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Oligosaccharide-camptothecin conjugates as potential antineoplastic drugs: Design, synthesis and biological
Maolin Li1, Wenchong Ye1, Kaishuo Fu1
1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China.
Abstract:
Thirty novel 20 (S)-O-linked camptothecin (CPT) glycoconjugates were synthesized. They showed more potent in vitro cytotoxicities over irinotecan, but very weak direct topoisomerase I (Topo I) inhibition was observed at 100.0 μM. Oligosaccharide types, length of a PEG linker and acetyl groups exerted obvious effects on cytotoxicity, selectivity, water solubility and stability of the newly synthesized CPT glycoconjugates. Construct 40, with a bleomycin (BLM) disaccharide linked to diethylene glycol in the introduced ester moiety, demonstrated a superior antitumor activity and a distinct selectivity compared to CPT. No toxicity was detectable in animal acute toxicity intravenously (160 mg/kg). Collectively, attachment of oligosaccharides with tumor targeting to 20 (S)-OH of CPT could offer a solution to the daunting problems posed by current Topo I poisons.
Insights
Novel camptothecin (CPT) glycoconjugates show potent anti-cancer activity and selectivity. Attaching tumor-targeting oligosaccharides to CPT offers a promising strategy for improved cancer therapeutics.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Cancer Therapeutics
Background:
- Camptothecin (CPT) derivatives are vital topoisomerase I (Topo I) poisons for cancer treatment.
- Current CPT analogs face challenges with efficacy, selectivity, and toxicity.
- Developing novel CPT conjugates with enhanced properties is crucial for advancing cancer therapy.
Purpose of the Study:
- To synthesize and characterize novel 20(S)-O-linked camptothecin (CPT) glycoconjugates.
- To evaluate the in vitro cytotoxicity, Topo I inhibition, and in vivo antitumor activity of these novel compounds.
- To investigate the impact of structural modifications, including oligosaccharide type, linker length, and acetylation, on CPT glycoconjugate properties.
Main Methods:
- Synthesis of thirty novel 20(S)-O-linked CPT glycoconjugates.
- In vitro cytotoxicity assays against cancer cell lines.
- Direct Topoisomerase I inhibition assays.
- In vivo antitumor activity studies and acute toxicity assessments in animal models.
Main Results:
- The synthesized CPT glycoconjugates exhibited potent in vitro cytotoxicities, surpassing irinotecan.
- Direct Topo I inhibition was weak at 100.0 μM, suggesting alternative mechanisms or indirect effects.
- Structural variations significantly influenced cytotoxicity, selectivity, solubility, and stability.
- Construct 40, featuring a bleomycin disaccharide and diethylene glycol linker, showed superior antitumor activity and selectivity compared to CPT.
- No acute toxicity was observed in animal studies at a dose of 160 mg/kg.
Conclusions:
- Attachment of tumor-targeting oligosaccharides to the 20(S)-OH position of CPT is a viable strategy to enhance anticancer efficacy and selectivity.
- These novel CPT glycoconjugates represent a promising new class of Topo I poisons with improved therapeutic potential.
- The findings suggest a potential solution to the limitations associated with current Topo I inhibitors.
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