BIODEGRADABLE MICROSPHERES .16. SYNTHESIS OF PRIMAQUINE-PEPTIDE SPACERS FOR LYSOSOMAL RELEASE FROM STARCH MICROPARTICLES

Classical procedures of peptide synthesis were applied to synthesize four groups of compounds, and analytical methods were developed for each of them. Two of the groups are tetrapeptide derivatives of the antileishmanial drug primaquine (PQ), with general structure NH2-X-Leu-Ala-Y-PQ. In the first group, Leu, Tyr, Lys, and Asp were used in the Y position, while X was Ala. In the second group, Ala, Tyr, Lys, and Asp were used in the X position, while Y was Leu. The derivatives are intended to be coupled, via their free alpha-amino group, to polyacryl starch microparticles, lysosomotropic drug carriers developed in our laboratory. Thus, a systematic study of the significance of the varying amino acid composition of the tetrapeptide spacer arm for the rate of lysosomal enzymatic release of PQ can be possible. A third group, comprising epsilon-aminocaproic acid-PQ derivatives which lack a free alpha-amino group, was synthesized. This was done to study the importance of enzymes, other than aminopeptidases, during lysosomal degradation of these derivatives. To allow HPLC analysis of the pattern of degradation of tetrapeptide-PQ derivatives, some shorter peptide-PQ derivatives (group four) were prepared as well.