Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants

K. W. Pankiewicz, K. Malinowski, H. N. Jayaram, K. Lesiak-Watanabe, K. A. Watanabe

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Mycophenolic acid (MPA) is the most potent and specific inhibitor of inosine monophosphate dehydrogenase (IMPDH). This compound was reported to bind the NAD site of IMPDH and mimic the binding of nicotinamide moiety of nicotinamide adenine dinucleotide. We linked MPA derivatives with the adenine moiety of NAD through a methylenebis(phosphonate) bridge to form novel mycophenolic adenine dinucleotides (MADs) which resemble well the intact natural cofactor. The MAD analogues differ by the length of the side chain (linker) between the aromatic ring of mycophenolic derivative and the β- phosphorus atom of the adenosine bis(phosphonate) moiety. Regardless of the linker size, MADs were found to be potent inhibitors of human IMPDH type I and type II with K(i)'s = 0.25-0.52 μM, an order of magnitude less potent than MPA itself (K(i) = 0.01-0.04 μM). The growth of K562 cells was inhibited by MPA (IC50 = 0.3 μM) and the MAD analogues (IC50 = 0.1-1.5 μM) with a similar potency. Accordingly, a suppression of alloantigen- induced proliferation of human lymphocytes by the MAD analogues at concentration of 10-20 μM was equally effective as that observed for MPA. In contrast to MPA, MAD analogues were found to be resistant to glucuronidation in vitro. Since therapeutic potential of MPA is limited by its undesirable glucuronidation, the glucuronidation-resistant MAD analogues may be superior immunosuppressants if they are not glucuronidated in vivo.

Original languageEnglish
Pages (from-to)629-634
Number of pages6
JournalCurrent Medicinal Chemistry
Volume6
Issue number7
StatePublished - 1999

Fingerprint

Mycophenolic Acid
Organophosphonates
Adenine
Immunosuppressive Agents
Inosine Monophosphate
NAD
Oxidoreductases
Inhibitory Concentration 50
Derivatives
Niacinamide
Isoantigens
Lymphocytes
K562 Cells
mycophenolic adenine dinucleotide
Adenosine
Phosphorus
Atoms
Growth

ASJC Scopus subject areas

  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology

Cite this

Pankiewicz, K. W., Malinowski, K., Jayaram, H. N., Lesiak-Watanabe, K., & Watanabe, K. A. (1999). Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants. Current Medicinal Chemistry, 6(7), 629-634.

Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants. / Pankiewicz, K. W.; Malinowski, K.; Jayaram, H. N.; Lesiak-Watanabe, K.; Watanabe, K. A.

In: Current Medicinal Chemistry, Vol. 6, No. 7, 1999, p. 629-634.

Research output: Contribution to journalArticle

Pankiewicz, KW, Malinowski, K, Jayaram, HN, Lesiak-Watanabe, K & Watanabe, KA 1999, 'Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants', Current Medicinal Chemistry, vol. 6, no. 7, pp. 629-634.
Pankiewicz KW, Malinowski K, Jayaram HN, Lesiak-Watanabe K, Watanabe KA. Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants. Current Medicinal Chemistry. 1999;6(7):629-634.
Pankiewicz, K. W. ; Malinowski, K. ; Jayaram, H. N. ; Lesiak-Watanabe, K. ; Watanabe, K. A. / Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants. In: Current Medicinal Chemistry. 1999 ; Vol. 6, No. 7. pp. 629-634.
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