Functionalized Cyclopentenones with Low Electrophilic Character as Anticancer Agents

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Biomass Valorization

Background:

• Cyclic enones are known cytotoxic agents but often fail due to toxicity from unselective biomacromolecule alkylation, frequently via Michael addition.
• Non-Michael acceptor cyclopentenones (CPs) offer a potential strategy to mitigate toxicity while retaining anticancer activity.

Purpose of the Study:

• To synthesize novel 2,4-substituted cyclopentenones (CPs) from biomass-derived furfural as potential anticancer agents.
• To evaluate the reactivity and cytotoxicity of these novel CPs, focusing on their reduced susceptibility to Michael addition.

Main Methods:

• Synthesis of 2,4-substituted CPs from furfural using a tandem furan ring opening/Nazarov electrocyclization pathway.
• Assessment of reactivity towards sulfur nucleophiles to confirm non-Michael acceptor properties.
• In vitro cytotoxicity testing against multiple human cancer cell lines (HT-29, MCF-7, NCI-H460, HCT-116, MDA-MB 231) and a healthy cell line (HEK 293T).

Main Results:

• Successfully synthesized novel 2,4-substituted CPs from furfural.
• Experimentally confirmed that the synthesized CPs exhibit no reactivity towards sulfur nucleophiles, indicating they are non-Michael acceptors.
• Demonstrated significant cytotoxicity against a panel of cancer cell lines while showing no toxicity against healthy HEK 293T cells.
• Calculated drug-like properties suggest favorable characteristics for therapeutic development.

Conclusions:

• Novel 2,4-substituted cyclopentenones derived from furfural are effective anticancer agents with a reduced risk of toxic side effects.
• These compounds represent a promising new class of anticancer drugs with improved safety and efficacy profiles.