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Biomedical subjects

Jonathan A Ellman

Publications and source records attributed to Jonathan A Ellman.

67 records · Page 4Linked to original sources
PubMed2002

Asymmetric synthesis of beta-amino acid derivatives incorporating a broad range of substitution patterns by enolate additions to tert-butanesulfinyl imines.

Addition of Ti(Oi-Pr)(3) ester enolates to tert-butanesulfinyl aldimines and ketimines provided beta-substituted, alpha,beta- and beta,beta-disubstituted, alpha,beta,beta- and alpha,alpha,beta-trisubstituted, and alpha,alpha,beta,beta-tetrasubstituted beta-amino acid derivatives in high yields and with high diastereoselectivites. The N-sulfinyl-beta-amino ester products were further employed as versatile intermediates for both standard solution-phase and solid-phase synthetic transformations, including the synthesis of beta-peptide foldamers.

Amino Acids↗
PubMed2002

General solid-phase method to prepare novel cyclic ketone inhibitors of the cysteine protease cruzain.

A series of constrained ketone-based inhibitors has been developed that show low nanomolar Ki values. These ketone inhibitors showed promising activity towards cruzain, the cysteine protease implicated in Chagas' disease. This series of constrained inhibitors, which can be accessed quickly and efficiently using a solid-phase combinatorial strategy, should be applicable to other members of the cysteine protease class.

Cathepsin B↗
PubMed2002

Design and synthesis of novel inhibitors of gelatinase B.

A new method was developed to identify nonpeptidic metalloproteinase inhibitors with novel zinc binding groups. Application of this method to matrix metalloproteinase-9 resulted in the identification of aminomethyl benzimidazole analogue 7a with an IC(50)=13 microM.

Benzimidazoles↗
PubMed2002

Asymmetric synthesis of syn- and anti-1,3-amino alcohols.

The first application of metalloenamines derived from N-sulfinyl imines is reported for the highly diastereoselective addition to aldehydes. Reduction of the beta-hydroxy-N-sulfinyl imine products with catecholborane and LiBHEt3 provides syn- and anti-1,3-amino alcohol derivatives, respectively, with very high diastereomeric ratios.

Amino Alcohols↗
PubMed2002

Intermediacy of an N-heterocyclic carbene complex in the catalytic C-H activation of a substituted benzimidazole.

An N-heterocyclic carbene complex was found to be the active catalyst in the Rh(I)-catalyzed intramolecular coupling of an alkenyl group to a C-H bond of a substituted benzimidazole. Kinetic studies demonstrated that the catalytic cyclization is zero-order in substrate and first-order in catalyst. Furthermore, DFT calculations with a model system suggest that the rate-limiting step involves insertion of the alkenyl double bond into the rhodium-carbene bond.

Benzimidazoles↗
PubMed2002

Expedient solid-phase synthesis of fluorogenic protease substrates using the 7-amino-4-carbamoylmethylcoumarin (ACC) fluorophore.

A highly efficient solid-phase synthesis method for the preparation of fluorogenic protease substrates based upon the bifunctional leaving group 7-amino-4-carbamoylmethylcoumarin (ACC) is reported. Methods for the large-scale preparation of the novel fluorogenic leaving-group ACC are provided (Scheme 1). Detailed procedures are also provided for loading a diverse set of amino acids to support-bound ACC in good yields and with minimal racemization. Finally, procedures are included for the preparative synthesis of optimized ACC substrates for HIV-1 protease and plasmin.

Amino Acids↗
PubMed2002

Identification of potent and selective mechanism-based inhibitors of the cysteine protease cruzain using solid-phase parallel synthesis.

Targeted libraries of ketone-based cysteine protease inhibitors were synthesized and screened against cruzain, a cysteine protease implicated in Chagas' disease. A number of single digit nanomolar, low molecular weight inhibitors were identified and optimized for solubility and potency. Specifically, the best inhibitors identified have K(i) values of 0.9-10 nM and molecular weights between 499 and 609 Da. The most effective inhibitor was also found to be greater than 1000-fold selective for cruzain relative to cathepsin B and 100-fold selective for cruzain relative to cathepsin L.

Animals↗
PubMed2002

Novel and potent anti-malarial agents.

Readily accessible, novel, and potent anti-malarial compounds have been developed. Optimization of the initial lead structure resulted in derivatives with IC50 values from 7 to 35 nM against chloroquine-sensitive and 70-350 nM against chloroquine-resistant strains of Plasmodium falciparum.

