Nigel Robert Arnold Beeley

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.

Towards tumour imaging with indium-111 labelled macrocycle–antibody conjugates

C-Functionalised triazacyclododecane and triazacyclononane triacid macrocycles have been covalently attached to a monoclonal antibody and may be labelled with 111In to form kinetically inert radiolabelled complexes.

Potent and selective inhibitors of gelatinase-a 1. hydroxamic acid derivatives

Abstract A series of hydroxamic acid derivatives were prepared. By introducing aromatic substituents at the P1′ and P3′ positions highly potent gelatinase-A inhibitors, which possess a high degree of selectivity over collagenase and stromelysin, were obtained. These inhibitors may be of therapeutic value in the control of tumour metastasis.

Potent and selective inhibitors of gelatinase-A 2. carboxylic and phosphonic acid derivatives

Abstract A series of zinc binding groups was introduced into a pseudopeptide sequence containing aromatic groups in the P1′ position in order to obtain selective inhibitors of gelatinase-A. Carboxylic acid and phosphonic acid groups provided the most potent inhibitors

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.

A general synthesis of N-substituted isothiazol-3(2H)-ones

A general route to the synthesis of N-substituted isothiazol-3(2H)-ones (4a–i) is described which proceeds via trichloroacetic acid-mediated ring closure of N-substituted (Z)-3(benzylsulfinyl)propenamides (15a–i).

A stable, non-aromatic, adduct derived from ‘ipso’-nitration

Nitration of N-[(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]propanamide (5) gave not only the expected products (6) and (7) but also the tricyclic adduct (8), the structure of which was confirmed by a single crystal X-ray analysis.

Novel oxidative elimination in a norbornyl iodide

A norbornyl iodide is shown to undergo oxidative elimination to yield a norbornene, the double bond of which is sufficiently hindered not to react with oxidizing species present in the reaction mixture.