Robin D. G. Cooper

Glycopeptide antibiotic derivatives

The present invention provides glycopeptide antibiotic derivative compounds. These derivative compounds possess antibacterial activity aginst a wide variety of bacteria, including activity against vancomycin-resistant isolates. Methods of making and using these glycopeptide antibiotic derivative compounds are also provided.

Activities of the semisynthetic glycopeptide LY191145 against vancomycin-resistant enterococci and other gram-positive bacteria.

LY191145 is the prototype of a series of compounds with activities against vancomycin-resistant enterococci derived by modification of the glycopeptide antibiotic LY264826. LY191145 had MICs for vancomycin- and teicoplanin-resistant enterococci of < or = 4 micrograms/ml for 50% of isolates and < or = 16 micrograms/ml for 90% of isolates. Its MICs for vancomycin-resistant, teicoplanin-susceptible enterococci were 1 to 8 micrograms/ml. LY191145 retains the potent activities of its parent compound against staphylococci and streptococci. In vivo studies in a mouse infection model confirmed these activities. This compound indicates the potential of semisynthetic glycopeptides as agents against antibiotic-resistant gram-positive bacteria.

The enzymes involved in biosynthesis of penicillin and cephalosporin; their structure and function.

The biosynthetic pathway resulting in the penicillins and cephalosporins contains two Fe2+ oxidase enzymes which are responsible for the conversion of alpha-aminoadipoyl-L-cysteinyl-D-valine into isopenicillin N and penicillin N into deacetoxycephalosporin C. We will discuss the studies delineating the ligand binding of these enzymes and present a possible secondary structure.

Structural studies on penicillin derivatives. X. Chlorination of azetidinone derivatives

Abstract The allylic methyl group of several azetidinone derivatives can be cleanly chlorinated by a mechanism which appears to be that of an ene-reaction.

Chemistry of cephalosporin antibiotics. Part XVI. Configurational and conformational analysis of deacetoxy-Δ2- and -Δ3-cephalosporins and their corresponding sulphoxide isomers by nuclear magnetic resonance

The results of solvent-shift and hydrogen-bonding studies indicate that the (S)-sulphoxide configuration can be assigned to the major sulphoxide oxidation products of Δ2- and Δ3-deacetoxycephalosporin (III) and (VI) respectively. From a comparison of sulphoxide-bond solvent and anisotropy shifts recorded for analogous penicillin and cephalosporin systems, we are able to assign the conformation of the dihydrothiazine ring in these cephalosporin derivatives. These conformations are supported by results obtained from a study of internal nuclear Overhauser effects (NOE) as well as from the magnitude of observed long-range and geminal coupling constants. Additional evidence is presented in support of the previously assigned stereochemistry at C-4 in Δ2-deacetoxycephalosporin (VI).

Chapter 14. Semisynthetic Glycopeptide Antibiotics

Publisher Summary In recent times, interest in the glycopeptide class of antibiotics has increased. A new development has been the interest in semisynthetic glycopeptides as the activity of this class can be expanded to include vancomycin resistant enterococci and even some gram-negative bacteria. The anti-bacterial effect exhibited by the glycopeptide class of antibiotics is attributed to their ability to inhibit the biosynthesis of peptidoglycan, a key structural component of the bacterial cell wall. Vancomycin and other glycopeptides antibiotics form complexes with the C-terminal D-Ala-D-Ala sequence of the bacterial cell wall precursor, thus preventing the subsequent transglycosylation and transpeptidation reactions necessary for the construction of the peptidoglycan. In addition to an affinity for D-Ala-D-Ala, other factors may also play an important role in the activity exerted by the glycopeptide antibiotics. The molecular basis of resistance to glycopeptide antibiotics is well understood. The bacteria have acquired the necessary enzymes to synthesize an altered cell wall precursor, terminating in D-lactate rather than D-alanine. The replacement of an amide linkage with an ester linkage results in the loss of one hydrogen-bond interaction between vancomycin and the ligand. Some of the most interesting semisynthetic molecules that have been reported are intrinsically complex to make and cost may limit the attractiveness of development. Nonetheless, the class provides an instructive example of the effectiveness of the union of natural product research and medicinal chemistry applied to new medical needs.

β-Lactamase inhibitors derived from N-tosyloxy-β-lactams

Abstract Electrophilic N -tosyloxy-β-lactams, N -tosyloxy-4-phenyl-2-azetidinone ( 2b ) and N -tosyloxy-3-( S )-phthalimido-4-( S )-2-azetidinone ( 2c ), are described. These agents are novel potent β-lactamase inhibitors.

Structural studies on penicillin derivatives: 13C nuclear magnetic resonance studies of some penicillins and related sulphoxides

13 C Chemical shift assignments are made for several penicillin and penicillin sulphoxide derivatives: shifts for γ-situated carbons are best explained if a sizeable steric effect is attributed to the S→O bond.

The Chemistry of Penicillin Sulfoxide

Publisher Summary This chapter focuses on the chemistry of penincillin sulfoxide. The fundamental reason for both the commercial and research importance of penicillin sulfoxides is that the thiazolidine, which is a 5-membered ring, can be quantitatively opened under relatively mild conditions without loss of the stereochemical integrity of carbons 5 or 3 in the starting penicillin. The penicillin sulfoxides are in thermal equilibrium with an unstable ring-open sulfenic acid olefin. A new and efficient method for the preparation of penicillin sulfoxide esters has been developed. This procedure involves treatment of the penicillin sulfoxide with a hydrazone in the presence of an oxidizing agent, such as iodine. This method is especially useful for the synthesis of benzhydryl esters. The use of a peroxyacid resin gives efficient oxidation of both penicillins and cephalosporins to their respective sulfoxides with the potential advantages of ease of product isolation and ability to recycle the resin. The nature of the products produced in a penicillin sulfoxide rearrangement are determined, in part, by the nature of the 3-substituent.

Carotenoids and related compounds. Part 37. Stereochemistry and synthesis of capsorubin

The two oxygen substituents in the end groups of capsorubin were shown to be trans to one another by synthesis of optically inactive forms of the carotenoid, and of the isomers which have the corresponding cis-structure. The 3S,5R,3′S,5′R configuration thus established for the natural carotenoid was confirmed by synthesis of this stereoisomer from (+)-camphor.Cryptocapsin has the 3′S,5′R configuration, and the racemic form has been synthesised.Capsanthin has the 3R,3′S,5′R configuration.