title: Targeting 5'-deoxy-5'-(methylthio)adenosine phosphorylase by 5'-haloalkyl analogues of 5'-deoxy-5'-(methylthio)adenosine.
abstract: A series of 5'-haloalkyl-modified analogues of 5'-deoxy-5'-(methylthio)adenosine (MTA), a nucleoside byproduct of polyamine biosynthesis, has been synthesized: 5'-deoxy-5'-[(2-monofluoroethyl)thio]adenosine (10), 5'-deoxy-5'-[(2-chloroethyl)thio]adenosine (4), 5'-deoxy-5'-[(2-bromoethyl)thio] adenosine (5), and 5'-deoxy-5'-[(3-monofluoropropyl)thio]adenosine (13). On the basis of their abilities to serve as substrates of MTA phosphorylase prepared from mouse liver, several of these analogues were characterized for their growth inhibitory effects in MTA phosphorylase-containing (murine L5178Y and human MOLT-4) and MTA phosphorylase-deficient (murine L1210 and human CCRF-CEM) leukemia cell lines. The MTA phosphorylase-containing tumor cell lines, especially of human origin, were found to be more sensitive to treatment by these analogues. Of the analogue series, 10 was the most potent inhibitor of growth in each of the cell lines tested. The analogues, especially compound 10, displayed a reduced capacity to alter polyamine pools relative to MTA, mechanistically indicating a decreased potential for interactions at sites other than MTA phosphorylase. The results indicate that of the analogues tested, compound 10 displayed the best inhibitor/substrate interaction with MTA phosphorylase, which, in turn, correlated with more potent growth inhibition in tumor cell lines containing MTA phosphorylase. Overall, this supports the concept that MTA phosphorylase plays a role in the activation of such analogues.
authors.affiliation: Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: J R
authors.initials: JR
authors.lastname: Sufrin
authors.forename: A J
authors.initials: AJ
authors.lastname: Spiess
authors.forename: D L
authors.initials: DL
authors.lastname: Kramer
authors.forename: P R
authors.initials: PR
authors.lastname: Libby
authors.forename: J T
authors.initials: JT
authors.lastname: Miller
authors.forename: R J
authors.initials: RJ
authors.lastname: Bernacki
authors.forename: Y H
authors.initials: YH
authors.lastname: Lee
authors.forename: R T
authors.initials: RT
authors.lastname: Borchardt
authors.forename: C W
authors.initials: CW
authors.lastname: Porter
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D043383:Adenosylhomocysteinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003839:Deoxyadenosines; D004355:Drug Stability; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors; D007939:Leukemia L1210 / Q000188:drug therapy; D007942:Leukemia, Experimental / Q000188:drug therapy; D008099:Liver / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D011073:Polyamines / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003839:Deoxyadenosines; D011073:Polyamines; D013872:Thionucleosides; C070497:5'-deoxy-5'-((2-monofluoroethyl)thio)adenosine; C008500:5'-methylthioadenosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine