Synthesis and evaluation of α,β-unsaturated α-aryl-substituted fosmidomycin analogues as DXR inhibitors

Devreux, Vincent; Wiesner, Jochen; Jomaa, Hassan; Eycken, Johan Van der; Calenbergh, Serge Van

doi:10.1016/j.bmcl.2007.06.026

Cited by 25 publications

(9 citation statements)

References 20 publications

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“…10) has shown promise in clinical trials for malaria by targeting the mevalonate-independent isoprenoid biosynthesis pathway in this bacterium. 71,73,74 Fosmidomycin inactivates the essential 1deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) enzyme in this pathway (IC 50 ¼ 35 nM in recombinant E. coli DXR). Devreux et al synthesized a small library of a-arylphosphonates (not shown) using either Stille or Suzuki coupling via fully protected a-bromophosphonate 47.…”

Section: A-bromophosphonates On a Carbohydrate Scaffoldmentioning

confidence: 99%

“…The results of assays with the a-functionalized phosphonates against recombinant E. coli DXR found that only a-bromophosphonate 47 had a submicromolar IC 50 (450 nM). 71 2.5. a-Bromophosphonocarboxylates and abromobisphosphonates Phosphonocarboxylates and bisphosphonates have a host of medicinally important effects ranging from the prevention of bone resorption to cancer chemotherapy as bioisosteres of pyrophosphate. 75,76 Bisphosphonates are well known to have affinity for bone.…”

Section: A-bromophosphonates On a Carbohydrate Scaffoldmentioning

confidence: 99%

“…10 Structures of fosmidomycin ( 46) and a-bromo-a,b-unsaturated phosphonate 47 that was screened against recombinant E. coli DXR. 71 Scheme 14 Access to a-bromo and a,a-dibromophosphonoacetates.…”

Section: A-bromophosphonates On a Carbohydrate Scaffoldmentioning

confidence: 99%

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Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

Downey

Cairo

2014

Med. Chem. Commun.

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Substrate phosphorylation is a key modulator of signal transduction. Abnormal phosphorylation in vivo is implicated in many diseases including cancer, diabetes, and Alzheimer's disease. Inhibitors of phosphaterecognizing proteins have potential as medicinal agents as well as tools to study phosphorylation pathways. A well-known and common inhibition strategy is to synthetically replace the labile phosphate moiety with a non-hydrolyzable phosphonate. Fully saturated, a-fluoro and a,a-difluorophosphonates are often effective phosphate bioisosteres and have been well studied. More recently a-brominated phosphonates have begun to emerge as inhibitors of phosphate recognizing enzymes, some of which operate by irreversible mechanisms. Herein we discuss the synthetic approaches to aliphatic and benzylic a-bromophosphonates and their biological activities.Scheme 5 The synthesis of an aliphatic a-bromophosphonate derivative. 52 Scheme 6 An improved synthetic strategy to alkyl abromophosphonates. 53This journal is

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Section: A-bromophosphonates On a Carbohydrate Scaffoldmentioning

confidence: 99%

Section: A-bromophosphonates On a Carbohydrate Scaffoldmentioning

confidence: 99%

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Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

Downey

Cairo

2014

Med. Chem. Commun.

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“…However, the high recurrence rate necessitated the combination with established second antimalarial [59][60][61]. More recently, a variety of aryl and alkyl derivatives of fosmidomycin (13) have been synthesized [51, 53, [62][63][64][65][66][67][68][69]. Some derivatives showed improved IC50 values, in the single digit nanomolar range, for IspC from P. falciparum.…”

Section: Elucidation Of the Non-mevalonate Pathway Using Genomicsmentioning

confidence: 99%

Biochemistry of the non-mevalonate isoprenoid pathway

Gräwert

Groll

Rohdich

et al. 2011

Cell. Mol. Life Sci.

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The non-mevalonate pathway of isoprenoid (terpenoid) biosynthesis is essential in many eubacteria including the major human pathogen, Mycobacterium tuberculosis, in apicomplexan protozoa including the Plasmodium spp. causing malaria, and in the plastids of plants. The metabolic route is absent in humans and is therefore qualified as a promising target for new anti-infective drugs and herbicides. Biochemical and structural knowledge about all enzymes involved in the pathway established the basis for discovery and development of inhibitors by high-throughput screening of compound libraries and/or structure-based rational design.

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“…N -acylhydroxylamine) functionality. Like the structurally-related hydroxamic acids, reverse hydroxamates possess the ability to complex active site zinc5 and have recently been employed as inhibitors of a number of medicinally relevant metalloenzymes, including peptide deformylase (PDF),6 TNF-α converting enzyme (TACE),7 matrix metalloproteinases (MMP’s),8 and 1-deoxy-D-xylulose-5-phosphate reductoisomerase9 (DXR, a prospective drug target for selected bacteria and for the protozoan parasite Plasmodium falciparum , a causative agent for malaria, where the reverse hydroxamate functionality complexes manganese instead of zinc10). Corresponding 6β-(hydroxymethyl)penicillinates, both as sulfides,11 3a , and as sulfones,12 3b , have been described previously.…”

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confidence: 99%

Approaches to the simultaneous inactivation of metallo- and serine-β-lactamases

Ganta

Perumal²,

Pagadala³

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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A series of cephalosporin-derived reverse hydroxamates and oximes were prepared and evaluated as inhibitors of representative metallo- and serine-β-lactamases. The reverse hydroxamates showed submicromolar inhibition of the GIM-1 metallo-β-lactamase. With respect to interactions with the classes A, C, and D serine β-lactamases, as judged by their correspondingly low Km values, the reverse hydroxamates were recognized in a manner similar to the non-hydroxylated N-H amide side chains of the natural substrates of these enzymes. This indicates that, with respect to recognition in the active site of the serine β-lactamases, the O=C-NR-OH functionality can function as a structural isostere of the O=C-NR-H group, with the NO-H group presumably replacing the amide N-H group as a hydrogen bond donor to the appropriate backbone carbonyl oxygen of the protein. The reverse hydroxamates, however, displayed kcat values up to three orders of magnitude lower than the natural substrates, thus indicating substantial slowing of the hydrolytic action of these serine β-lactamases. Although the degree of inactivation is not yet enough to be clinically useful, these initial results are promising. The substitution of the amide N-H bond by N-OH may represent a useful strategy for the inhibition of other serine hydrolases.

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Synthesis and evaluation of α,β-unsaturated α-aryl-substituted fosmidomycin analogues as DXR inhibitors

Cited by 25 publications

References 20 publications

Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

Synthesis of α-brominated phosphonates and their application as phosphate bioisosteres

Biochemistry of the non-mevalonate isoprenoid pathway

Approaches to the simultaneous inactivation of metallo- and serine-β-lactamases

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