Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors by catalytic C-H bond activation.
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Binding Sites↗
Biomedical subjects
Jonathan A Ellman
Publications and source records attributed to Jonathan A Ellman.
One-pot asymmetric synthesis of either diastereomer of tert-butanesulfinyl-protected amines from ketones.
A one-pot method for the asymmetric synthesis of tert-butanesulfinyl-protected amines is described. Condensation of aryl alkyl and dialkyl ketones with tert-butanesulfinamide followed by in situ reduction with the appropriate reagent provides either diastereomer of the sulfinamide products in good yields and with diastereomeric ratios of up to 99:1.
Amination↗
The total synthesis of tubulysin D.
The first total synthesis of tubulysin D is reported. The development and application of new tert-butanesulfinamide methods allowed for rapid syntheses of the tubuvaline and tubuphenylalanine fragments. Most significantly, a route was devised and implemented to introduce and carry forward the highly labile N,O-acetal functionality. Tubulysin D is the most active member of the tubulysin family, and the efficient synthetic route described herein will allow for the rapid syntheses of analogues to probe the biological activity of this important class of natural products.
Molecular Structure↗
Identification of selective, nonpeptidic nitrile inhibitors of cathepsin s using the substrate activity screening method.
The substrate activity screening method, a substrate-based fragment identification and optimization method for the development of enzyme inhibitors, was previously applied to cathepsin S to obtain low nanomolar 1,4-disubstituted-1,2,3-triazole-based aldehyde inhibitors (Wood, W. J. L.; Patterson, A. W.; Tsuruoka, H.; Jain, R. K.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 15521-15527). Replacement of the metabolically labile aldehyde pharmacophore with the nitrile pharmacophore provided inhibitors with moderate potency for cathepsin S. The inhibitors showed good selectivity over cathepsins B and L but no selectivity over cathepsin K. X-ray structures of two crystal forms (1.5 and 1.9 A) of a complex between cathepsin S and a triazole inhibitor incorporating a chloromethyl ketone pharmacophore guided the design of triazole substrates with increased cleavage efficiency and selectivity for cathepsin S over cathepsins B, L, and K. Conversion of select substrates to nitrile inhibitors yielded a low molecular weight (414 Da) and potent (15 nM) cathepsin S inhibitor that showed >1000-fold selectivity over cathepsins B, L, and K.
Amino Acid Sequence↗
Asymmetric synthesis of alpha,alpha-dibranched propargylamines by acetylide additions to N-tert-butanesulfinyl ketimines.
Addition of lithium acetylides prepared from 1-pentyne, phenylacetylene, and trimethylsilylacetylene to diverse N-tert-butanesulfinyl ketimines affords a range of alpha,alpha-dibranched propargyl sulfinamides in generally good yields (up to 87%) and with high diastereoselectivities (up to >99:1). Acidic cleavage of the tert-butanesulfinyl group provides the free alpha,alpha-dibranched propargylamines.
Chemistry, Organic↗
Functional phenotyping of human plasma using a 361-fluorogenic substrate biosensing microarray.
A microarray presenting glycerol nanodroplets of fluorogenic peptide substrates was used as a biosensor for the detection of multiple enzyme activities within human plasma. Using 10 different plasma proteases (kallikrein, factor XIIa, factor XIa, factor IXa, factor VIIa, factor Xa, thrombin, activated protein C, uPA and plasmin) and a 361-compound fluorogenic substrate library (Ac-Ala-P3-P2-Arg-coumarin for P = all amino acids except Cys), a database was created for deconvoluting the relative activity of each individual enzyme signal in human plasma treated with various activators (calcium, kaolin, or uPA). Three separate deconvolution protocols were tested: searching for "optimal" sensing substrate sequences for a set of 5 enzymes and using these substrates to detect protease signals in plasma; ranking the "optimal" sensing substrates for 10 proteases using local error minimization, resulting in a set of substrates which were bundled via weighted averaging into a super-pixel that had biosensing properties not obtainable by any individual fluorogenic substrate; and treating each 361-element map measured for each plasma preparation as a weighted sum of the 10 maps obtained for the 10 purified enzymes using a global error minimization. The similarity of the results from these latter two protocols indicated that a small subset of <90 substrates contained the majority of biochemical information. The results were consistent with the state of the coagulation cascade expected when treated with the given activators. This method may allow development of future biosensors using minimal and non-specific markers. These substrates can be applied to real-time diagnostic biosensing of complex protease mixtures.
