Total synthesis of borrelidin

Nagamitsu, Tohru; Harigaya, Yoshihiro; Ōmura, Satoshi

doi:10.2183/pjab.81.244

Cited by 11 publications

(8 citation statements)

References 21 publications

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“…The use of L-asparaginase, an asparagine hydrolyzing enzyme, in ALL therapy for more than 3 decades suggests that amino acid limitation may be used as a therapeutic approach to treat ALL [4,25]. The small molecule drug, borrelidin, is a selective inhibitor of threonyl tRNA synthetase [17,18]. This drug has attracted attention because it displays strong nanomolar antiangiogenic activity and shows anti-metastatic effects in animal models [17,18,26].…”

Section: Discussionmentioning

confidence: 99%

“…The small molecule drug, borrelidin, is a selective inhibitor of threonyl tRNA synthetase [17,18]. This drug has attracted attention because it displays strong nanomolar antiangiogenic activity and shows anti-metastatic effects in animal models [17,18,26]. Borrelidin potently inhibits capillary tube formation and induces apoptosis of the tube-forming cells via activation of the caspase-3 and caspase-8 pathways which leads to the disruption of the formed capillary tubes [17].…”

Section: Discussionmentioning

confidence: 99%

“…Borrelidin was also found to be a potent and selective inhibitor of bacterial and eukaryal threonyl-tRNA synthetase (ThrRS), an enzyme which functions to couple the essential amino acid threonine with its cognate tRNA. Aminoacyl-tRNAs are the products of the first step in protein biosynthesis, and borrelidin-mediated inhibition of aminoacyl tRNA synthesis, leads to an induction in the levels of uncharged tRNA and ultimately inhibition of protein synthesis [17,18]. Indoleamine 2, 3 dioxygenase (IDO), similarly to ASNase and borrelidin, induces amino acid deprivationmediated stress in cells through catabolism of tryptophan.…”

Section: Introductionmentioning

confidence: 99%

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Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia

et al. 2011

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Due to the poor prognosis and limited therapeutic options for adult patients with acute lymphoblastic leukemia (ALL), development of novel therapies is much needed to prolong patient survival and increase the efficacy of their treatment. Malignant T cells need high levels of nutrients to maintain their proliferation rate. Borrelidin, a small molecule nitrile-containing macrolide, is an inhibitor of bacterial and eukaryal threonyl-tRNA synthetase. Borrelidin-mediated inhibition of aminoacyl-tRNA synthesis, leads to an induction in the levels of uncharged tRNA, nutritional stress and ultimately inhibition of protein synthesis. The aim of the present study was to investigate whether borrelidin treatment inhibits the proliferation of malignant ALL cell lines, Jurkat and CEM cells, and study the mechanism by which this drug acts. Our results show that borrelidin was able to potently inhibit the proliferation of ALL cell lines with a half maximal inhibitory concentration of 50 ng/ml. Borrelidin showed a greater inhibitory effect on ALL cell lines compared to primary fibroblasts. Flow cytometry and western blot analysis indicated that borrelidin was able to increase the level of apoptosis and cause G(1) arrest in ALL cell lines. Activation of the general control nonderepressible-2 (GCN2) kinase stress responsive pathway and induction of CHOP protein was significantly higher in ALL cell lines treated with borrelidin. These findings collectively suggest for the first time that borrelidin targets ALL cell lines by inducing apoptosis and mediating G(1) arrest and that borrelidin treatment in ALL cell lines is correlated with activation of the GCN2 kinase pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia

et al. 2011

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“…Ester 40 was converted in 8 steps and 36 % overall yield to the C3‐C11 fragment 49 of angiogenesis inhibitor (−)‐borrelidine 50 via anti ‐selective alkylation of Meyer’s pseudo‐ephedrine auxiliary ( R , R )‐ 47 as the key step (Scheme ) 91. 92 As the conversion of compound 49 to the natural product 50 has been already reported,93 this chemoenzymatic sequence provides a formal total synthesis of (−)‐borrelidine 50 .…”

Section: Oxidation Of Non‐activated Sp3 Ch Bonds In Alkanes and Cmentioning

confidence: 99%

Selective Catalytic Oxidation of CH Bonds with Molecular Oxygen

et al. 2012

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Although catalytic reductions, cross‐couplings, metathesis, and oxidation of CC double bonds are well established, the corresponding catalytic hydroxylations of CH bonds in alkanes, arenes, or benzylic (allylic) positions, particularly with O2, the cheapest, “greenest”, and most abundant oxidant, are severely lacking. Certainly, some promising examples in homogenous and heterogenous catalysis exist, as well as enzymes that can perform catalytic aerobic oxidations on various substrates, but these have never achieved an industrial‐scale, owing to a low space‐time‐yield and poor stability. This review illustrates recent advances in aerobic oxidation catalysis by discussing selected examples, and aims to stimulate further exciting work in this area. Theoretical work on catalyst precursors, resting states, and elementary steps, as well as model reactions complemented by spectroscopic studies provide detailed insight into the molecular mechanisms of oxidation catalyses and pave the way for preparative applications. However, O2 also poses a safety hazard, especially when used for large scale reactions, therefore sophisticated methodologies have been developed to minimize these risks and to allow convenient transfer onto industrial scale.

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“…The polyketide natural product (-)-borrelidin (1, Scheme 1), first isolated from Streptomyces rochei in 1949 by Berger, [1] has received increasing interest due to its broad biological profile involving anti-Borrelia activity, [1][2][3] antiviral activity, [4] angiogenesis inhibitory activity, [5] and inhibition of a cyclin-dependent kinase, Cdc28/Cln2, of Saccharomyces cerevisiae [6] and of threonyl tRNA synthetase. [7] Wilkinson and co-workers recently succeeded in separating anti-angiogenetic and cytotoxic activities by modification at the C17 side chain in 1.…”

Section: Introductionmentioning

confidence: 99%