Pleiotropic focused anticancer approach by dihydropyridines, dihydropyrimidines and heteroaromatic compounds

Complex, focused anticancer therapy approach has been developed in the Latvian Institute of Organic Synthesis by making use of privileged partially hydrogenated nitrogen-containing heterocycles, namely dihydropyridines, dihydropyrimidines, their oxidized heteroaromatic derivatives. Topics of research include:

1. Conventional approach by chemotherapy and synergism of anticancer drugs [1];

2. Inhibition of multidrug resistance by inhibition of drug efflux pumps [2];

3. Mitigation of cancer risk factors – e.g., hepatitis B virus chemotherapy for prevention of chronic liver diseases, because chronic hepatitis, in up to 40% of cases, progresses to cyrrhosis and further to hepatocellular carcinoma [3];

4. Improvement of efficacy of cancer radiotherapy by use of radioprotectors to prevent damage of normal tissues. So, radioprotector diethone (dietone) for skin protection was discovered, elaborated, and developed as ointment. Compounds for protection of eyes, mucous tissues, salivary glands etc have been synthesized. Toxicity of dietone and novel radioprotectors is very low;

5.Amphiphilic compounds have been synthesized, nanoparticles for anticancer drug and gene delivery have been created, pleiotropic properties have been checked, inclusion of magnetic particles for targeted transport performed [4].

Acknowledgements

The research was partially supported by the Latvian State Program Biomedicine.

References

1.Bisenieks E., Duburs G. et al., Pharmaceutical combination of 5-fluorouracil and derivatives of 1,4-dihydropyridine. US 8492413B2, 2013.

2.Krauze A., Grinberga S. et al., Thieno[2,3-b]pyridines – a new class of multidrug resistance (MDR) modulators. Bioorg.Med.Chem. 2014, 22 (21), 5860-5870.

3.Sipola A., Dubova U., et al., Synthesis and evaluation of 1,4-dihydropyrimidine derivatives – hepatitis B virus capsid self-assembly inhibitors. EFMC International Symposium on Medicinal Chemistry. Ljubljana, Slovenia, 2018, P176.

4.Pajuste K. et al., Gene delivery agents possessing antiradical activity: Self-assembling cationic amphiphilic 1,4-dihydropyridine derivatives. New J.Chem. 2013, 37 (10), 3062-3075.