N6-cyclopropyl-PMEDAP: a novel derivative of 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) with distinct metabolic, antiproliferative, and differentiation-inducing properties

摘要: N6-Cyclopropyl-PMEDAP (cPr-PMEDAP) is a novel derivative of the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP). Its cytostatic activity was found to be 8- 20-fold more pronounced than that PMEDAP and equivalent guanine 9-(2-phosphonylmethoxyethyl)guanine (PMEG) against variety tumor cell lines. Unlike PMEDAP, but like PMEG, cPr-PMEDAP equally wild-type 9-(2-phosphonylmethoxyethyl)adenine/PMEDAP-resistant variants human erythroleukemia K562 murine leukemia L1210 Also, PMEG proved equipotent inducers rat choriocarcinoma RCHO differentiation, whereas differentiation-inducing 5- 25-fold less pronounced. Furthermore, compared were 10- potent in inhibiting progression cells through S phase cycle, resulting marked accumulation four 2'-deoxyribonucleoside 5'-triphosphate pools. The biological effects cPr-PMEDAP, not reversed by adenylate deaminase inhibitor 2'-deoxycoformycin (dCF). Formation deaminated (i.e. PMEG) demonstrated crude extracts from metabolism studies with radiolabeled PMEG. This very first example an analogue susceptible deamination. However, recognized as substrate purified adenosine or deaminase. These findings might point yet unidentified cellular enzyme, sensitive dCF different common AMP deaminases. Our data demonstrate superior antiproliferative on cells, parent compound based unique metabolic properties this compound.