Novel Mycophenolic Adenine Bis(phosphonate) Analogues As Potential Differentiation Agents against Human Leukemia

Pankiewicz, Krzysztof W.; Lesiak‐Watanabe, K.; Watanabe, Kyoichi A.; Patterson, Steven; Jayaram, Hiremagalur N.; Yalowitz, Joel A.; Miller, Michael D.; Seidman, Michael M.; Majumdar, Angshuman; Prehna, Gerd; Goldstein, Barry

doi:10.1021/jm0104116

Cited by 52 publications

(39 citation statements)

References 31 publications

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“…Indeed, NAD(P)-binding domains usually show a relatively high degree of conservation among different enzymes. Contrary to this observation, potent and selective in vitro and in vivo inhibitors of different NAD(P)-dependent oxidoreductases have been found [112][113][114][115]. This finding can be rationalized by the concept that even subtle differences among the properties of the active sites of different dehydrogenases greatly affect their sensitivity toward different inhibitors.…”

Section: Future Directions: Defining Specific Ptfnr Inhibitorsmentioning

confidence: 90%

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Seeber¹,

Aliverti²,

Zanetti

2005

CPD

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Apicomplexa are unicellular, obligate intracellular parasites of great medical importance. They include human pathogens like Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease (toxoplasmosis). They alone affect several hundred million people worldwide so that new drugs, especially for plasmodial infections, are urgently needed. This review will focus on a recently emerged, potential drug target, a plant-type redox system consisting of ferredoxin-NADP(+) reductase (FNR) and its redox partner, ferredoxin (Fd). Both reside in an unique organelle of these parasites, named apicoplast, which is of algal origin. The apicoplast has been shown to be required for pathogen survival. In addition to other pathways already identified in this compartment, the FNR/Fd redox system represents a promising drug target because homologous proteins are not present in host organisms. Furthermore, a wealth of structural information exists on the closely related plant proteins, which can be exploited for structure-function studies of the apicomplexan protein pair. T. gondii and P. falciparum FNRs have been cloned, and the T. gondii enzyme was shown to be a flavoprotein active as a NADPH-dependent oxidoreductase. Both phylogenetic and biochemical analyses indicate that T. gondii FNR is similar in function to the isoform present in non-photosynthetic plastids whereby electron flow is from NADPH to oxidized Fd. The resulting reduced Fd is then presumably used as a reductant for various target enzymes whose nature is just starting to emerge. Among the likely candidates is the iron-sulfur cluster biosynthesis pathway, which is also located in the apicoplast and dependent on reducing power. Furthermore, lipoic acid synthase and enzymes of the isoprenoid biosynthetic pathway may be other conceivable targets. Since all these metabolic steps are vital for the parasite, blocking electron flow from FNR to Fd by inhibition of either FNR activity or its molecular interaction with Fd should also interfere with these pathways, ultimately killing the parasite. Although the three-dimensional structure of FNR from T. gondii is not yet known, experimental and computational evidence shows that apicomplexan and plant enzymes are very similar in structure. Furthermore, single amino acid changes can have profound effects on the enzyme activity and affinity for Fd. This knowledge may be exploited for the design of inhibitors of protein-protein interaction. On the other hand, specifically tailored NAD(P) analogues or mimetics based on previously described substances might be useful lead compounds for apicomplexan FNR inhibitors.

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Section: Future Directions: Defining Specific Ptfnr Inhibitorsmentioning

confidence: 90%

The Plant-Type Ferredoxin-NADP+ Reductase/Ferredoxin Redox System as a Possible Drug Target Against Apicomplexan Human Parasites

Seeber¹,

Aliverti²,

Zanetti

2005

CPD

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“…Strikingly, the A sub-site of the enzyme was empty. Thus, we linked the adenosine moiety to the MPA's truncated side chain through a metabolically stable methylenebis(phosphonate) linker and prepared the corresponding mycophenolic adenine dinucleotide analogue of NAD, called C2-MAD [60].…”

Section: Heterocyclic Inhibitors Bound At the N Sub-sitementioning

confidence: 99%

“…Earlier we prepared C4-MAD and C6-MAD analogues containing 4 and 6 carbon atoms, respectively, in the MPA side chain [60], Fig. (31).…”

Section: Binding At the P-groovementioning

confidence: 99%

Rehab of NAD(P)-Dependent Enzymes with NAD(P)-Based Inhibitors

Felczak

Pankiewicz

2011

CMC

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A large number of enzymes that use nicotinamide adenine dinucleotide NAD or its phosphorylated form NADP as a cofactor or substrate were found to play an important role in the growth and reproduction of living organisms. NAD(P)-dependent and NAD(P)-utilizing enzymes [NAD(P)-addicted?] have been extensively investigated and implicated in a wide variety of diseases. NAD, generally considered a key component involved in redox reactions, has been found to participate in a broad spectrum of cellular processes, including signal transduction, DNA repair, and post-translational protein modifications. The reduced form of NADP, i.e. NADPH, guards the cell against oxidative stress and it has been suggested that suppression of NADPH oxidase activity could result in anti-angiogenesis and anticancer effects. Consequently, small molecule NAD(P)-based inhibitors that selectively bind at the NAD(P)-binding domain of the targeted enzyme have been designed for novel treatment of medical disorders. The NAD(P)-binding domain is modular in nature; it can be divided into three sub-sites, the nicotinamide monophosphate (NMN) binding sub-site (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Each sub-site plays an important role in securing proper and tight binding; however, each has its own requirements. In this review we discuss a number of conformational and structural factors that might affect (improve) the affinity of various inhibitors to these sub-sites, as well as to the whole binding domain. We have focused on potential selectivity of NAD(P)-like molecules toward targeted enzymes and their potential application in biology and medicine.

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“…As a result, numerous MPA modifications together with their biological evaluations were reported. [7][8][9][10][11][12][13][14][15][16][17][18] Although MPA is produced in industrial scale via fermentation processes, 19 its price for laboratory scale is still high. In the chemical literature are described attempts of total synthetic MPA from commercially available substrates.…”

Section: Introductionmentioning

confidence: 99%