TY - JOUR
T1 - Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia
AU - Pankiewicz, Krzysztof W
AU - Lesiak-Watanabe, Krystyna B.
AU - Watanabe, Kyoichi A.
AU - Patterson, Steven E.
AU - Jayaram, Hiremagalur N.
AU - Yalowitz, Joel A.
AU - Miller, Michael D.
AU - Seidman, Michael
AU - Majumdar, Alokes
AU - Prehna, Gerd
AU - Goldstein, Barry M.
PY - 2002/1/31
Y1 - 2002/1/31
N2 - 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 benzyl-protected 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 (IC50 = 0.7, μM and IC50 = 0.1 μM, respectively) as potently as mycophenolic acid (IC50 = 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.
AB - 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 benzyl-protected 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 (IC50 = 0.7, μM and IC50 = 0.1 μM, respectively) as potently as mycophenolic acid (IC50 = 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.
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U2 - 10.1021/jm0104116
DO - 10.1021/jm0104116
M3 - Article
C2 - 11806722
AN - SCOPUS:0037204010
VL - 45
SP - 703
EP - 712
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -