Topoisomerase inhibitors as anticancer agents: a patent update

Area of Science:

• * Pharmacology
• * Medicinal Chemistry
• * Molecular Biology

Background:

• * Topoisomerases (topos) are essential nuclear enzymes involved in DNA topology.
• * Topo inhibitors are potent antineoplastic agents due to their role in vital cellular processes and cancer cell death.

Purpose of the Study:

• * To review patents on topoisomerase I (topo I) and topoisomerase I and II (topo I/II) inhibitors.
• * To focus on chemical entities developed through structure-activity relationship (SAR) studies and computational drug design.

Main Methods:

• * Review of patents covering topo I, topo I/II inhibitors, including camptothecin (CPT) analogs, lamellarins, and synthetic pyridines.
• * Examination of SAR studies on benzo[c]phenanthridine (nitidine) and protoberberine (coralyne) derivatives.
• * Discussion of indenoisoquinolines and evodiamines discovered via COMPARE analysis and virtual screening (VS).

Main Results:

• * Identification of diverse chemical scaffolds targeting topoisomerases, including natural products and synthetic compounds.
• * Emphasis on systematic SAR studies for optimizing antineoplastic activity.
• * Integration of computational approaches like VS and molecular modeling in drug discovery.

Conclusions:

• * Computer-aided tools (VS, molecular modeling, docking) are vital for rational drug design and development of topoisomerase inhibitors.
• * Understanding topo I/II-DNA-drug interactions through structural studies is key.
• * Combined computational and screening methods will accelerate the discovery of novel anticancer drugs.