Frans M. Kaspersen

A review of the methods of chemical synthesis of sulphate and glucuronide conjugates

1. Methods for the synthesis of drug conjugates with sulphuric acid have been reviewed. 2. Some analytical methods are presented for the analysis of sulphate conjugates. 3. The synthesis of several types of N, O and C beta-D-glucuronides is reviewed. Different beta-coupling reactions of protected glucuronides are presented. 4. Application of n.m.r. and mass spectrometry to the analysis of beta-D-glucuronides is discussed.

The nature of the astatine-protein bond

Abstract The electrophilic astatination of a number of proteins is studied. Two types of binding of the astatine to the protein are observed: a relatively stable one in the case of SH containing proteins—probably by the formation of a SAt bond—and a weaker binding of a still unknown nature for proteins lacking a free SH-group. The two types of protein-astatine bond are destroyed by addition of sulphite, thio-sulphate, thiourea, cysteine, iodoacetamide, thiocyanate, Hg2+-salts and potassium iodide.

Biotransformation of mianserin in laboratory animals and man

1. The biotransformation and excretion of the antidepressant mianserin were studied after oral administration of the labelled drug to rats, mice, rabbits, guinea pigs and humans. Mianserin was well absorbed and almost completely metabolized in all five species. 2. Major metabolic pathways of mianserin were p-oxidation of the N-substituted aromatic ring followed by conjugation, and oxidation and demethylation of the N-methyl moiety, followed by conjugation. Direct conjugation of the N-methyl moiety was observed as a metabolic pathway specific for man. 3. Conjugated metabolites were isolated by h.p.l.c. and identified by 1H-n.m.r. and FAB spectrometry. Novel metabolites such as an N-O-glucuronide in the guinea pig and an N-sulphonate in rat and guinea pig, were identified using these techniques. A quaternary N-glucuronide was found only in man.

The biological behaviour of some organic astatine compounds in rats

Abstract The tissue distribution of several organic astatine compounds has been studied in rats in comparison with inorganic astatine. It can be concluded that astatinated compounds, like their iodine analogues, are easily dehalogenated.

Synthesis and biological evaluation of immunoconjugates of adriamycin and a human IgM linked by poly[N5-(2-hydroxyethyl)-L-glutamine]

The synthesis and purification of radiolabelled immunoconjugates, composed of a human IgM monoclonal antibody (IgM 16.88) directed against an intracellular tumour-associated antigen, the drug carrier poly[N5-(2-hydroxyethyl)--glutamine] (PHEG) and the cytostatic drug adriamycin (ADR) are described. The immunoconjugates were constructed to allow selective release of ADR in the putatively acidic environment of the tumour through a novel acid-labile maleamic acid linker. The conjugate of PHEG and the acid-labile ADR derivative effectively released ADR in cytotoxic amounts at a pH of 6.0 as judged from incubation in buffer and from inhibition of the growth of HT-29 colon tumour cells in vitro. Immunoconjugates were prepared by coupling of PHEG-ADR having a hydrolytically stable amide bond with 131I-labelled antibody through thioether bond formation involving a single thiol group at the C-terminus of the polymer chain and maleimido groups introduced onto the

The preparation and stability of 211At-astato-imidazoles

Several 211At-astato-imidazoles (4-At-imidazole; 2,4-At, I-imidazole; 5-At-4-methylimidazole; 2,5-At, I-4-methylimidazole; 5-At-histidine) have been synthesized by reaction of 211At/I2 with the corresponding chloromercury imidazoles. All compounds investigated are stable under both acidic and alkaline conditions; they decompose by reaction with sulphite or hydrogen peroxide.

Passive immunotherapy of cancer: perspectives and problems

Abstract The past decade has witnessed an exponential growth in the field of immunotherapy of cancer. Efforts have been directed to obtain proof of the concept that monoclonal antibodies, by virtue of their specificity in tumour cell recognition, are ideally suitable as carrier molecules of therapeutic agents. To date, the mass studies on targeting of protein toxins, radioisotopes and drugs have not yet seen a breakthrough to a clinically useful therapy. A review is given on the problems still to be solved in the design of immunoconjugates for clinical use.

Radioiodinated o-iodobenzoic acid as impurity in Hippuran preparations

Some factors determininghe presence of labelled o-iodobenzoic acid in preparations of Hippuran have been studied. Labelling procedures resulting in low o-iodobenzoic acid contents are presented.

Synthesis and biodistribution of immunoconjugates of a human IgM and polymeric drug carriers

The synthesis and purification of radiolabelled immunoconjugates, composed of a human IgM monoclonal antibody directed against an intracellular tumour-associated antigen and either poly (alpha-L-glutamic acid) (PGA) or poly[N5-(2-hydroxyethyl)-L-glutamine] (PHEG) is described. Coupling of polymers to the antibody was performed through disulfide bond formation involving a single thiol group at the C-terminus of the polymer chain and 2-pyridyldisulfide groups introduced onto the antibody. The antibody was iodinated with 131I before conjugation. The polymers contained tyrosinamide in a low degree of substitution and were radiolabelled with 125I. 125I-labelled PGA and PHEG were found to be stable for at least 3 days in murine and human plasma. The biodistribution in mice of the doubly labelled immunoconjugates was studied and was compared with the pharmacokinetics of the individual components. PHEG showed a relatively slow blood clearance, the half-life being approximately 10 h with low uptake in liver, kidneys and spleen. PGA was rapidly cleared from the circulation and was significantly taken up in liver, kidneys and spleen. The biodistribution of both immunoconjugates was indistinguishable from that of the IgM proper, with plasma half-lives of approximately 6 h, indicating that the pharmacokinetic properties of the immunoconjugates are largely determined by the antibody part.

Calix[4]arene-triacids as receptors for lanthanides; synthesis and luminescence of neutral Eu3+ and Tb3+ complexes

Calix[4]arene triacids (3a–d) have been prepared that are able to form neutral complexes with lanthanides. Complexes of 3a–d with Eu3+ and Tb3+ have been studied with respect to their luminescent properties in a protic solvent (methanol). In all cases it was found that the luminescent lifetime of the complexed lanthanide ions is significantly enhanced compared with that of the free ions in the same solvent. Solvent deuterium isotope effects confirm that shielding of the lanthanide ion from the solvent in the calixarene complexes is the main mechanism responsible for the lifetime difference between free and complexed ions, however, the calixarene itself also exerts a moderate lifetime-shortening effect. Excitation spectra show that in the complexes efficient energy transfer to the lanthanide ions occurs both from the calixarene aromatic moieties as well as from aromatic (pyridine) chromophores attached to it.