Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia

Krzysztof W. Pankiewicz, Krystyna B. Lesiak-Watanabe, Kyoichi A. Watanabe, Steven E. Patterson, Hiremagalur N. Jayaram, Joel A. Yalowitz, Michael D. Miller, Michael Seidman, Alokes Majumdar, Gerd Prehna, Barry M. Goldstein

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)703-712
Number of pages10
JournalJournal of Medicinal Chemistry
Volume45
Issue number3
DOIs
StatePublished - Jan 31 2002

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Organophosphonates
Adenine
Leukemia
Inhibitory Concentration 50
Inosine Monophosphate
K562 Cells
Oxidoreductases
Alcohols
Mycophenolic Acid
Hydrides
NAD
C2-mycophenolic adenine dinucleotide
Derivatives
C4-mycophenolic adenine dinucleotide
Enzymes
Growth
mycophenolic adenine dinucleotide

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Pankiewicz, K. W., Lesiak-Watanabe, K. B., Watanabe, K. A., Patterson, S. E., Jayaram, H. N., Yalowitz, J. A., ... Goldstein, B. M. (2002). Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. Journal of Medicinal Chemistry, 45(3), 703-712. https://doi.org/10.1021/jm0104116

Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. / Pankiewicz, Krzysztof W.; Lesiak-Watanabe, Krystyna B.; Watanabe, Kyoichi A.; Patterson, Steven E.; Jayaram, Hiremagalur N.; Yalowitz, Joel A.; Miller, Michael D.; Seidman, Michael; Majumdar, Alokes; Prehna, Gerd; Goldstein, Barry M.

In: Journal of Medicinal Chemistry, Vol. 45, No. 3, 31.01.2002, p. 703-712.

Research output: Contribution to journalArticle

Pankiewicz, KW, Lesiak-Watanabe, KB, Watanabe, KA, Patterson, SE, Jayaram, HN, Yalowitz, JA, Miller, MD, Seidman, M, Majumdar, A, Prehna, G & Goldstein, BM 2002, 'Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia', Journal of Medicinal Chemistry, vol. 45, no. 3, pp. 703-712. https://doi.org/10.1021/jm0104116
Pankiewicz KW, Lesiak-Watanabe KB, Watanabe KA, Patterson SE, Jayaram HN, Yalowitz JA et al. Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. Journal of Medicinal Chemistry. 2002 Jan 31;45(3):703-712. https://doi.org/10.1021/jm0104116
Pankiewicz, Krzysztof W. ; Lesiak-Watanabe, Krystyna B. ; Watanabe, Kyoichi A. ; Patterson, Steven E. ; Jayaram, Hiremagalur N. ; Yalowitz, Joel A. ; Miller, Michael D. ; Seidman, Michael ; Majumdar, Alokes ; Prehna, Gerd ; Goldstein, Barry M. / Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 3. pp. 703-712.
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AU - Yalowitz, Joel A.

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AU - Goldstein, Barry M.

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