[Total synthesis of oxa-9-anthracyclines]

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Glycoscience

Context:

• Anthracyclines are a class of compounds with significant clinical applications, primarily as anticancer agents.
• The development of novel anthracycline analogs is crucial for overcoming drug resistance and improving therapeutic efficacy.
• Synthetic strategies for accessing complex anthracycline structures are of great interest in drug discovery.

Purpose:

• To synthesize novel racemic and chiral 9-oxa-anthracyclinone derivatives.
• To explore glycosylation strategies using modified L-fucose and L-hexose sugars.
• To evaluate the cytotoxic activity of the synthesized anthracycline glycosides against L 1210 leukemia cells.

Summary:

• Racemic 7-hydroxy-9-oxa-anthracyclinone was synthesized in seven steps from quinizarin and resolved after glycosylation.
• Chiral pool syntheses yielded (8S)-8-hydroxymethyl-9-oxa-anthracyclinone and its 10-methylated derivatives.
• Glycosylation with modified sugars produced novel anthracyclines, which were tested for biological activity.

Impact:

• The study presents a synthetic route to novel anthracycline analogs with potential for further derivatization.
• The lack of significant cytotoxicity at tested concentrations provides a baseline for future structure-activity relationship studies.
• This research contributes to the understanding of structure-activity relationships in anthracycline-based compounds.