Jonathan P. L. Cox

The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates

Yttrium binding ligands DOTA, caDTPA and CT-DTPA were each conjugated to monoclonal antibody B72.3, labelled with 90Y and injected into mice in order to assess the in vivo inertness of the antibody-linked 90Y-ligand complexes. Levels of 90Y in femur shafts of the DOTA-B72.3 mice were low, being approximately 7 and 44%, respectively, of levels in the femur shafts of the caDTPA-B72.3 and CT-DTPA-B72.3 treated mice. This finding demonstrates the greater inertness and by implication the greater suitability for immunotherapy of the DOTA-90Y complex.

Synthesis of a kinetically stable yttrium-90 labelled macrocycle–antibody conjugate

Lysine is a precursor for the synthesis of an aminobutyl C-functionalised tetra-azacyclododecane tetra-acid which has been linked to B72.3 antibody and may be labelled with 90Y to form a kinetically stable complex of potential use in radioimmunotherapy.

Implementation of macrocycle conjugated antibodies for tumour-targetting

Monoclonal antibodies may be selectively functionalised with macrocyclic ligands, permitting the transport of an imaging or c totoxic metal radionuclide specifically to a tumour. Antibodies conju ated to p13) and (14)-membered tetraazamacrocycles allow 64Cu or 67Cu labefled antibody to be used for imaging or therapy.

Synthesis of C- and N-functionalised derivatives of 1,4,7-triazacyclononane-1,4,7-triyltriacetic acid (NOTA), 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetrayltetra-acetic acid (DOTA), and diethylenenetriaminepenta-acetic acid (DTPA): bifunctional complexing agents for the derivatisation of antibodies

Using (2S)-lysine as a precursor, the syntheses of aminobutyl derivatives of 1,4,7-triazacyclononane, 1,4,7,10-tetra-azacyclododecane, and 3-azapentane-1,5-diamine are described. Transformation into their reactive maleimide derivatives is described and alternative strategies for synthesising the title complexing agents involving nitrogen functionalisation are defined.

Retention of native-like structure in an acyclic counterpart of a β-sheet antibiotic

An acyclic derivative of the cyclic peptide antibiotic, ramoplanin, has been prepared. In aqueous solution, two‐dimensional NMR spectroscopy indicates that the acyclic form adopts a threshold population of conformers in which at least part of the β‐sheet characteristic of the intact ramoplanin persists. Thus, despite losing the entropic benefit which the macrocycle must lend to β‐sheet formation, the polypeptide chain of the acyclic ramoplanin appears to display an innate tendency to adopt a native‐like conformation.

Molecular recognition in aqueous solution: an estimate of the intrinsic binding energy of an amide–hydroxy hydrogen bond

The intrinsic binding energy of an amide–hydroxy hydrogen bond [NHCO ⋯ HO] has been estimated (ca.– 12 kJ mol–1 at 293 K); the major contribution to this value appears to be entropic, hydrogen bond formation being driven by the release of ordered water from the carbonyl group.

Comparison of the intrinsic reactivities of carbon and oxygen nucleophiles at the 1,3,5-trinitro-substituted aromatic ring

Kinetic and equilibrium data are reported for nucleophilic attack by nitroalkane anions at unsubstituted ring positions of 1,3,5-trinitrobenzene and of 2,4,6-trinitrotoluene. The results allow the calculation for this reaction type of values for intrinsic rate coefficients, k0, of 0.18 for CH2NO2– and 0.22 for MeCHNO2–. The corresponding value for the malononitrile anion, CH(CN)2–, is 2.5 × 104, and for the methoxide ion the value is 103. The results are discussed in terms of the electronic-structural and solvational reorganisation occurring during reaction.