Faust, Andreas,Keul, Petra,Wagner, Stefan,Breyholz, Hans-J?rg,H?ltke, Carsten,Schober, Otmar,Sch?fers, Michael,Levkau, Bodo
, p. 6704 - 6715 (2007/10/03)
Caspases are the unique enzymes responsible for the execution of the cell death program and may represent an exclusive target for the specific molecular imaging of apoptosis in vivo. 5-Pyrrolidinylsulfonyl isatins represent potent nonpeptidyl caspase inhibitors that may be suitable for the development of caspase binding radioligands (CBRs). (S)-5-[1-(2-Methoxymethylpyrrolidinyl) sulfonyl]isatin (7) served as a lead compound for modification of its N-1-position. Corresponding pairs of N-1-substituted 2-methoxymethyl- and 2-phenoxymethylpyrrolidinyl derivatives were examined in vitro by biochemical caspase inhibition assays. All target compounds possess high in vitro caspase inhibition potencies in the nanomolar to subnanomolar range for caspase-3 (Ki = 0.2-56.1 nM). As shown for compound (S)-1-(4-(2-fluoroethoxy) benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (35), the class of N-1-substituted 5-pyrrolidinylsulfonyl isatins competitively inhibits caspase-3. All caspase inhibitors show selectivity for the effector caspases-3 and -7 in vitro. The 2-methoxymethylpyrrolidinyl versions of the isatins appear to possess superior caspase inhibition potencies in cellular apoptosis inhibition assays compared with the 2-phenoxymethylpyrrolidinyl inhibitors.
HIV protease inhibitors
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Page/Page column 35, (2010/02/11)
Combinatorial libraries of HIV and FIV protease inhibitors are characterized by alpha-keto amide or hydroxyethylamine core structures flanked by on one side by substituted pyrrolidines, piperidines, or azasugars and on the other side by phenylalanine, tyrosine, or substituted tyrosines. The libraries are synthesized via a one step coupling reaction. Highly efficacious drug candidates are identified by screening the libraries for binding and inhibitory activity against both HIV and FIV protease. Drug candidates displaying clinically useful activity against both HIV and FIV protease are identified as being potentially resistive against a loss of inhibitory activity due to development of resistant strains of HIV.
Photochemical and thermal isomerization processes of a chiral auxiliary based donor-acceptor substituted chiroptical molecular switch: Convergent synthesis, improved resolution and switching properties
Van Delden, Richard A.,Hurenkamp, Johannes H.,Feringa, Ben L.
, p. 2845 - 2853 (2007/10/03)
A new type of chiroptical molecular switch is presented where irradiation employing different wavelengths of light induces a reversible helix inversion of a sterically overcrowded alkene bearing a second chiral entity in the form of a stereogenic center present in a pyrrolidine unit. The additional stereogenic center in the chiral auxiliary group has a distinct influence on the switching selectivity of this system and greatly facilitates the resolution of the different diastereoisomers, which is a considerable improvement compared with previously reported systems. In addition, the pyrrolidine stereogenic center causes small energetic differences between the various states of the switch system resulting in a small but significant directional preference in the helix inversion steps.