Algorithms↗
Asymmetric synthesis of protected arylglycines by rhodium-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters.
A new method for the Rh(I)-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters has been developed for the asymmetric synthesis of arylglycine derivatives. This method provides high yields (61-90%) and diastereoselectivities (>98:2) for a variety of functionalized arylboronic acids. The N-sulfinyl arylglycine ester products are versatile intermediates for further transformations, including selective protecting group removal, conversion to beta-amino alcohols, and direct incorporation into peptides.
Amino Alcohols↗
Stereoselective alkylation of alpha,beta-unsaturated imines via C-H bond activation.
The stereoselective alkylation of alpha,beta-unsaturated imines via C-H activation followed by imine hydrolysis produces tri- and tetrasubstituted alpha,beta-unsaturated aldehydes. In the presence of a rhodium catalyst, alpha,beta-unsaturated N-benzyl imines derived from methacrolein, crotonaldehyde, and tiglic aldehyde undergo directed C-H activation at the beta-position and react with terminal alkenes and alkynes to form the tri- and tetrasubstituted alpha,beta-unsaturated imines with very high stereoselectivity. Hydrolysis to provide alpha,beta-unsaturated aldehydes can be performed under carefully controlled conditions that maintain the stereochemistry of the beta-alkylated imine products. Alternatively, for beta-alkylation products of the N-benzyl imine of methacrolein, hydrolysis can be performed under conditions that provide complete isomerization to the E isomer.
Alkylation↗
Enantioselective synthesis of a PKC inhibitor via catalytic C-H bond activation.
[reaction: see text] The syntheses of two biologically active molecules possessing dihydropyrroloindole cores (1 and 2) were completed using rhodium-catalyzed imine-directed C-H bond functionalization, with the second of these molecules containing a stereocenter that can be set with 90% ee during cyclization using chiral nonracemic phosphoramidite ligands. Catalytic decarbonylation and direct indole/maleimide coupling provide efficient access to 2.
Catalysis↗
Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities.
The substrate specificities of papain-like cysteine proteases (clan CA, family C1) papain, bromelain, and human cathepsins L, V, K, S, F, B, and five proteases of parasitic origin were studied using a completely diversified positional scanning synthetic combinatorial library. A bifunctional coumarin fluorophore was used that facilitated synthesis of the library and individual peptide substrates. The library has a total of 160,000 tetrapeptide substrate sequences completely randomizing each of the P1, P2, P3, and P4 positions with 20 amino acids. A microtiter plate assay format permitted a rapid determination of the specificity profile of each enzyme. Individual peptide substrates were then synthesized and tested for a quantitative determination of the specificity of the human cathepsins. Despite the conserved three-dimensional structure and similar substrate specificity of the enzymes studied, distinct amino acid preferences that differentiate each enzyme were identified. The specificities of cathepsins K and S partially match the cleavage site sequences in their physiological substrates. Capitalizing on its unique preference for proline and glycine at the P2 and P3 positions, respectively, selective substrates and a substrate-based inhibitor were developed for cathepsin K. A cluster analysis of the proteases based on the complete specificity profile provided a functional characterization distinct from standard sequence analysis. This approach provides useful information for developing selective chemical probes to study protease-related pathologies and physiologies.
Animals↗
Rhodium-catalyzed direct C-H addition of 3,4-dihydroquinazolines to alkenes and their use in the total synthesis of vasicoline.
The inter- and intramolecular couplings of unactivated alkenes to 3,4-dihydroquinazolines with a Rh(I) catalyst are reported. Coupling between olefins and NH-3,4-dihydroquinazoline was found to occur consecutively with heterocycle dehydrogenation in the presence of a Rh(I)/PCy3/HCl catalyst. The reaction was used to develop an effective method for the synthesis of 2-substituted quinazolines through an oxidative workup step. The regiocontrolled synthesis and Rh-catalyzed cyclization of alkene-tethered 3,4-dihydroquinazolines are also described. Applying this method, the second total synthesis of vasicoline was achieved. The key Rh-catalyzed cyclization step was made possible by the use of a rigid bicyclic phosphine ligand. The synthesis further demonstrates a challenging Cu-catalyzed amidation of an ortho-substituted aryl chloride.
