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

Classical procedures of peptide synthesis were applied to synthesize f our groups of compounds, and analytical methods were developed for eac h of them. Two of the groups are tetrapeptide derivatives of the antil eishmanial 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 po sition, while X was Ala. In the second group, Ala, Tyr, Lys, and Asp w ere used in the X position, while Y was Leu. The derivatives are inten ded to be coupled, via their free alpha-amino group, to polyacryl star ch microparticles, lysosomotropic drug carriers developed in our labor atory. Thus, a systematic study of the significance of the varying ami no acid composition of the tetrapeptide spacer arm for the rate of lys osomal enzymatic release of PQ can be possible. A third group, compris ing epsilon-aminocaproic acid-PQ derivatives which lack a free alpha-a mino group, was synthesized. This was done to study the importance of enzymes, other than aminopeptidases, during lysosomal degradation of t hese 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.