Separation of anti-angiogenic and cytotoxic activities of borrelidin by modification at the C17 side chain

Wilkinson, Barrie; Gregory, Matthew A.; Moss, Steven J.; Carletti, Isabelle; Sheridan, Rose; Kaja, Andrew L.; Ward, Michael J.; Olano, Carlos; Méndez, Cármen; Salas, José A.; Leadlay, Peter F.; vanGinckel, Rob; Zhang, Ming‐Qiang

doi:10.1016/j.bmcl.2006.08.073

Cited by 37 publications

(51 citation statements)

References 23 publications

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“…The antimalarial activity of borrelidin is thought to arise from inhibition of ThrRS, which in Plasmodium, is present as a single enzyme dually targeted to cytosol and apicoplast (28). However, its high cytotoxicity in humans limits its use (29). Moreover, a borrelidin analog was recently described with an antimalarial activity 10-fold lower than borrelidin, but with a cytotoxic effect against human cells 70-fold lower than the parent compound (30).…”

Section: Significancementioning

confidence: 99%

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo.aminoacyl-tRNA synthetase | malaria | drug design | borrelidin | plasmodium

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Section: Significancementioning

confidence: 99%

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Novoa

Camacho

Tor

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…[14] Importantly, cytotoxicity is not essential for the inhibition of cell migration; the mechanisms of action for these two processes were shown to be distinct in taxanes and the vinca alkaloids, and demonstrated to be separable in the case of borrelidin analogues. [15] Haptotaxis inhibitors with reduced cytotoxicity would be highly desirable, both to contain the growth of existing tumors and to restrain new tumor formation.…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Mutasynthesis of Scrambled Beauvericins, Cyclooligomer Depsipeptide Cell Migration Inhibitors from Beauveria bassiana

Wijeratne

Espinosa-Artiles

et al. 2009

ChemBioChem

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Fungal cyclooligomer depsipeptides such as beauvericin, bassianolide, and enniatins display antibiotic, antifungal, insecticidal, broad-spectrum cancer cell antiproliferative, and cell migration inhibitory activities. We have identified a gene encoding a novel enzyme, ketoisovalerate reductase (KIVR), which is the sole provider of D-hydroxyisovalerate (D-Hiv), a common precursor for cyclooligomer depsipeptide biosynthesis in Beauveria bassiana. KIVR and related hypothetical oxidoreductases encoded in fungal genomes are similar to ketopantoate reductases but not to D-hydroxycarboxylate dehydrogenases. We demonstrate that a KIVR knockout B. bassiana strain can be used for the efficient mutasynthesis of unnatural beauvericin congeners. Simultaneous feeding of precursor analogues enabled the combinatorial mutasynthesis of scrambled beauvericins, some assembled entirely from unnatural precursors. The effects of the introduced structural changes on the antiproliferative and cell migration inhibitory activities of these analogues were evaluated.

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“…In addition, the reduced toxicity of carboxyl-cyclobutanyl-borrelidin was confirmed in vivo using nude mice, in which its maximum tolerated dose was at least ninefold higher than that of borrelidin. 52 These findings demonstrated that the therapeutic index of borrelidin can be significantly improved using combinatorial biosynthesis. 53 In particular, daunorubicin and doxorubicin are the most widely used anthracycline drugs.…”

Section: Keeping On Polyketide Biosynthesismentioning

confidence: 77%

“…51 The cytotoxicity of these novel analogs was analyzed against 12 human cancer cell lines in vitro. 51,52 The most promising compounds were further examined to evaluate their antiproliferative and antiangiogenic activities in vitro against human umbilical endothelial cells. 52 The carboxyl-cyclobutane analog of borrelidin was found to be 15-fold less cytotoxic than borrelidin but sixfold more antiangiogenic.…”

Section: Keeping On Polyketide Biosynthesismentioning

confidence: 99%

“…51,52 The most promising compounds were further examined to evaluate their antiproliferative and antiangiogenic activities in vitro against human umbilical endothelial cells. 52 The carboxyl-cyclobutane analog of borrelidin was found to be 15-fold less cytotoxic than borrelidin but sixfold more antiangiogenic. In addition, the reduced toxicity of carboxyl-cyclobutanyl-borrelidin was confirmed in vivo using nude mice, in which its maximum tolerated dose was at least ninefold higher than that of borrelidin.…”

Section: Keeping On Polyketide Biosynthesismentioning

confidence: 99%

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Hutchinson's legacy: keeping on polyketide biosynthesis

Olano

2010

J Antibiot

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Professor Charles Richard Hutchinson (Hutch) dedicated his research to the study of polyketide compounds, in particular, those produced by actinomycetes. Hutch principally centered his efforts to study the biosynthesis of bioactive compounds, antibiotic and antitumor drugs, and to develop new derivatives with improved therapeutic properties. After dedicating 40 years to the study of polyketides, Hutch leaves us, as legacy, the knowledge that he and his collaborators have accumulated and shared with the scientific community. The best tribute we can offer to him is keeping on the study of polyketides and other bioactive compounds, in an effort to generate more safer and useful drugs. In this review, the work on the polyketides, borrelidin, steffimycin and streptolydigin, performed at the laboratory of Professors Salas and Mé ndez at University of Oviedo (Spain) during the last 10 years, is summarized.

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Separation of anti-angiogenic and cytotoxic activities of borrelidin by modification at the C17 side chain

Cited by 37 publications

References 23 publications

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

Combinatorial Mutasynthesis of Scrambled Beauvericins, Cyclooligomer Depsipeptide Cell Migration Inhibitors from Beauveria bassiana

Hutchinson's legacy: keeping on polyketide biosynthesis

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