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A Designer Bleomycin with Significantly Improved DNA Cleavage Activity
- Source :
- Journal of the American Chemical Society. 134:13501-13509
- Publication Year :
- 2012
- Publisher :
- American Chemical Society (ACS), 2012.
-
Abstract
- The bleomycins (BLMs) are used clinically in combination with a number of other agents for the treatment of several types of tumors, and the BLM, etoposide, and cisplatin treatment regimen cures 90-95% of metastatic testicular cancer patients. BLM-induced pneumonitis is the most feared, dose-limiting side effect of BLM in chemotherapy, which can progress into lung fibrosis and affect up to 46% of the total patient population. There have been continued efforts to develop new BLM analogues in the search for anticancer drugs with better clinical efficacy and lower lung toxicity. We have previously cloned and characterized the biosynthetic gene clusters for BLMs from Streptomyces verticillus ATCC15003, tallysomycins from Streptoalloteichus hindustanus E465-94 ATCC31158, and zorbamycin (ZBM) from Streptomyces flavoviridis SB9001. Comparative analysis of the three biosynthetic machineries provided the molecular basis for the formulation of hypotheses to engineer novel analogues. We now report engineered production of three new analogues, 6'-hydroxy-ZBM, BLM Z, and 6'-deoxy-BLM Z and the evaluation of their DNA cleavage activities as a measurement for their potential anticancer activity. Our findings unveiled: (i) the disaccharide moiety plays an important role in the DNA cleavage activity of BLMs and ZBMs, (ii) the ZBM disaccharide significantly enhances the potency of BLM, and (iii) 6'-deoxy-BLM Z represents the most potent BLM analogue known to date. The fact that 6'-deoxy-BLM Z can be produced in reasonable quantities by microbial fermentation should greatly facilitate follow-up mechanistic and preclinical studies to potentially advance this analogue into a clinical drug.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
medicine.medical_treatment
ved/biology.organism_classification_rank.species
Antineoplastic Agents
Bleomycin
Biochemistry
Streptomyces
Article
Catalysis
chemistry.chemical_compound
Colloid and Surface Chemistry
medicine
DNA Cleavage
Etoposide
Pneumonitis
Cisplatin
Chemotherapy
Molecular Structure
biology
urogenital system
ved/biology
Glycopeptides
nutritional and metabolic diseases
General Chemistry
medicine.disease
biology.organism_classification
Recombinant Proteins
Streptomyces flavoviridis
chemistry
Streptomyces verticillus
Cancer research
medicine.drug
Subjects
Details
- ISSN :
- 15205126 and 00027863
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society
- Accession number :
- edsair.doi.dedup.....64264691f8bcae5853c0e510b889fb61