New Disubstituted Quindoline Derivatives Inhibiting Burkitt's Lymphoma Cell Proliferation by Impeding c-MYC...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• The c-MYC oncogene is frequently overactivated in Burkitt's lymphoma.
• Targeting c-MYC transcriptional activity is a promising anticancer strategy.
• G-quadruplex structures in the c-MYC promoter are potential therapeutic targets.

Purpose of the Study:

• To synthesize and evaluate novel disubstituted quindoline derivatives as ligands for the c-MYC promoter G-quadruplex.
• To assess the binding affinity, stability, and selectivity of these compounds.
• To investigate their potential to inhibit Burkitt's lymphoma cell proliferation and tumor growth.

Main Methods:

• Synthesis of four series of disubstituted quindoline derivatives.
• In vitro evaluation of DNA binding affinity, stability, and selectivity using G-quadruplex and duplex DNA.
• Assessment of inhibition of transcription factor NM23-H2 binding to c-MYC G-quadruplex.
• In vitro studies in RAJI cells to evaluate c-MYC transcription and NM23-H2/c-MYC interaction.
• In vivo studies using a human Burkitt's lymphoma xenograft model.

Main Results:

• All synthesized compounds demonstrated enhanced stability and binding affinity for the c-MYC G-quadruplex compared to the reference compound.
• Most derivatives showed improved selectivity for G-quadruplex over duplex DNA.
• The novel ligands effectively prevented the binding of transcription factor NM23-H2 to the c-MYC G-quadruplex.
• The lead compound, 7a4, down-regulated c-MYC transcription by targeting the promoter G-quadruplex and disrupting the NM23-H2/c-MYC interaction in RAJI cells.
• Compound 7a4 inhibited Burkitt's lymphoma cell proliferation via cell cycle arrest and apoptosis and suppressed tumor growth in vivo.

Conclusions:

• Disubstituted quindoline derivatives are effective ligands for the c-MYC promoter G-quadruplex.
• The lead compound 7a4 demonstrates therapeutic potential for Burkitt's lymphoma by down-regulating c-MYC and inhibiting tumor growth.
• Targeting the c-MYC G-quadruplex offers a viable strategy for Burkitt's lymphoma treatment.