Louis Nickolaus Jungheim

Crystal structure of the human PRMT5:MEP50 complex

Protein arginine methyltransferases (PRMTs) play important roles in several cellular processes, including signaling, gene regulation, and transport of proteins and nucleic acids, to impact growth, differentiation, proliferation, and development. PRMT5 symmetrically di-methylates the two-terminal ω-guanidino nitrogens of arginine residues on substrate proteins. PRMT5 acts as part of a multimeric complex in concert with a variety of partner proteins that regulate its function and specificity. A core component of these complexes is the WD40 protein MEP50/WDR77/p44, which mediates interactions with binding partners and substrates. We have determined the crystal structure of human PRMT5 in complex with MEP50 (methylosome protein 50), bound to an S-adenosylmethionine analog and a peptide substrate derived from histone H4. The structure of the surprising hetero-octameric complex reveals the close interaction between the seven-bladed β-propeller MEP50 and the N-terminal domain of PRMT5, and delineates the structural elements of substrate recognition.

Bicyclic pyrazolidinones, a new class of antibacterial agent based on the β-lactam model

Abstract Several bicyclic pyrazolidinones were synthesized as γ-lactam analogs of the β-lactam antibiotics. Two of these compounds exhibited in vitro antibacterial activity, and thus constitute a new class of antibacterial agents.

Tachykinin receptor antagonists

The present invention relates to selective NK-1 receptor antagonists of Formula (I); or a pharmaceutically acceptable salt thereof, for the treatment of disorders associated with an excess of tachykinins

Bicyclic pyrazolidinone antibacterial agents. Synthesis of side chain analogues of carbapenems PS-5 and thienamycin

Abstract Bicyclic pyrazolidinone analogues of carbapenems, bearing either an ethyl or hydroxyethyl side chain at C-7, were prepared via the 1,3-dipolar cycloaddition chemistry of pyrazolidinium ylides.

A novel targeted delivery system utilizing a cephalosporin-oncolytic prodrug activated by an antibody β-lactamase conjugate for the treatment of cancer

Abstract Cephalosporins substituted at C-3′ with oncolytic agents such as vinca alkaloids have been developed as prodrugs for the treatment of solid tumors. Conversion of prodrug to drug is mediated by an immunoconjugate consisting of a β-lactamase enzyme covalently attached to a monoclonal antibody Fab′ fragment which is pre-localized at the tumor.

Bicyclic pyrazolidinones, steric and electronic effects on antibacterial activity

Abstract Bicyclic pyrazolidinones were synthesized as γ-lactam analogs of the β-lactam antibiotics. Several of these compounds exhibited broad spectrum in vitro antibacterial activity.

1,3-Dipolar cycloaddition reactions of pyrazolidinium ylides with vinyl sulfones. A regioselective synthesis of bicyclic pyrazolidinone antibacterial agents

Abstract The 1, 3-dipolar cycloaddition reaction of pyrazolidinium ylide 1 with substituted vinyl sulfones 5 was studied. Elimination of benzenesulfinic acid from the resulting cycloadducts gave rise to bicyclic pyrazolidinones 3 . The (E)-olefin isomers were found to undergo cycloaddition in a highly regioselective fashion. These pyrazolidinones 3 represent the nuclei of an exciting new class of potent antibacterial agents that mimic β-lactams.

Inhibition of human rhinovirus 3C protease by homophthalimides

Abstract Homophthalimides 2a and 3a were found to be inhibitors of Rhinovirus 3C protease through a blind screening effort. SAR studies resulted in compound 3g, which exhibited improved enzyme inhibition, in addition to whole cell antiviral activity. Molecular modeling studies suggest a preferred enzyme/inhibitor interaction, and LC/MS experiments confirmed tight/covalent binding of 3g to the enzyme.

POTENT, ORALLY BIOAVAILABLE HIV-1 PROTEASE INHIBITORS CONTAINING NONCODED D-AMINO ACIDS

Abstract Novel noncoded D-amino acids have been combined with decahydroisoquinoline, octahydrothienopyridine, and urea hydroxyethylamine isosteres to provide potent HIV-1 protease inhibitors with excellent HIV-1 antiviral activity. LY314613 shows a promising combination of potency and oral bioavailability. Trends in the SAR and comparisons to other isostere derivatives will be discussed.

Thioaldehydes in cycloaddition reactions. Synthesis of nuclear analogues of pyrazolidinone antibacterial agents

Abstract In situ generated thioaldehydes have been found to undergo 1,3-dipolar cycloadditions with a pyrazolidinium ylide to produce a nuclear analogue of pyrazolidinone antibacterial agents.