Alkylation↗
PubMed2002

Interference with heme binding to histidine-rich protein-2 as an antimalarial strategy.

The erythrocytic growth stage of Plasmodium falciparum involves hemoglobin proteolysis as the primary nutrient source with the concomitant release of free heme. The liberated heme is processed by the parasite into hemozoin, a polymeric porphyrin dimer. Histidine-rich protein binds heme and mediates the formation of hemozoin, which is inhibited by the antimalarial drug chloroquine. Interference with heme binding was determined using a microtiterplate assay. Combinatorial libraries were screened and tested against parasite growth, revealing a good correlation between heme binding interference and the inhibition of parasite growth. Several of these compounds retain their potency against a chloroquine-resistant strain of Plasmodium falciparum. The most potent compounds have IC(50) values less than or equal to 50 nM against chloroquine-resistant and chloroquine-sensitive parasites.

Animals↗
PubMed2002

N-tert-butanesulfinyl imines: versatile intermediates for the asymmetric synthesis of amines.

N-tert-Butanesulfinyl aldimines 3 and ketimines 4 are exceedingly versatile intermediates for the asymmetric synthesis of amines. The N-tert-butanesulfinyl imines are prepared in high yields by condensing enantiomerically pure tert-butanesulfinamide 1, which is readily available in either configuration, with a wide range of aldehydes and ketones. The tert-butanesulfinyl group activates the imines for the addition of many different classes of nucleophiles, serves as a powerful chiral directing group, and after nucleophilic addition is readily cleaved by treatment of the product with acid. A wide range of highly enantioenriched amines, including alpha-branched and alpha,alpha-dibranched amines, alpha- and beta-amino acids, 1,2- and 1,3-amino alcohols, and alpha-trifluoromethyl amines, are efficiently synthesized using this methodology. In addition, N-tert-butanesulfinyl imine derivatives provide a new family of ligands for asymmetric catalysis.

Journal Article↗
PubMed2002

Benzodiazepine-induced superoxide signals B cell apoptosis: mechanistic insight and potential therapeutic utility.

The properties of a proapoptotic 1,4-benzodiazepine, Bz-423, identified through combinatorial chemistry and phenotype screening are described. Bz-423 rapidly generated superoxide (O(2)(-)) in transformed Ramos B cells. This O(2)(-) response originated from mitochondria prior to mitochondrial transmembrane gradient collapse and opening of the permeability transition pore. Bz-423-induced O(2)(-) functioned as an upstream signal that initiated an apoptotic program characterized by cytochrome c release, mitochondrial depolarization, and caspase activation. Pretreatment of cells with agents that either block the formation of Bz-423-induced O(2)(-) or scavenge free radicals attenuated the death cascade, which demonstrated that cell killing by Bz-423 depends on O(2)(-). Parallels between Ramos cells and germinal center B cells prompted experiments to determine whether Bz-423 had therapeutic activity in vivo. This possibility was tested using the (NZB x NZW)F(1) murine model of lupus, in which the pathologically enhanced survival and expansion of germinal center B cells mediate disease. Administration of Bz-423 for 12 weeks specifically controlled germinal center hyperplasia and reduced the histological evidence of glomerulonephritis. Collectively, these studies define a new structure-function relationship for benzodiazepines and point to a new target and mechanism that could be of value for developing improved drugs to manage systemic lupus erythematosus and related disorders.

Animals↗
PubMedDate not supplied

Synthesis of a diverse library of mechanism-based cysteine protease inhibitors.

We report improvements of our method for the solid-phase synthesis of mechanism-based mercaptomethyl ketone inhibitors of cysteine proteases (Lee, A.; Huang, L.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 9907-9914). Specifically, Fmoc-protected chloromethyl ketones were used, rather than the Alloc-protected counterparts. In addition, we further demonstrated that diverse polar functionality can be incorporated at the R1', R1, and R2 sites, in contrast to our previous efforts, where primarily hydrophobic groups were incorporated at these positions. On the basis of these results, a 2016-membered library of potential mercaptomethyl ketone inhibitors was prepared that incorporated diverse functionality. The library was screened against cathepsin B, which is implicated in cancer, resulting in the identification of single-digit nanomolar inhibitors. Because of the diverse functionality incorporated in this library, it should be a rich source of potent inhibitors against many other cysteine proteases.

Cysteine Proteinase Inhibitors↗