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

Abstract

Potent inhibitors of purine nucleoside phosphorylase (PNP) are expected to act as selective agents against T‐cell tumours. Five compounds with guanine, three with hypoxanthine, and five with 9‐deazaguanine, all connected by a linker with difluoromethylene phosphonic acid, were studied on their inhibitory potential against human and calf PNPs. Antiproliferative activity of these analogues against lymphocytes as well as lymphoma and leukaemia cells has been also investigated. All tested compounds act as multisubstrate analogue inhibitors of PNP with the apparent inhibition constants in the range 5–100 nm, and also show a slight antiproliferative activity. Analogues with 9‐deazaguanine aglycone have better anti‐leukaemic and anti‐lymphoma activities compared to the guanine and hypoxanthine analogues, and applied in the concentration of 100 μm, caused a statistically significant decrease in the cell viability in all human leukaemia and lymphoma cells used. Despite the high PNP inhibitory potential of tested analogues, no differences were observed between the effects on the growth of tumour cells sensible to the inhibition of PNP, such as human adult T‐cell leukaemia and lymphoma cells, and other investigated cells. Obtained poor effects on cell proliferation could be explained probably by a poor ability of tested compounds to penetrate cell membranes.

SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP

“…Finally, we tested whether other PNP inhibitors might induce death of SAMHD1-deficient cells in the presence of dG. Indeed, BMDMs showed reduced viability upon exposure to either homo-DFPP-DG or 6C-DFPP-DG (Glavas-Obrovac et al, 2010;Hikishima et al, 2007Hikishima et al, , 2010 together with low doses of dG (Figures 4M and 4N). Taken together, these data show that SAMHD1 protected cells against death that was synergistically induced by PNP inhibitors and dG.…”

SAMHD1 limits the efficacy of forodesine in leukaemia by protecting cells against cytotoxicity of dGTP

“…Finally, we tested whether other PNP inhibitors might induce death of SAMHD1-deficient cells in the presence of dG. Indeed, BMDMs showed reduced viability upon exposure to either homo-DFPP-DG or 6C-DFPP-DG (Glavas-Obrovac et al, 2010; Hikishima et al, 2007, 2010) together with low doses of dG (Figure 4M,N). Taken together, these data showed that SAMHD1 protected cells against death that was synergistically induced by PNP inhibitors and dG.…”

Medicinal Chemistry of Fluorinated Cyclic and Acyclic Nucleoside Phosphonates

“…Another series of guanine analogues 199–203 (Fig. ) containing a branched aliphatic chain terminated with the α , α ‐(difluoromethylene)phosphonate group was confirmed to be the multisubstrate PNP inhibitors with activities ranging from 7.2 to 15 nM . Very potent PNP inhibitors among the ANPs represent the 9‐deazaguanine analogues 204–208 (Fig.…”

“…48) containing a branched aliphatic chain terminated with the α,α-(difluoromethylene)phosphonate group was confirmed to be the multisubstrate PNP inhibitors with activities ranging from 7.2 to 15 nM. 182 Very potent PNP inhibitors among the ANPs represent the 9-deazaguanine analogues 204-208 ( Fig. 48), designed by Yokomatsu et al 183 Among them, 9 -(5,5 -difluoro-5 -phosphonopentyl)-9-deazaguanine (DFPP-DG, 205) possesses subnanomolar activities measured on calf PNP (K i = 85 pM) and is almost as potent as the transition state inhibitors immucillins, [184][185][186][187] for example, immucillin H 209 (K i = 23 pM, calf PNP).…”