Drug Delivery Systems Employing 1,4- or 1,6-Elimination:  Poly(ethylene glycol) Prodrugs of Amine-Containing Compounds

• Published in: Journal of medicinal chemistry 1999-09, Vol.42 (18), p.3657-3667
• Main Authors: Greenwald, Richard B, Pendri, Annapurna, Conover, Charles D, Zhao, Hong, Choe, Yun H, Martinez, Anthony, Shum, Kwok, Guan, Shuiyun
• Format: Article
• Language: English
• Subjects: Amines - chemical synthesis; Amines - pharmacology; Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Carbamates - chemical synthesis; Carbonates - chemical synthesis; Cell Division - drug effects; Daunorubicin - analogs & derivatives; Drug Delivery Systems; Esters - chemical synthesis; General aspects; Hydrolysis; Medical sciences; Mice; Mice, Inbred Strains; Pharmacology. Drug treatments; Polyethylene Glycols - chemical synthesis; Polyethylene Glycols - pharmacology; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Rats; Rats, Inbred Strains; Solubility; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990166e

A general methodology for synthesizing poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed and constitutes the basis for solubilization of insoluble drugs, extending plasma circulating half-lives and, in the case of anticancer agents, apparent tumor accumulation. Thus, we have successfully designed PEG conjugated specifiers or “triggers” as part of a double-prodrug strategy that relies, first, on enzymatic separation of PEG followed by the classical and rapid 1,4- or 1,6-benzyl elimination reaction releasing the amine (drug) bound in the form of a carbamate. The prodrug trigger was comprised of ester, carbonate, carbamate, or amide bonds in order to secure predictable rates of hydrolysis. Further refinement of the hydrolysis was accomplished by the introduction of steric hindrance through the use of ortho substituents on the benzyl component of the prodrug. This modification led to longer circulating plasma half-lives of the final tripartate form. The “ortho” effect also had the beneficial effect of directing nucleophilic attack almost exclusively to the activated benzyl 6-position of the heterobifunctional intermediates. In vivo testing of the PEG daunorubicin prodrugs (transport forms) prepared in the course of this study ultimately identified the type 1 carbamate (34b), with a circulating t 1/2 of 4 h, as the most effective derivative for solid tumor growth inhibition.