Selection of Natural Compounds with HMGA-Interfering Activities and Cancer Cell Cytotoxicity

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• High Mobility Group A (HMGA) proteins are intrinsically disordered chromatin architectural factors crucial for embryonic development.
• HMGA proteins are re-expressed in cancers, driving neoplastic transformation and progression.
• Targeting HMGA-DNA interactions offers a potential strategy for cancer therapy.

Purpose of the Study:

• To identify novel small molecules that bind to AT-rich DNA minor grooves.
• To discover compounds that can compete with HMGA proteins for DNA binding.
• To explore new chemotypes for developing anticancer agents.

Main Methods:

• Docking-based virtual screening of a natural product library (~1000 compounds).
• Electrophoretic mobility shift assays (EMSA) to assess HMGA/DNA displacement activity.
• Cytotoxicity assays on cancer cell lines.

Main Results:

• 16 natural compounds were identified as potential minor groove binders.
• Sorocein C, a Diels-Alder adduct from *Sorocea* species, demonstrated significant HMGA/DNA-displacing activity.
• Sorocein A and Sorocein B also showed activity, with all tested compounds exhibiting cytotoxicity against cancer cells.

Conclusions:

• The Sorocein structural family represents a promising source of novel minor groove binders.
• These compounds may serve as lead structures for developing new anticancer agents targeting HMGA-DNA interactions.