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The C-terminal amine exerted a major impact on the antitumor selectivity and activity of BLM family compounds.
The deoxidized gulose unit attenuated the pulmonary toxicity of 6'-DO-BLM Z without distinct effect on antitumor activity.
The sequential decrease of ROS level, caspase-1 activity and inflammatory response contributed to the reduced pulmonary toxicity in 6'-DO-BLM Z.
Bleomycins (BLMs) are broad-spectrum antitumor drugs, but the dose-dependent lung toxicity has restricted their therapeutic applications. Many efforts have contributed to develop novel BLM analogues, but mainly focused on single functional domain owing to the structural complexity of BLM. Benefit from the engineered production of two novel analogues 6'-deoxy-BLM Z (6'-DO-BLM Z) and BLM Z, they together with clinical BLM-sulfate comprised a good model with varied sugar or C-terminal domain in any two of them, allowing us to study their structure-activity relationships pairwise. Our investigations suggested the biological activities of BLM or its analogues are mainly depended on the C-terminal amine, while the changed C-terminal amine endowed BLM Z with much higher pulmonary toxicity comparing to BLM-sulfate, whereas the deoxidized gulose unit with same C-terminal amine evidently attenuated the pulmonary toxicity of 6'-DO-BLM Z without effect on antitumor activity. Further mechanistic studies revealed that the alleviation of pulmonary toxicity in 6'-DO-BLM Z by a slight change in the sugar moiety could attribute to the decrease of ROS production and thereby reduce the subsequent caspase-1 activity and resulting inflammatory response. Therefore, the synergistic modifications on C-terminal amine and sugar moiety provide new insights to efficiently develop potential BLM candidate with good clinical performance.El texto completo de este artículo está disponible en PDF.
Keywords : Bleomycin and analogues, Sugar moiety, Antitumor activity, Pulmonary toxicity, ROS production
Vol 136Artículo 111222- avril 2021 Regresar al número
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