Synthesis of a Methylenebis(phosphonate) Analogue of Mycophenolic Adenine Dinucleotide: A Glucuronidation-Resistant MAD Analogue of NAD (original) (raw)
Related papers
Journal of Medicinal Chemistry, 2002
Novel mycophenolic adenine dinucleotide (MAD) analogues have been prepared as potential inhibitors of inosine monophosphate dehydrogenase (IMPDH). MAD analogues resemble nicotinamide adenine dinucleotide binding at the cofactor binding domain of IMPDH; however, they cannot participate in hydride transfer and therefore inhibit the enzyme. The methylenebis-(phosphonate) analogues C2-MAD and C4-MAD were obtained by coupling 2′,3′-O-isopropylideneadenosine 5′-methylenebis(phosphonate) (22) with mycophenolic alcohols 20 and 21 in the presence of diisopropylcarbodiimide followed by deprotection. C2-MAD was also prepared by coupling of mycophenolic methylenebis(phosphonate) derivative 30 with 2′,3′-O-isopropylideneadenosine. Compound 30 was conveniently synthesized by the treatment of benzylprotected mycophenolic alcohol 27 with a commercially available methylenebis(phosphonic dichloride) under Yoshikawa's reaction conditions. C2-MAD and C4-MAD were found to inhibit the growth of K562 cells (IC 50 ) 0.7 µM and IC 50 ) 0.1 µM, respectively) as potently as mycophenolic acid (IC 50 ) 0.3 µM). In addition, C2-MAD and C4-MAD triggered vigorous differentiation of K562 cells an order of magnitude more potently than tiazofurin, and MAD analogues were resistant to glucuronidation in vitro. These results show that C2-MAD and C4-MAD may be of therapeutic interest in the treatment of human leukemias.
Synthesis and Stability of a 2′-O-[N-(Aminoethyl)carbamoyl]methyladenosine-Containing Dinucleotide
European Journal of Organic Chemistry, 2013
Working towards the synthesis of 2Ј-O-[N-(aminoethyl)carbamoyl]methyl-modified di-and oligonucleotides, we have synthesised a protected 2Ј-O-[N-(aminoethyl)carbamoyl]methyl-modified adenosine where the modification is introduced in a convenient one-pot three-step procedure. The corresponding H-phosphonate building block was also synthesised, and from this intermediate, a 2Ј-O-[N-(aminoethyl)carbamoyl]methyl-containing dinucleotide could be made. We also performed studies on the chemical and enzymatic stability of this dinucleotide. The dinucleotide was subjected to different ammonolysis and other basic conditions,
Helvetica Chimica Acta, 2007
Scheme 1 a) MsCl, 4-(dimethylamino)pyridine (DMAP), pyridine, r.t., 14 h. b) NaN 3 , DMF, 808, 31 h. c) 80% AcOH, 958, 1 h. d) 1. POCl 3 , (MeO) 3 PO, 08, 3 h; 2. H 2 O, NH 4 OH. e) 1. H 2 (30 psi), PtO 2 · H 2 O, H 2 O/ MeOH, r.t., 2 h; 2. Dowex 50WX4-400 (Na þ ). f) H 2 O/MeOH, Et 3 NH þ HCO À 3 , 408, 4 d. g) 1. AgNO 3 , DMF, pyridine, r.t., 40 h; 2. LiOH.