4-Chromone derivatives as DNA polymerase ƞ inhibitors and anticancer agents
DNA polymerase ƞ (Pol η) is an essential enzyme for the correction of pyrimidine dimers, DNA damage that is often caused by UV-rays. In addition, it has been reported in literature that Pol η in cancer cells is also capable of overcoming DNA damage caused by chemotherapy drugs, such as cisplatin, leading to chemoresistance. The compounds derived from 4-chromone are able to inhibit the activity of ɳ polymerase and, therefore, can be usefully used in co-treatment with cisplatin for the treatment of tumors.
The development of drug resistance is one of the main problems in the treatment of tumors. An example are platinum-based drugs and nucleoside analogues, which are regularly used in the treatment of cancer. However, although they are effective, their use is limited by drug resistance. The study of the causes of the development of resistance has led to the identification of DNA polymerase ƞ (Pol ƞ) as one of the main responsible, and consequently to the identification of a new pharmaceutical target. To date, aurintricarboxylic acid, ellagic acid and more recently ITBA-16 have been the only inhibitors of Pol ƞ, characterized by poor selectivity. In this context, the invention is represented by the compounds derived from 4-chromone, which have been found to be inhibitors of Pol ƞ with a low cellular toxicity, but with a synergistic effect with cispatin, thus increasing its effectiveness. Such formulations can be administered orally, nasally, subcutaneously, and intramuscularly. In addition, the compounds described are referred to as small molecules, so they are small molecules, which can be easily synthesized.
Medical use, for the treatment of neoplastic diseases represented by: ovarian cancer, breast cancer, pancreatic cancer, lung cancer, gastric adenocarcinoma, mucosal-derived squamous cell neck cancer
- Highly effective and specific
- Low cellular toxicity
- Main structure and substructures that act as scaffolds, ensuring good chemical diversity and allow the investigation of many compounds with similar structure
- Easily synthesized