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Synthesis of Macromolecular Conjugates of a Urokinase Inhibitor: Amiloride

Chemical Institute, Chemical Research Center, Pusztaszeri u. 59-67, 1525 Budapest, Hungary

Karel Ulbrich

Institute of Macromolecular Chemistry, Heyrovsky Sq. 2, 16206 Prague 6, Czech Republic

Vladimir Subr

Institute of Macromolecular Chemistry, Heyrovsky Sq. 2, 16206 Prague 6, Czech Republic

Peter Baker

Department of Surgery, University of Birmingham, B152THBirmingham, UK

Gábor Mezö

Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Pázmány P s. 2, 1518 Budapest, Hungary

Ferenc Hudecz

Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös L. University, Pázmány P s. 2, 1518 Budapest, Hungary

Amiloride is a potent inhibitor of a urokinase type plasminogen activator which is involved in the invasive process of cancer cells leading to the initiation of metastasis. Synthesis, characterization and in vitro tests of four macromolecular conjugates of Amiloride are presented. One of them is a degradable derivative, HPMA-Gly-D,l-Phe-Leu-Gly-amiloride. In this case the in vitro release of Amiloride was monitored. Other conjugates are stable containing a new amiloride derivative, 6-aminohexyl amiloride [AHA], coupled to different polymeric carriers: a branched polypeptide, poly-[Lys(AcGlu_1.0-D,l-Ala_4.5)] [AcEAK], poly-[N-(2-hydroxy propyl) metacrylamide] [HPMA] and poly-[1-vinyl-2-pyrrolidone-co-maleic acid] [NVP MA]. Inhibition of uPA, plasminogen activation and proteinases secreted by cancer cells was measured as well as basement membrane degradation in vitro. Each amiloride AHA and the corresponding conjugates retained their activity in these experiments.

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