Alkenes↗
Microwave-promoted rhodium-catalyzed arylation of heterocycles through C--H bond activation.
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Azoles↗
Experimental and computational studies on the mechanism of N-heterocycle C-H activation by Rh(I).
Evidence is presented for a proposed mechanism of C-H activation of 3-methyl-3,4-dihydroquinazoline (1) by (PCy(3))(2)RhCl. One intermediate (3), a coordination complex of 1 with (PCy(3))(2)RhCl, was identified along the path to the Rh-N-heterocyclic carbene product of this reaction (2). Isotopic labeling and reaction-rate studies were used to demonstrate that C-H activation takes place intramolecularly on the reaction coordinate between 3 and 2. Computational studies corroborate the proposed mechanism and suggest that the rate-limiting step is oxidative addition of the C-H bond to the metal center. The consequences of this mechanism for coupling reactions of N-heterocycles that occur via Rh-catalyzed C-H bond activation are discussed.
Catalysis↗
Rapid identification of potent nonpeptidic serine protease inhibitors.
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Chymotrypsin↗
Reassignment of the configuration of salvianolic acid B and establishment of its identity with lithospermic acid B.
Salvianolic acid B and lithospermic acid B are the major components of Salvia miltiorrhiza, which is one of the most popular herbal traditional medicines in Asian countries. Salvianolic acid B and lithospermic acid B are reported to have identical structures except for the configurational assignments of two stereocenters. Through chemical correlation between a degradation product of salvianolic acid B and synthetic material, the absolute configuration of salvianolic acid B has been corrected to establish that salvianolic acid B and lithospermic acid B are in fact the same compound.
Benzofurans↗
Asymmetric conjugate addition of copper reagents to alpha,beta-unsaturated tert-butanesulfinyl imines.
[reaction: see text] Addition of organocuprates to N-sulfinyl alpha,beta-unsaturated imines proceeds in good yields and with good diastereoselectivities. alpha,beta-Unsaturated sulfinyl ketimines and aldimines have both been shown to be suitable substrates for this reaction.
Journal Article↗
Substrate activity screening: a fragment-based method for the rapid identification of nonpeptidic protease inhibitors.
A new fragment-based method for the rapid development of novel and distinct classes of nonpeptidic protease inhibitors, Substrate Activity Screening (SAS), is described. This method consists of three steps: (1) a library of N-acyl aminocoumarins with diverse, low molecular weight N-acyl groups is screened to identify protease substrates using a simple fluorescence-based assay, (2) the identified N-acyl aminocoumarin substrates are optimized by rapid analogue synthesis and evaluation, and (3) the optimized substrates are converted to inhibitors by direct replacement of the aminocoumarin with known mechanism-based pharmacophores. The SAS method was successfully applied to the cysteine protease cathepsin S, which is implicated in autoimmune diseases. Multiple distinct classes of nonpeptidic substrates were identified upon screening an N-acyl aminocoumarin library. Two of the nonpeptidic substrate classes were optimized to substrates with >8000-fold improvements in cleavage efficiency for each class. Select nonpeptidic substrates were then directly converted to low molecular weight, novel aldehyde inhibitors with nanomolar affinity to cathepsin S. This study demonstrates the unique characteristics and merits of this first substrate-based method for the rapid identification and optimization of weak fragments and provides the framework for the development of completely nonpeptidic inhibitors to many different proteases.
Aminocoumarins↗
Total synthesis of (+)-lithospermic acid by asymmetric intramolecular alkylation via catalytic C-H bond activation.
The total synthesis of (+)-lithospermic acid is described. The efficient synthesis features an asymmetric alkylation via C-H bond activation to assemble the dihydrobenzofuran core of the natural product. This was accomplished via a chiral imine-directed C-H bond functionalization and represents the first application of this C-H activation method to natural product synthesis. Furthermore, a challenging deprotection of a late-stage permethylated lithospermic acid was achieved.
Alkylation↗