title: 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 mum, 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.
authors.affiliation: School of Medicine, J.J. Strossmayer University of Osijek and University Hospital Osijek J. Huttlera 4, Osijek, HR-31000, Croatia. glavas-obrovac.ljubica@kbo.hr
authors.forename: Ljubica
authors.initials: L
authors.lastname: Glavas-Obrovac
authors.forename: Mirjana
authors.initials: M
authors.lastname: Suver
authors.forename: Sadao
authors.initials: S
authors.lastname: Hikishima
authors.forename: Mariko
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yokomatsu
authors.forename: Lucyna
authors.initials: L
authors.lastname: Magnowska
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Bzowska
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D063065:Organophosphonates / Q000737:chemistry* / Q000627:therapeutic use; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D006147:Guanine; C076777:9-deazaguanine; D011683:Purine-Nucleoside Phosphorylase