Foreign moieties

A variant of the original immunotoxin approach is the so-called immunocytokines. In these constructs the antibody targeting moiety is maintained, but the toxin as the effector molecule is replaced by a cytokine. In contrast to toxins, cytokines are often proteins endogenously produced in man. If both the antibody and cytokine are of human origin, then no foreign proteins are introduced which could provoke an antibody response from the host immune system when the drug targeting preparation is clinically applied. 

Conjugation involves addition of an endogenous moiety to a foreign molecule, which may be a product of a phase 1 reaction. Major phase 2 routes conjugation with glucuronic acid, sulfate, glutathione amino acids acetylation methylation. Enzymes involved are transferases except in the case of amino acid conjugation where the first step is catalyzed by an acyl CoA synthetase, then a transferase is involved. 

Exploitation of Pendant Reactive Groups. Pendant and linkage forming stabilizing moieties can be created in this way. Macromolecular stabilizers thus formed have general structures B, C, and E (Scheme 1) and are formally structurally related to stabilizers prepared by other polyreactions. The distribution mode of stabilizing moieties and the presence of foreign structures and mentioned above represent the main difference between stabilizers prepared via different synthetic approaches. 

This concept has been extended. Thus the trione (696) rapidly and irreversibly inactivates human erythrocyte nucleoside phosphorylase (PNPase), which catalyzes the reversible phosphorylation of inosine and guanosine to the respective bases and ribose 1-phosphate. Inhibitors of this enzyme have several potential medical applications, for example, in the prevention of foreign tissue rejection, in the treatment of gout and malaria, and for the potentiation of antineoplastic nucleosides. Mechanistically the 5,8-dione (quinone) (696) enters the enzyme active site. An active-site nucleophilic residue subsequently converts the quinone moiety to a hydroquinone by reductive addition (701). The resulting hydroquinone affords an alkylating quinone methide species by elimination of HCl (702) and then traps a second nucleophilic enzyme residue by a Michael type reaction (703). Cross-linking of the active site rationalizes the observed potency <91B8480>. 

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