Novel inhibitors of prolyl 4-hydroxylase. Part 4 pyridine-2-carboxylic acid analogues with alternative 2-substituents

Dowell, Robert I.; Hales, NH; Tucker, Howard

doi:10.1016/0223-5234(93)90019-b

Cited by 25 publications

(24 citation statements)

References 21 publications

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“…Thus, considerable effort has been made to explore 25PDC derivatives. In particular, a variety of substitutions have been made at both the 2-position 50 and the 5-position 51 of the pyridine ring (Figure 5B). Regrettably, all of the substitutions for the 2-carboxyl group ( i.e ., N -acyl sulfonamides, tetrazole, hydroxamic acids, 2-imidazolyl, 2-pyrroyl, and others) were made in the absence of the 5-carboxyl group, thereby obfuscating comparisons.…”

Section: Akg Mimeticsmentioning

confidence: 99%

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Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

Vasta

Raines

2018

J. Med. Chem.

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Collagen is the dominant protein of the extracellular matrix. Its distinguishing feature is a three-stranded helix of great tensile strength. (2 S,4 R)-4-Hydroxyproline residues are essential for the stability of this triple helix. These residues arise from the post-translational modification of (2 S)-proline residues by collagen prolyl 4-hydroxylases (CP4Hs), which are members of the Fe(II)- and α-ketoglutarate (AKG)-dependent dioxygenase family. Here, we provide a framework for the inhibition of CP4Hs as the basis for treating fibrotic diseases and cancer metastasis. We begin with a summary of the structure and enzymatic reaction mechanism of CP4Hs. Then, we review the metal ions, metal chelators, mimetics of AKG and collagen strands, and natural products that are known to inhibit CP4Hs. Our focus is on inhibitors with potential utility in the clinic. We conclude with a prospectus for more effective inhibitors.

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Section: Akg Mimeticsmentioning

confidence: 99%

“…In general, though, modification of the 2-position in the absence of the 5-position carboxyl group did not yield potent inhibitors. 50 For example, many inhibitors were more potent than the parent pyridine-2-carboxylic acid, but most still exhibited IC 50 values in the mid-micromolar range, 50 and have not been developed further.…”

Section: Akg Mimeticsmentioning

confidence: 99%

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

Vasta

Raines

2018

J. Med. Chem.

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“…1C). The HAG mechanism was also employed to guide the de novo synthesis of prolyl 4-hydroxylase inhibitors [5,[28][29][30][31][32][33][34][35]. In fact, major reviews on the development of antifibrotic drugs have routinely included the reproduction of some version of Fig.…”

Section: The Hag Mechanism : a Synopsis Of Experimental Evidencementioning

confidence: 99%

The HAG Mechanism: A Molecular Rationale For The Therapeutic Application Of Iron Chelators In Human Diseases Involving the 2-Oxoacid Utilizing Dioxygenases

Hanauske-Abel¹,

Popowicz²

2003

CMC

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'Iron chelation' is widely understood as synonymous with non-specificity and viewed as a purely physicochemical mode of action, without any defined biomolecular target, broadly interfering with metalloenzymes. The 2-oxoacid-utilizing dioxygenases challenge this preconception. A family of non-heme iron enzymes that rely on chelation-dependent catalysis, they employ common molecules like Krebs cycle intermediates as endogenous iron chelators and consume atmospheric oxygen, inserting one of its atoms into cellular components. These enzymes control the adaptation of cells to hypoxia; the reversal of mutagenic DNA alkylations, the initiation of DNA replication, the translation of mRNAs; the production of extracellular matrix proteins like collagens and fibrillins; and numerous metabolic pathways: from the synthesis of the gibberellin growth hormones of plants, and the formation of carnitine, atropine, endotoxins, and cephalosporin antibiotics, to the breakdown of amino acids. Their pivotal roles in human pathology encompass oncogenesis and cancer angiogenesis, scarring and organ fibrosis, inherited diseases, and retroviral infections. Their unique catalysis, termed earlier the 'HAG mechanism' and known in subatomic detail, requires at least three different substrates to form three different products, and proceeds as a ligand reaction at the non-heme iron atom inside the active site pocket, without any direct involvement of apoenzyme residues. The apoenzyme sterically controls ligand access to the metal. The HAG mechanism-based concept of catalytic chelation directed by an apoenzyme, not merely by complexation parameters, has enabled knowledge-guided design of systemic and tissue-selective inhibitors, and of clinical trials. The HAG mechanism also lends itself to the development of novel, man-made biocatalysts.

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“…Because of its stability, ease of functionalization, and chelating metalcoordination, 2,2 0 -bipyridine, in particular, has been heavily used to link metals to other molecular subunits. [1] Additionally, bipyridines have played important roles in constructing supramolecular assemblies, [1][2][3] developing pharmaceuticals [4][5][6][7][8][9][10] and sensors, [11,12] and mimicking photosynthetic light conversion. [13] Recently, bipyridines have also been used to make functionalized polymers [14][15][16][17] and photocatalysts.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 5-(2,2′-Bipyridinyl and 2,2′-Bipyridinediiumyl)-2′-Deoxyuridine Nucleosides: Precursors to Metallo-Dna Conjugates

Gaballah

Kerr

Eaton

et al. 2002

Nucleosides, Nucleotides and Nucleic Acids

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The synthesis of 2,2'-bipyridinyl-2'-deoxyuridine metal-chelator nucleosides (Bipy-dU) with either ethynyl or ethylenyl linkers was now been accomplished. These new nucleosides will permit the construction of a number of corresponding metallo-DNA conjugates where many types of metals can be complexed to the 2,2'-bipyridinyl chelator group and the resulting metallo-dU conjugates incorporated into DNA oligonucleotides. Additionally this paper also reports the synthesis of a di-N-alkylated bipyridinediiumyl-2'-deoxyuridine nucleoside (Bipy(2+)-dU) with an ethylenyl linker. The Bipy(2+)-dU nucleoside was found to decompose under basic conditions precluding its use in standard automated DNA-synthesis by the phosphoramidite method. No such restrictions apply to the two Bipy-dU nucleosides reported here for use as metal chelators.

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Novel inhibitors of prolyl 4-hydroxylase. Part 4 pyridine-2-carboxylic acid analogues with alternative 2-substituents

Cited by 25 publications

References 21 publications

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

Collagen Prolyl 4-Hydroxylase as a Therapeutic Target

The HAG Mechanism: A Molecular Rationale For The Therapeutic Application Of Iron Chelators In Human Diseases Involving the 2-Oxoacid Utilizing Dioxygenases

Synthesis of 5-(2,2′-Bipyridinyl and 2,2′-Bipyridinediiumyl)-2′-Deoxyuridine Nucleosides: Precursors to Metallo-Dna Conjugates

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