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N4*

Calixpyrrole-based antitumor compounds

Prof. Franz Heinrich Kohnke, University of Messina; Dr Camillo Rosano, University of Messina; Prof. Alberto Izzotti, University of Messina; Dr Grazia Cafeo, University of Messina

University of Messina


Challenge

Development of novel chemoterapic compounds for cancer treatment.


Technology

Organic synthesis of compounds that target the DNA elicit apoptosis in cancer cells.

This invention regards the discovery of cytoxicity of certain calixpyrrole derivatives against specific cancer cell lines (in particular A549 lung cancer). These compounds seem to act via the formation of covalent adducts with DNA, where the genetic damage induces cell death by apoptosis. The formation of covalent adducts was detected using ‘32P postlabelling’. We believe these adducts are formed by the initial complexation of the DNA phosphate unit by the calixpyrrole fragment and/or intercalation of the DNA major groove as shown in ‘in silico’ trials and subsequently by the reaction with the nucleobases of compounds 1 and 2 (or their activated metabolites). Preliminary pharmacokinetic tests (A/J mice) showed 1 and 2 to have extremely low toxicity in vivo and also their ability to cross the blood-brain barrier. This discovery paves the way for the development of calixpyrrole derivatives as potential drugs to treat cancer. Of particular interest is the ability of these compounds to pass the blood-brain barrier meaning they may be able to attack brain metastases as well as primary tumors (e.g. lung). (https://www.nature.com/articles/s41598-018-29314-9).


Commercial Opportunity

Lung cancer (considered as one of the four “Big Killers”) is the most commonly occurring cancer in men and the third most commonly occurring cancer in women. There were 2 million new cases in 2018 worldwide. The global lung cancer therapeutics market is expected to have a high growth. This market, in fact, is expected to grow at a compound annual growth rate (a measure of growth over multiple time periods – aka. CAGR) of 13.5% from 2015 to 2020. Current chemotherapy and radiation therapy are severely limited by adverse side effects. Our discovery paves the way to the development of novel calixpyrrole-based chemoterapic compounds with low toxicity.


Development Status

MTT in vitro study on various cell lines completed. The tested compounds were found most active against A549 lung cancer cells. Initial toxicology and pharmacokinetic tests in vivo (mouse) have been conducted.


Patent Situation

A International patent application has been filed recently. Worldwide patent protection is possible.


Further Reading

A detailed account of the scientific work concerning this invention has been published recently:

A novel calix[4]pyrrole derivative as a potential anticancer agent that forms genotoxic adducts with DNA. M. Geretto, M. Ponassi, M. Casale, A. Pulliero, G. Cafeo, F. Malagreca, A. Profumo, E. Balza, R. Bersimbaev, F. H. Kohnke, C. Rosano, A. Izzotti, Scientific Reports, 2018, 8, 11075.

(https://www.nature.com/articles/s41598-018-29314-9).


 

Calixpyrrole-based antitumor compounds