The discovery and development of microbial bleomycin analogues

Abstract

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.

The isolation of water-soluble natural products – challenges, strategies and perspectives

“…Bleomycins A2 ( 168 ) and B2 ( 169 ) from cultures of Streptomyces verticillus were the first discovered bleomycins. 537 Subsequently, several natural bleomycin derivatives have been isolated and hundreds of analogues have been synthesized for drug-development, since the mixture of 168 and 169 has been used for more than 40 years for the treatment of a variety of malignancies. The combination of 168 and 169 with etoposide and cisplatin is particularly effective in the treatment of metastatic testicular cancer, but presents considerable side effects, mainly pulmonary dysfunction.…”

Pulmonary Delivery of Recombinant Human Bleomycin Hydrolase Using Mannose-Modified Hierarchically Porous UiO-66 for Preventing Bleomycin-Induced Pulmonary Fibrosis

“…However, the progress on this issue is far from satisfactory. 6 The BLM-induced PF has been attributed to the low expression level of the hBLMH gene in the lung tissue, which encodes the human BLM hydrolase (hBLMH). 7 hBLMH is a cysteine protease that hydrolyzes the β-aminoalanine amide moiety of BLMs to afford the inactive deamido-BLMs.…”

“…5 In patients receiving BLM chemotherapy, chest X-rays often show decreased lung volume and interstitial damage near the lung bases. 5,6 The bleomycin-induced pulmonary toxicity can affect up to 46% of the population receiving BLM-based chemo-therapy. The mortality of patients with PF is approximately 3%, which is unacceptable for patients with curable cancers.…”

“…However, BLMs can induce dose-dependent and cumulative pulmonary toxicity, ranging from hypersensitivity pneumonitis to acute interstitial pneumonia and progressive pulmonary fibrosis (PF) . In patients receiving BLM chemotherapy, chest X-rays often show decreased lung volume and interstitial damage near the lung bases. , The bleomycin-induced pulmonary toxicity can affect up to 46% of the population receiving BLM-based chemotherapy. The mortality of patients with PF is approximately 3%, which is unacceptable for patients with curable cancers .…”

Surfactin Ameliorated the Internalization and Inhibitory Performances of Bleomycin Family Compounds in Tumor Cells

“…Bleomycin (BLM) is a broad-spectrum chemotherapy drug clinically applied to treat various malignant tumors such as Hodgkins lymphoma and testicular tumor etc. 1 However, the BLM accumulation in lungs due to the lack of BLM-hydrolase could increase the production of reactive oxygen species (ROS) and therefore stimulate the inflammatory responses, which may further induce lung fibrosis. 2 Such lung toxicity has limited clinical applications of BLM.…”