Peptide T-araC conjugates: Solid-phase synthesis and biological activity of N-4-(acylpeptidyl)-araC

Due to the capability of peptidyl derivatives of araC to behave as prodrugs of this antimetabolite, and because of the well known biological propertie s of peptide T and its analogues (in particular that of targeting CD4(+) ce lls), new peptide T-araC conjugates were prepared and tested in vitro for a ntiproliferative activity. The aim was that of specifically delivering the antitumor drug to CD4(+) cells. N-4-(Acylpeptidyl)-derivatives of araC were synthesized by a new general approach involving solid-phase synthesis, whi ch allows mild conditions, avoids the usually required protection of the gl ycoside portion of nucleosides and affords high yields of the final product s. After the demonstration that peptide T-araC conjugates were able to acti vate chemotaxis by binding CD4 receptor on monocyte membranes, the antiprol iferative activity was evaluated against a panel of leukemia lymphoma and c arcinoma cell lines derived from human tumors, three CD4(+) cell lines incl uded. Title compounds resulted effective as antiproliferative agents at con centrations 4- to 10-fold higher than those of araC alone, did not preferen tially inhibit CD4(+) cells and proved stable not only in cell culture medi um containing 20% FCS, but also in human plasma. All this suggests their po tential utility in vivo. (C) 2000 Elsevier Science Ltd. All rights reserved .