Novel and expanded jadomycins incorporating non-proteogenic amino acids

Jakeman, David L.; Graham, Cathy L.; Reid, Taryn R.

doi:10.1016/j.bmcl.2005.08.047

Cited by 26 publications

(26 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The amino acid side chain has an effect on the cytotoxic activities of jadomycins B, V, S, T and F [11]. We have determined that non-natural amino acids are also incorporated into the jadomycin oxazolone ring [4,5] and recently described the effects of aqueous conditions upon the structure of the oxazolone ring [9]. At basic pH the antibiotic interconverts between two isomeric forms at C3 through a novel aldehyde intermediate, as shown in Fig.…”

Section: Introductionmentioning

confidence: 94%

Culture conditions improving the production of jadomycin B

Jakeman

Graham

Young

et al. 2006

J IND MICROBIOL BIOTECHNOL

Self Cite

View full text Add to dashboard Cite

The jadomycins are a unique family of benzoxazolophenanthridine antibiotics produced by Streptomyces venezuelae ISP5230 following heat or ethanol shock or phage infection. We have modified the culture conditions by altering the carbon source, buffer, inoculum size, and timing of ethanol shock, thereby reducing growing times and improving jadomycin B production. Our optimized conditions use glucose as the carbon source, MOPS as buffer, low concentrations of phosphate, a defined inoculum concentration and an immediate ethanol shock to induce jadomycin B production; results that contrast previous studies. The altered media will facilitate the isolation of related jadomycin B congeners.

show abstract

Section: Introductionmentioning

confidence: 94%

Culture conditions improving the production of jadomycin B

Jakeman

Graham

Young

et al. 2006

J IND MICROBIOL BIOTECHNOL

Self Cite

View full text Add to dashboard Cite

show abstract

“…Jadomycin analogs with distinct functional groups on the oxazolone ring can be created by adding different amino acids to the Streptomyces growth media as the sole nitrogen source (Jakeman et al. ,b). Current data support a broad spectrum of jadomycin anticancer activity, including activity against multiple breast cancer cell subtypes.…”

Section: Introductionmentioning

confidence: 99%

Jadomycin breast cancer cytotoxicity is mediated by a copper‐dependent, reactive oxygen species–inducing mechanism

Hall

Blundon

Ladda

et al. 2015

Pharmacology Res & Perspec

Self Cite

View full text Add to dashboard Cite

Jadomycins are natural products biosynthesized by the bacteria Streptomyces venezuelae which kill drug-sensitive and multidrug-resistant breast cancer cells in culture. Currently, the mechanisms of jadomycin cytotoxicity are poorly understood; however, reactive oxygen species (ROS)–induced DNA cleavage is suggested based on bacterial plasmid DNA cleavage studies. The objective of this study was to determine if and how ROS contribute to jadomycin cytotoxicity in drug-sensitive MCF7 (MCF7-CON) and taxol-resistant MCF7 (MCF7-TXL) breast cancer cells. As determined using an intracellular, fluorescent, ROS-detecting probe, jadomycins B, S, SPhG, and F dose dependently increased intracellular ROS activity 2.5- to 5.9-fold. Cotreatment with the antioxidant N-acetyl cysteine lowered ROS concentrations to below baseline levels and decreased the corresponding cytotoxic potency of the four jadomycins 1.9- to 3.3-fold, confirming a ROS-mediated mechanism. Addition of CuSO4 enhanced, whereas addition of the Cu(II)-chelator d-penicillamine reduced, the ROS generation and cytotoxicity of each jadomycin. Specific inhibitors of the antioxidant enzymes, superoxide dismutase 1, glutathione S-transferase, and thioredoxin reductase, but not catalase, enhanced jadomycin-mediated ROS generation and anticancer activity. In conclusion, the results indicate that jadomycin cytotoxicity involves the generation of cytosolic superoxide via a Cu(II)-jadomycin reaction, a mechanism common to all jadomycins tested and observed in MCF7-CON and drug-resistant MCF7-TXL cells. The superoxide dismutase 1, glutathione, and peroxiredoxin/thioredoxin cellular antioxidant enzyme pathways scavenged intracellular ROS generated by jadomycin treatment. Blocking these antioxidant pathways could serve as a strategy to enhance jadomycin cytotoxic potency in drug-sensitive and multidrug-resistant breast cancers.

show abstract

“…Even D-amino acids and non-natural amino acids can be incorporated. 11,[15][16][17][18][19] Thus, a considerable range of jadomycins can be evaluated for bioactivity, notably against tumor cells. Jadomycins show cytotoxicity to several tumor cell lines, including human hepatocellular carcinoma cell line HepG2, human lymphoblast immunoglobulin-secreting cell line IM-9, non-small-cell lung cancer cell line H460 20 and human breast ductal carcinoma cell lines T-47D and MDA-MB-435.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

et al. 2012

View full text Add to dashboard Cite

The jadomycins are a unique family of angucycline-derived antibiotics with interesting cytotoxic activities. In this work, six new jadomycin derivatives were produced in vivo by providing non-natural amino acids in fermentation media. They were further purified and identified by MS and NMR analyses. The cytotoxicities of these derivatives were evaluated against tumor cell lines MCF-7 and HCT116, as well as the normal human microvascular epithelial cells. The derivatives with alkyl side chains showed similar levels of cytotoxicity as jadomycin B and other known derivatives with nonpolar side chains, with IC 50 ranging from 1.3 to 10 lM; but the activities are not selective as these compounds also showed similar levels of cytotoxicity toward the normal human microvascular epithelial cells in the same concentration range. For the first time, derivatives with amino side chains (jadomycin Orn and K) were prepared and evaluated. Significantly, jadomycin Orn showed differential activity against normal and tumor cell lines. This result points to a new direction to modify jadomycin structure. The insights on the structure-activity relationship of jadomycins will guide further efforts to generate new and improved jadomycin derivatives against tumor cells.

show abstract

Novel and expanded jadomycins incorporating non-proteogenic amino acids

Cited by 26 publications

References 6 publications

Culture conditions improving the production of jadomycin B

Culture conditions improving the production of jadomycin B

Jadomycin breast cancer cytotoxicity is mediated by a copper‐dependent, reactive oxygen species–inducing mechanism

Evaluation of the cytotoxic activity of new jadomycin derivatives reveals the potential to improve its selectivity against tumor cells

Contact Info

Product

Resources

About