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NC1101, a novel tetrahydropyrimidine-containing bleomycin analog from Streptomyces verticillus var. pingyangensis n. var
Abstract
Keywords: antitumor activity; bleomycin; NC1101; structure elucidation
... Among them, BLM A5 (also named Pingyangmycin, 3) and BLM A6 (also named Boanmycin, 4) have been clinically approved in China as the alternatives of Blenoxane (He et al. 2016), while acetyl-BLM A6 (also named Boningmycin, 5) was reported under clinical trials in China (Qi et al. 2017). Recently, two new BLM congeners NC0604 (6) (Chen et al. 2008) and NC1101 (7) (Ren et al. 2012) have also been successfully isolated from S. verticillus var. pingyangensis n. var. ...
... pingyangensis n. var. In spite of the discovery of these congeners that have displayed better performances than the original BLM drug, their lung toxicity still could not be ignored (Gao et al. 2011;Ren et al. 2012;Shi et al. 2010). ...
The bleomycins (BLMs) belong to a subfamily of glycopeptide antibiotics and are clinically applied in combination chemotherapy regimens to treat various malignancies. But the therapeutic applications of BLMs are restricted by the accompanied dose-dependent lung toxicity and potential incidence of lung fibrosis. Many efforts have been devoted to develop novel BLM analogues, for seeking of drug leads with improved antitumor activity and/or reduced lung toxicity. The progresses in the biosynthetic studies of BLMs have greatly expedited the process to achieve such goals. This review highlights the discovery and development of microbial BLM analogues in the past two decades, especially those derived from engineered biosynthesis. Moreover, the summarized structure-activity relationship, which is specifically focusing on the sugar moiety, shall shed new insights into the prospective development of BLM analogues.
... Streptomyces mobaraensis US-43 (former named S. verticillus var. pingyangensis n. var, CPCC 203575), isolated from a soil sample collected from Pingyang, Zhejiang Province, China, produced a series of glycopeptide antibiotics such as bleomycin analogues [1][2][3]. Among them, pingyangmycin and boanmycin have been approved by SFDA for cancer treatment in China. ...
Background:
Herbicidin F has an undecose tricyclic furano-pyrano-pyran structure with post-decorations. It was detected from Streptomyces mobaraensis US-43 fermentation broth as a trace component by HPLC-MS analysis. As herbicidins exhibit herbicidal, antibacterial, antifungal and antiparasitic activities, we are attracted to explore more analogues for further development.
Results:
The genome of S. mobaraensis US-43 was sequenced and a herbicidin biosynthetic gene cluster (hcd) was localized. The cluster contains structural genes, one transporter and three potential transcription regulatory genes. Overexpression of the three regulators respectively showed that only hcdR2 overexpression significantly improved the production of herbicidin F, and obviously increased the transcripts of 7 structural genes as well as the transporter gene. After performing homology searches using BLASTP in the GenBank database, 14 hcd-like clusters were found with a cluster-situated hcdR2 homologue. These HcdR2 orthologues showed overall structural similarity, especially in the C-terminal DNA binding domain. Based on bioinformatics analysis, a 21-bp consensus binding motif of HcdR2 was detected within 30 promoter regions in these genome-mined clusters. EMSA results verified that HcdR2 bound to the predicted consensus sequence. Additionally, we employed molecular networking to explore novel herbicidin analogues in hcdR2 overexpression strain. As a result, ten herbicidin analogues including six new compounds were identified based on MS/MS fragments. Herbicidin O was further purified and confirmed by 1H NMR spectrum.
Conclusions:
A herbicidin biosynthetic gene cluster (hcd) was identified in S. mobaraensis US-43. HcdR2, a member of LuxR family, was identified as the pathway-specific positive regulator, and the production of herbicidin F was dramatically increased by overexpression of hcdR2. Combined with molecular networking, ten herbicidin congeners including six novel herbicidin analogues were picked out from the secondary metabolites of hcdR2 overexpression strain. The orthologues of herbicidin F pathway-specific regulator HcdR2 were present in most of the genome-mined homologous biosynthetic gene clusters, which possessed at least one consensus binding motif with LuxR family characteristic. These results indicated that the combination of overexpression of hcdR2 orthologous regulator and molecular networking might be an effective way to exploit the "cryptic" herbicidin-related biosynthetic gene clusters for discovery of novel herbicidin analogues.
Covering: July 2010 to June 2012. Previous review: Nat. Prod. Rep., 2011, 28, 1143-1191.Structurally diverse alkaloids containing five-membered heterocyclic subunits, such as imidazole, oxazole, thiazole, as well as their saturated congeners, are widely distributed in terrestrial and marine organisms and microorganisms. These naturally occurring secondary metabolites often exhibit extensive and pharmacologically important biological activities. The latest progress involving isolation, biological activities, chemical synthetic studies, and biosynthetic pathways of these natural products has been summarized in this review.
NC0604, a new analogue of bleomycin, was isolated from fermentation broth of Streptomyces verticillus var. pingyangensis n.var. The structure of NC0604 was elucidated by spectroscopic analyses. NC0604 had the same kernel structure as bleomycin, but a different terminal amine moiety determined as amidepropyl spermidine. NC0604 exhibited antibacterial activity against a wide range of bacterial species and showed cytotoxicity in vitro against human HepG(2), KB, MCF-7, HCT116, BGC-823 and MCF-7/DOX cells with IC(50) values of 1.18, 1.21, 1.41, 1.83, 2.02, 1.45 muM, respectively. The antitumor activity of NC0604 against these cells was 3~9 times higher than that of bleomycin; and the pulmonary toxicity of NC0604 was much lower than that of bleomycin.
During chemical studies of bleomycin, many fragments and derivatives have been isolated and characterized. The 13C-NMR spectra of these compounds were taken and analyzed for structural information, and the complete assignment of the spectra was achieved. The 13C-chemical shift map thus obtained contains information about the structure and conformation and will be useful for studies on the chemistry and biology of bleomycin and related compounds.
When administered to mice by the intratracheal route, bleomycin analogs produce pulmonary toxicity of varying severity. Analogs differ from each other by chemical groups (terminal substituents) linked to the bithiazole rings. Amines with structures identical to the terminal substituents of bleomycins A2′-a, A2′-b, A2′-c, A5, A6, and B2 were administered to mice endotracheally (10–500 nmol). Discrete end groups produced the same spectrum of pathological changes in the lung as did intact bleomycins, namely, pulmonary fibrosis and metaplasia. Relative to Blenoxane, bleomycin A5 is as toxic while the toxicity of bleomycin B2 is comparatively mild. The severity of pulmonary fibrosis and metaplasia of these bleomycins can be attributed to the terminal substituents, spermidine and agmatine. Spermidine produced severe fibrosis and metaplasia, comparable to that produced by bleomycin A5. Agmatine, the end group of bleomycin B2 was the least toxic of the terminal substituents, suggesting that the diminished pulmonary toxicity of bleomycin B2 can be accounted for by the terminal agmatine moiety. These studies indicate an important role for the terminal substituent in bleomycin-induced lung injury.
A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
Studies on Zhengguangmycins. Taxonomy of Streptomyces verticillus var. pingyangensis n.var
- Y Y Zhao
- M Y Xie
- G L Wang
- YY Zhao