Synthesis and anticancer properties of 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene derivatives

  • S. A. Demchenko SI «Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine», Kyiv
  • A. E. Dudnik SI «Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine», Kyiv
  • T. A. Bukhtiarova SI «Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine», Kyiv
  • L. S. Bobkova SI «Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine», Kyiv
  • A. M. Demchenko SI «Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine», Kyiv
Keywords: 2,2а,8а-triazacyclopenta[cd]azulenes, condensation, (2-isopropyl-5-methylphenoxy)acetic acid hydrazide, anticancer activity

Abstract

In recent years, attention to itself is attracted to the problem of treatment of cancer that is caused by increase in patients, especially of working age. Therefore, the enlargement of the arsenal of anticancer medicines of a wide spectrum of action is actual.

The purpose of the study was to synthesize substances with potentially antitumor properties in a series 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene derivatives and to study the effect of synthesized compounds on inhibition of growth (or their destruction) of a wide range of cancer.

The objects of the study were derivatives of 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene, which were synthesized by refluxing 3-(2-isopropyl-5-methylphenoxymethyl)-6,7,8,9-tetrahydro-5Н-[1,2,4]triazolo[4,3-a]azepine with с appropriate α-halogenketones in ethyl acetate and further cyclization in an alkaline medium. Использовали данные NMR 1Н spectroscopy data were used. The primary evaluation of anticancer activity was carried out National Cancer Institute of Health, USA within the Development Therapeutic Program.

A series of new of 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene derivatives was synthesized, their structure and purity were confirmed by NMR 1Н spectroscopy. The anticancer activity of the synthesized compounds was studied both at a concentration of  10-5 mol/l and in a concentration gradient of 10-4‒10-8 mol/l in experiments in vivo on cancer cell lines. It is shown that insertion of methyl group into position 3 of heterocyclic system of the basic structure of 4-aryl-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[cd]azulene leads to an increase in the anticancer effect.

It is found that the tested compounds showed high anticancer effect on all types of cancer cell lines investigated – leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer.

References

1. Baum M., Cuzick J., Forbes J. et al. (The ATAC Trialists Group): Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early stage breast cancer. Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses // Cancer. – 2003. – V. 98. – P. 1802–1810.

2. «World Cancer Report». International Agency for Research on Cancer. 2008. Retrieved 2011-02-26. (cancer statistics often exclude non-melanoma skin cancers such as basal cell carcinoma, which are common but rarely fatal).

3. Kulabaş Necla, Tatar Esra, Bingöl Özakpınar Özlem et al. // Europ. J. Med. Chem. – 2016. – V. 121. – P. 58–70.

4. Granik V. G., Zhidkova A. M., Kuryatov N. S. i dr. Atsetali laktamov. VII. Issledovaniye alkilirovaniya N-metillaktamov i laktimnykh efirov dimetilsul'fatom // KHGS. – 1973. – № 11. – S. 1532–1535.

5. Beverly A. Teicher, Paul A. Andrews. Anticancer drug development guide: preclinical screening, clinical // Medical. – 2004. – V. 1. – 450 р.

6. Alley M. C., Scudiero D. A., Monks P. A. et al. Feasibility of drug screening with panels of human tumor cell lines using a microculture Tetrazolium assay // Cancer Res. – 1988. – V. 48. – P. 589–601.

7. Carter P H., Scherle P. A., Muckelbauer J. A. et al. Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α // Proc. Natl. Acad. Sci. USA. – 2001. – V. 98. – P. 11879–11886.

8. Grever M. R., Schepartz S. A., Chabner B. A. The National Cancer Institute: cancer drug discovery and development program // Seminars in Oncol. – 1992. – V. 19, N 6. – P. 622–638.
Published
2018-08-14
How to Cite
Demchenko, S. A., Dudnik, A. E., Bukhtiarova, T. A., Bobkova, L. S., & Demchenko, A. M. (2018). Synthesis and anticancer properties of 1-(2-isopropyl-5-methylphenoxymethyl)-3R-4-aryl-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[cd]azulene derivatives. Farmatsevtychnyi Zhurnal, (1-2), 51-60. https://doi.org/10.32352/0367-3057.1-2.18.06
Section
Synthesis and analysis of biologically active compounds