N-6-cyclopropyl-PMEDAP: A novel derivative of 9-(2-phosphonylmethoxyethyl)2-6-diaminopurine (PMEDAP) with distinct metabolic, antiproliferative, and differentiation-inducing properties

N-6-Cyclopropyl-PMEDAP (cPr-PMEDAP) is a novel derivative of the acyclic nu cleoside phosphonate 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP ). Its cytostatic activity was found to be 8- to 20-fold more pronounced th an that of PMEDAP and equivalent to that of the guanine derivative 9 (2-pho sphonylmethoxyethyl)guanine(PMEG) against a variety of tumor cell lines. Un like PMEDAP, but like PMEG, cPr-PMEDAP was equally cytostatic to wild-type and 9-(2-phosphonyrmethoxyethyl)adenine/ PMEDAP resistant Variants of the h uman erythroleukemia K562 and the murine leukemia L1210 cell lines. Also, c Pr-PMEDAP and PMEG proved to be equipotent inducers of K562 and rat chorioc arcinoma RCHO cell differentiation, whereas the differentiation-inducing ac tivity of PMEDAP was 5- to 25-fold less pronounced. Furthermore, compared t o PMEDAP, cPr-PMEDAP and PMEG were 10- to 25-fold more potent in inhibiting the progression of K562 cells through the S phase of the cell cycle, resul ting in a marked accumulation of the four 2'-deoxyribonucleaside 5' triphos phate pools. The biological effects of cPr-PMEDAP, but not PMEDAP, were rev ersed by the adenylate deaminase inhibitor 2'-deoxycoformycin (dCF). Format ion of the deaminated derivative of cPr-PMEDAP (i.e. PMEG) was demonstrated in crude extracts from K562 and L1210 cells and in metabolism studies with radiolabeled cPr-PMEDAP and PMEG. This is the very first example of an acy clic nucleoside phosphonate analogue that is susceptible to deamination. Ho wever, cPr-PMEDAP was not recognized as a substrate by purified adenosine d eaminase or by adenylate deaminase. These findings might point to an as yet unidentified cellular enzyme, sensitive to dCF but different from the comm on adenosine and AMP deaminases. Our data demonstrate the superior antiprol iferative and differentiation-inducing effects of cPr-PMEDAP on tumor cells , as compared to the parent compound PMEDAP, based on the unique metabolic properties of this novel compound. (C) 1999 Elsevier Science Inc.