Synthesis of nonhydrolyzable analogues of thiazole-4-carboxamide and benzamide adenine dinucleotide containing fluorine atom at the C2' of adenine nucleoside: induction of K562 differentiation and inosine monophosphate dehydrogenase inhibitory activity.
Thiazole-4-carboxamide adenine dinucleotide (TAD) analogue 7 containing a fluorine atom at the C2' arabino configuration of the adenine nucleoside moiety was found to be a potent inducer of differentiation of K562 erythroid leukemia cells. This finding prompted us to synthesize its hydrolysis-resistant methylenebis(phosphonate) and difluoromethylenebis(phosphonate) analogues 8 and 9, respectively. Since both TAD and benzamide adenine dinucleotide (BAD) are potent inhibitors of inosine monophosphate dehydrogenase (IMPDH), the corresponding fluorine-substituted methylenebis(phosphonate) analogue 12 of BAD was also synthesized. Thus, 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (13) was converted in five steps into the corresponding methylenebis(phosphonate) analogue 18. Dehydration of 18 with DCC led to the formation of the bicyclic trisanhydride intermediate 19a, which upon reaction with 2',3'-O-isopropylidenetiazofurin (20) or -benzamide riboside (21) followed by hydrolysis and deprotection afforded the desired methylene-bridged dinucleotides 8 and 12, respectively. The similar displacement of the 5'-mesyl function of 2',3'-O-isopropylidene-5'-O-mesyltiazofurin (24) with the difluoromethylenebis(phosphonic acid) derivative gave the phosphonate 25 which was coupled with 13 to afford 26. The desired difluoromethylenebis(phosphonate) analogue 9 was obtained by deprotection with Dowex 50/H+. This compound as well as beta-CF2-TAD (4) showed improved differentiation-inducing activity over beta-CH2-TAD (3), whereas analogues containing the -CH2-linkage (8 and 12) were inactive.
Lesiak
K
K
Division of Medicinal Chemistry, Codon Pharmaceuticals, Inc., Gaithersburg, Maryland 20877, USA.
Watanabe
K A
KA
Majumdar
A
A
Seidman
M
M
Vanderveen
K
K
Goldstein
B M
BM
Pankiewicz
K W
KW
D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005461:Fluorine; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D004791:Enzyme Inhibitors; C100366:benzamide adenine nucleotide; D005461:Fluorine; C038167:thiazole-4-carboxamide adenine dinucleotide; D007168:IMP Dehydrogenase