Introduction

Human type II topoisomerase (topoII) enzymes are a validated anticancer drug target. A new class of molecular entities was generated merging key pharmacophoric elements of etoposide and merbarone, two well known topoII blockers. The derivatives are effective inhibitors of topoII and have good antiproliferative activity on human cancer cells. Furthermore a subset of compounds act through the poison mechanism against topoII similarly etoposide endorsing their further exploration for anticancer drug discovery.

Technical features

The inventors have found that a class of compounds having a 5-carbamoyl-2- thiobarbituric scaffold, with substituents in selected positions of the phenyl group, are effective poison inhibitors of the human type II topoisomerase (topo II) enzymes. These compounds have been shown to actively block the proliferation of cancerous cells, making them effective in cancer treatment. The patent describes:

• A new entity of type I explored through the functionalization of E ring (image above);
• A linear, efficient and versatile synthesis of 3 steps provided easily all desired derivatives (image below);
• Compounds active against 3 human cancer cell lines;
• Compounds showed good potency against topoII enzyme;
• Selected compounds displayed good drug-like properties (solubility and stability);
• Results described in 2 publication: J. Med. Chem. 2018, 61, 3, 1375-1379, J. Med. Chem. 2020, 63, 7, 3508-3521

Possible Applications

• Treatment of cancer;
• Development of new clinical drug.

Advantages

• New compounds easily accessible;
• Potent human topoII inhibitors;
• Compounds with promising antiproliferative activity in cancer human cells;
• Extensive characterisation, including a favourable in vivo PK.