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Antiproliferative Activity of Purine Nucleoside Phosphorylase Multisubstrate Analogue Inhibitors Containing Difluoromethylene Phosphonic Acid against Leukemia and Lymphoma Cells

Proliferative capacity of lymphocytes, especially of T-cells, depends on purine salvage metabolism mostly. Purine nucleoside phosphorylase (PNP, E.C.2.4.2.1) catalyzes the reversible phosphorolysis of nucleosides and deoxynucleosides which is an important step of purine catabolism pathway. Type IV autoimmune disorders, T-cell proliferative disorders, as well as adult T-cell leukaemia and lymphoma, are very interesting targets for compounds with PNP inhibiting activity. In our search for compounds efficient as PNP inhibitors, five compounds with guanine moiety, three with hypoxanthine moiety, and five compounds with 9-deazaguanine moiety, all connected by a linker with difluoromethylene phosphonic acid were synthesized and tested for PNP inhibitory potential in vitro on calf spleen and human erythrocyte PNPs, respectively. Their antiproliferative potential in vitro against seven human haematological malignancies using MTT test was investigated also. Obtained results show that all analogues inhibit mammalian PNPs with inhibition constants ranging from 5 to 70 nM. Screening of their in vitro anti-leukaemia and anti-lymphoma activity has evidences that compounds with 9-deazaguanine moiety has better inhibitory potential in comparison with guanine and hypoxantine analogues. No differences were observed between the effects on the growth of tumour cells sensible to inhibition of PNP activity, such as human adult T-cell leukaemia and lymphoma cells, and other leukaemia and lymphoma cells of B-cell, or non-T-, and non-B-cell lineages.

T-cell leukaemia and lymphoma cells; antiproliferative activity; purine nucleoside phosphorylase inhibtors; Deazaguanine ananlogues with difluoromethylene phosphonic acid

DOI: 10.1111/j.1742-4658.2009.07049.x