R.Paul Beckett

Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor.

ABSTRACT Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified anN-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we determined the crystal structures of BB-3497 and actinonin bound to Escherichia coli PDF at resolutions of 2.1 and 1.75 Å, respectively. In both complexes, the active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, and activity against some gram-negative bacteria. Time-kill analysis showed that the mode of action of BB-3497 was primarily bacteriostatic. The mechanism of resistance was via mutations within the formyltransferase gene, as previously described for actinonin. While actinonin and its derivatives have not been used clinically because of their poor pharmacokinetic properties, BB-3497 was shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h after intraperitoneal injection of S. aureus Smith or methicillin-resistant S. aureusprotected mice from infection with median effective doses of 8 and 14 mg/kg of body weight, respectively. These data validate PDF as a novel target for the design of a new generation of antibacterial agents.

Matrix metalloproteinase inhibitors 1998

Inhibition of matrix metalloproteinases (MMPs) as an approach to treatment of diseases such as cancer, arthritis and multiple sclerosis (MS) is now an area of intense interest within the pharmaceutical industry. This review summarises developments in the design and clinical evaluation of synthetic MMP inhibitors since the subject was last covered in this journal in 1996.

α-Amino ester derivatives as nucleophiles in stereoselective palladium catalysed allylic substitution reactions

Abstract The stereoselective palladium catalysed reaction between allyl acetates and imino esters is reported. For suitable substrates, diastereoselectivities are good (up to 84:16), and in the presence of enantiomerically pure phosphorus-containing oxazoline ligands, the enantioselectivities (up to 97% ee) are very high.

Structure-activity relationships of the peptide deformylase inhibitor BB-3497: Modification of the metal binding group

A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.

α-Aminophosphonate derivatives as nucleophiles in diastereoselective and enantioselective palladium catalysed allylic substitution reactions

Abstract The palladium catalysed reaction between allyl acetates and Schiff base derivatives of α-aminophosphonates is reported. For suitable substrates, the observed diastereoselectivities (up to 87:13) and enantioselectivities (>96% ee) are high.

Asymmetric synthesis of (1R,8S)- and (1S,8S)-1-hydroxypyrrolizidin-3-ones via the aldol reaction between N-boc-(S)-prolinal and chiral acetate enolate equivalents derived from (S)- and (R)-[(η5-C5H5)Fe(CO)(PPh3)COCH3]

Abstract Syntheses of both title compounds have been achieved with excellent stereocontrol using chiral acetate enolate equivalents derived from the iron acetyl complex [(η5-C5H5)Fe(CO)(PPh3)COCH3]. The different diastereoselectivities in the two syntheses are rationalised in terms of the concept of double asymmetric induction and the transition state models for the aldol reactions of such enolates are discussed.

Inhibition of Matrix Metalloproteinases: An examination of the S1′ pocket

Abstract Peptidomimetic carboxylate- and hydroxamate-based inhibitors of matrix metalloproteinases containing extended P1′ groups have been prepared. Potent inhibition and good selectivity for MMP-2 has been observed for the compounds produced.

The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors

Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.

The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement

Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.

Asymmetric synthesis of bb-3497—A potent peptide deformylase inhibitor

By screening a library of metalloenzyme inhibitors, the N-formyl-hydroxylamine derivative BB-3497 was identified as a potent inhibitor of Escherichia coli peptide deformylase with antibacterial activity both in vitro and in vivo. The homochiral synthesis of BB-3497, involving a novel asymmetric Michael addition reaction is described.