Borrelidin

Chemoselective enrichment as a tool to increase access to bioactive natural products: Case study borrelidin.[Pubmed:26255540]

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4767-4769.

Chemoselective purification technologies have seen great success in biomolecule isolation, with a classic example being the genetically-encoded His tag utilized to enrich desired proteins from a crude lysate. We sought to translate this purification tactic into a powerful tool for the isolation of natural products and demonstrate that chemoselective enrichment can reduce the number of purification steps required and increase the yield obtained for important natural products, as compared to the use of traditional chromatography methods alone. To date, we have reported reversible enrichment tags for three functional groups, carboxylic acids and aliphatic or aryl hydroxyls. To illustrate the power of chemoselectivity-mediated purification of natural products, we present here an improved isolation of Borrelidin. Application of our carboxylic acid tag yielded pure Borrelidin in only two steps and with double the yield acquired with traditional chromatography methods. These results highlight the utility of this orthogonal strategy to facilitate the isolation of natural products, which are often present in minute quantities in their source materials.

Borrelidin Induces the Unfolded Protein Response in Oral Cancer Cells and Chop-Dependent Apoptosis.[Pubmed:26617965]

ACS Med Chem Lett. 2015 Sep 8;6(11):1122-7.

Oral squamous cell carcinoma (OSCC) is the most common cancer affecting the oral cavity, and US clinics will register about 30,000 new patients in 2015. Current treatment modalities include chemotherapy, surgery, and radiotherapy, which often result in astonishing disfigurement. Cancers of the head and neck display enhanced levels of glucose-regulated proteins and translation initiation factors associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Previous work demonstrated that chemically enforced UPR could overwhelm these adaptive features and selectively kill malignant cells. The threonyl-tRNA synthetase (ThRS) inhibitor Borrelidin and two congeners were discovered in a cell-based chemical genomic screen. Borrelidin increased XBP1 splicing and led to accumulation of phosphorylated eIF2alpha and UPR-associated genes, prior to death in panel of OSCC cells. Murine embryonic fibroblasts (MEFs) null for GCN2 and PERK were less able to accumulate UPR markers and were resistant to Borrelidin. This study demonstrates that UPR induction is a feature of ThRS inhibition and adds to a growing body of literature suggesting ThRS inhibitors might selectively target cancer cells.

Borrelidin Isolated from Streptomyces sp. Inhibited Adipocyte Differentiation in 3T3-L1 Cells via Several Factors Including GATA-Binding Protein 3.[Pubmed:26424016]

Biol Pharm Bull. 2015;38(10):1504-11.

An inhibitor of 3T3-L1 adipocyte differentiation was isolated from Streptomyces sp. TK08330 and identified by spectroscopy as the 18-membered macrolide Borrelidin. Treatment with 1.0 muM Borrelidin suppressed intracellular lipid accumulation by 80% and inhibited the expression of adipocyte-specific genes. Borrelidin suppressed the mRNA expression of two master regulators of adipocyte differentiation, peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha). Studies on well-known upstream regulators of PPARgamma revealed that Borrelidin down-regulated C/EBPdelta mRNA expression but did not affect expression of C/EBPbeta. Borrelidin increased mRNA expression of negative regulators of differentiation such as GATA-binding protein (GATA) 3, Kruppel-like factor (KLF) 3 and KLF7, as well as positive regulators, KLF4, KLF6 and KLF15, at early stages of differentiation. To elucidate a primary mediator of Borrelidin differentiation inhibitory activity, small interfering RNA (siRNA) transfection experiments were performed. The mRNA expression of PPARgamma, which was down-regulated by Borrelidin, was not changed by KLF3 and KLF7 siRNA treatment. In contrast, expression of PPARgamma in GATA-3 siRNA-treated cells was not significantly different from that of control siRNA-treated cells. Borrelidin significantly inhibited lipid accumulation in control siRNA-treated cells, and treatment with GATA-3 siRNA slightly reduced the inhibitory effect of Borrelidin. These results indicate that Borrelidin inhibited adipocyte differentiation partially via GATA-3.

Truncated borrelidin analogues: synthesis by sequential cross metathesis/olefination for the southern fragment and biological evaluation.[Pubmed:27523181]

Org Biomol Chem. 2016 Sep 21;14(35):8261-9.

The construction of novel Borrelidin analogues is reported in which the northern fragment is truncated to a simple hydroxyundecanecarboxylate and the original cyclopentanecarboxylic acid in the southern fragment is replaced with different six-membered rings. The required precursors were prepared by cross metathesis of the appropriate carbocycle-based homoallylic alcohol with crotonaldehyde followed by HWE olefination of the resulting enal with bromocyanophosphonate. The key aldehyde for intramolecular cross coupling was accessible by oxidation of the hydroxy group of the linked undecanecarboxylate unit. Grignard mediated macrocyclization finally yielded the Borrelidin related products. The investigation is complemented by SAR studies and quantum-chemical calculations.

Borrelidin (Treponemycin) is a bacterial and eukaryal threonyl-tRNA synthetase inhibitor which is a nitrile-containing macrolide antibiotic isolated from Streptomyces rochei. Borrelidin (Treponemycin) is an inhibitor of Cdc28/Cln2 of the budding yeast, with an IC50 of 24 μM. Borrelidin (Treponemycin) is a potent angiogenesis inhibitor, with an IC50 of 0.8 nM, and induces apoptosis of the tube-forming cells. Borrelidin (Treponemycin) has strong antimalarial activities, with IC50s of 1.9 nM and 1.8 nM against K1 and FCR3 strains of Plasmodium falciparum.

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