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Nicotinamide Adenine Dinucleotide Based Therapeutics, Update
No full textAbout 500 NAD (P)-dependent enzymes in the cell use NAD (P) as a cofactor or a substrate. This family of broadly diversified enzymes is crucial for maintaining homeostasis of all living organisms. The NAD binding domain of these enzymes is conserved and it was believed that NAD mimics would not be of therapeutic value due to lack of selectivity. Consequently, only mycophenolic acid which selectively binds at the cofactor pocket of NAD-dependent IMP-dehydrogenase (IMPDH) has been approved as an immunosuppressant. Recently, it became clear that the NAD (P)-binding domain was structurally much more diversified than anticipated and numerous highly potent and selective inhibitors of NAD (P) dependent enzymes have been reported. It is likely, that as in the case of protein kinases inhibitors, inhibitors of NAD (P)-dependent enzymes would find soon their way to the clinic. In this review, recent developments of selective inhibitors of NAD-dependent human IMPDH, as well as inhibitors of IMPDHs from parasites, and from bacterial sources are reported. Therapies against Cryptosporidium parvum and the development of new antibiotics that are on the horizon will be discussed. New inhibitors of bacterial NAD-ligases, NAD-kinases, NMN-adenylyl transferases, as well as phosphoribosyl transferases are also described. Although none of these compounds has yet to be approved, the progress in revealing and understanding crucial factors that might allow for designing more potent and efficient drug candidates is enormous and highly encouraging
SYNTHESIS OF NAD ANALOGS AS SELECTIVE INHIBITORS OF INOSINE MONOPHOSPHATE DEHYDROGENASE
No full textC-nucleosides are composed of an aromatic moiety linked to a carbohydrate derivative thanks to a stable carbon-carbon bond rather than a hydrolysable carbon-nitrogen bond present in regular nucleosides. C-nucleosides are generally synthesized by two main approaches. In the first approach heterocyclic bases are built, starting from a functional group introduced at the anomeric position of the carbohydrate. The second approach is based on the direct attachment of aromatic or heterocylic moieties to the protected ribose derivative. Two C-nucleosides, tiazofurin and benzamide riboside, show a potent inhibitory activity against Inosine Monophosphate Dehydrogenase (IMPDH) when converted to their corresponding tiazofurin- and benzamide adenine dinucleotide (TAD and BAD). We will discuss the synthesis of TAD analogues containing a substituent at the C2 of adenine ring that inhibit IMPDH with Ki in 1-10 nM range. We will also report modified BAD analogues with inhibitory activity against NAD kinase and M. tuberculosis enoyl ACP reductase
Compact NAD mimics as selective inhibitors of NAD kinases
No full textWe have examined sequence diversity of 147 co-crystal structures of proteins utilizing NAD as a cofactor or as a substrate. Most of these proteins bind NAD in an extended conformation (e.g. the distance between the adenine 6-amino group of NAD and the nicotinamide amide carbon is 16 Å or more). However, there are clear exceptions to this general trend. Several bacterial reductases bind NAD in an extremely folded conformation (the distance of 6 Å) and NAD kinases bind NAD in bent (compact) conformations with the distance of 11-12 Å. Although NAD can be accommodated in all of the above conformations it is likely that compact NAD mimics (with the distance of 11-12 Å) should not fit to the binding domains of majority of NAD-utilizing enzymes that require an extended conformation of NAD. It may be expected, therefore, that such compounds could be selective against NAD kinases.
Tiazofurin adenine dinucleotide (TAD) is a potent inhibitor (Ki = 100 nM) of NAD-dependent IMP-dehydrogenase. This NAD mimic binds at the cofactor binding domain in the extended conformation. As a proof of concept, we prepared tiazofurin-5’-yl adenosine-5’-yl disulfide (1) by replacing the pyrophosphate (-O-P-O-P-O-) linkage by a short (-S-S-) disulfide bridge. We found that this compact disulfide analogue of TAD has lost its activity against IMPDH and became a moderate inhibitor of M. tuberculosis (IC50 = 80 μM) NAD kinase. We also found that di(adenosine-5’yl) disulfide (2), a by-product in the synthesis of 1, showed slightly better activity against mycobacterium (IC50 = 45 μM) as well as human (IC50 = 87 μM) NAD kinase. Introduction of bromine at the C-8 of adenine ring results in restriction of conformation of 8-bromo-adenosine to the syn conformation. We prepared the corresponding 8-bromo disulfide (3) and found further improvement in the inhibitory activity against human (IC50 = 6 μM) and mycobacterium (IC50 = 14) NAD kinase. Compound 3 is the most potent inhibitor of NAD kinases reported so far. Using a simple method for preparation of disulfide 2 we synthesized a number of nucleobase and sugar modified analogues that have been evaluated against these enzymes, and we will discuss our results
DESIGN AND SYNTHESIS OF NOVEL INHIBITORS OF INOSINE MONOPHOSPHATE DEHYDROGENASE
No full textInosine Monophosphate Dehydrogenase (IMPDH) is a well known therapeutic target for new drug development against organ transplant rejection, viral infection and cancer due to its key role in de novo synthesis of purine nucleotides. Following our discovery of mycophenolic adenine dinucleotide (MAD) analogues such as C2-MAD, we designed and synthesized a series of C2-MAD analogues and evaluated their activities against IMPDH (type I and type II). We introduced different functional groups at the 2-position of adenine improving the potency and selectivity of new compounds against the type I and type II isoforms of the human enzyme. We also designed and synthesized compounds with new linkages between adenosine and mycophenolic moiety. Some of them showed more potent inhibition of IMPDH than the parent MAD analogues
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Cofactor-type inhibitors of inosine monophosphate dehydrogenase via modular approach: Targeting the pyrophosphate binding sub-domain
No full textCofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide
adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the
three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding subsite
(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). Mycophenolic acid (MPA) shows high affinity to the N
sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the
MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues
that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue
4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(
phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (Ki = 5 nM), and
one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC50 = 0.45 lM).
Compound 4 was as potent as Gleevec (IC50 = 0.56 lM) heralded as a ‘magic bullet’ against chronic myelogenous
leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate)
linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation.
Some novel MAD analogues described herein containing linkers of different length and geometry
were found to inhibit IMPDH with Ki’s lower than 100 nM. Thus, such linkers can be used for connection
of other molecular fragments with high affinity to the N- and A-sub-site of IMPDH
Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure
No full textSmall molecules that act on multiple biological targets have been proposed to combat the drug resistance
commonly observed for cancer chemotherapy. By combining the structural features of known inhibitors
of inosine monophosphate dehydrogense (IMPDH) and histone deacetylase (HDAC), dual inhibitors of
IMPDH and HDAC based on the scaffold of cinnamic hydroxamic acid (CHA) have been designed, synthesized,
and evaluated in biological assays. Key features, including the linker length, linker functionality,
substitution position, and interacting groups, have been explored. Their individual contribution to the
inhibitory activities against human IMPDH1 and IMPDH2 as well as HDAC has been assessed
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