Abstract
Camptothecin (CPT) has been shown to block disassembly of the topoisomerase I (Topo I)/DNA cleavable complex. However, the poor aqueous solubility, intrinsic instability, and severe toxicity of CPTs have limited their clinical applications. Herein, we report the design and synthesis of H2O-soluble and orally bioavailable hexacyclic CPT derivatives. By analysis of a virtual chemical library and cytotoxicity screening in vitro, 9 and 11 were identified as potential prodrugs and chosen for further characterization in vivo. Both compounds exhibited remarkable anticancer and anti-inflammation efficacies in animals and improved drug-like profiles.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Camptothecin / chemistry*
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Camptothecin / pharmacology*
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Cell Proliferation
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Drug Design*
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Humans
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Lipopolysaccharides / toxicity
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Nude
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Neoplasms / drug therapy*
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Neoplasms / pathology
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Sepsis / chemically induced
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Sepsis / drug therapy*
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Sepsis / pathology
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Solubility
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Anti-Inflammatory Agents
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Antineoplastic Agents
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Lipopolysaccharides
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Camptothecin