Synthesis and anti-tumor properties of derivatives [4- (41-chlorophenyl)-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[c,d]azulen-1-yl-metil]-para-tolylamine

Keywords: derivatives of [4-(41-chlorophenyl)-5,6,7,8-tetrahydro-2,2a,8a-triaza¬cyclopenta[c,d]azulen-1-yl-metil]-para-tolylamine, antitumor properties, leukemia, 5-fluorouracil

Abstract

Leukemia, as a part of hemoblastosises, is a malignant blood system disease, which is characterized by bone marrow damage, caused by leukemic stem cells, which appear due to disruption of self-renewal and differentiation of hempoetic stem cells and predecessor cells. In their turn, hemoblastoses are divided into two groups: bone marrow (acute leukemia, chronical leukemia, paraproteinemic hemoblastoses) and outside bone marrow (lymphogranulomatosis, or Hodgkin lymphoma, and non-Hodgkin malignant mymphomas).

Nowadays in Ukraine, different kinds of leukemia are cured by various drugs, which have many side effects. Increase in effectivity of chemotherapy of tumor disease is primarily related to creation of new antitumor drugs of selective action. Which is why search for biologically active compounds with antitumor activity is a perspective direction in creation of new drugs.

Aim of this work was synthesis of compounds with potential antitumor properties in a variety of [4-(41-chlorophenyl)-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[c,d]-azulen-1-yl-methyl]-para-tolylamin derivatives.

As the objects of our studies, we have picked the derivatives of [4-(41-chlorophenyl)-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[c,d]-azulen-1-yl-methyl]-para-tolilamin (8 and 10 a, b). [4-(41-Chlorphenyl)-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[c,d]azulen-1-yl-methyl]-para-tolylamin (8) was obtained by boiling of equimolar quantities of 3-(41-methylphenyl)aminomethyl-6,7,8,9-tetrahydro-5Н-[1,2,4]triazolo[4,3-a]azepin (5) and α-brom-4-chloracetophenon in ethylacetate. Thioamides (10 a, b) were obtained by interaction of amin (8) with corresponding arylisothiocyanates (9 а, b) in dry benzene.

Antitumor activity of [4-(41-chlorphenyl)-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[c,d]azulen-1-yl-methyl]-para-tolylamin (8) was studied in National Cancer Institute of Health, USA within Development Therapeutic Program.

In experimental conditions [4-(41-chlorphenyl)-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[c,d]azulen-1-yl-methyl]-para-tolylamin (8) showed ability to inhibit growth of cancerous leukemia cells of CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and SR lines, higher than standard – 5-fluorouracil. Towards HL-60(TB) cells [4-(41-chlorphenyl)-5,6,7,8-tetrahydro-2,2а,8а- triazacyclopenta[c,d]azulen-1-yl-methyl]-para-tolylamin exceeds standard in effectivity by 64.68%. For K-562, MOLT-4, RPMI-8226 and SR cells, those numbers are equal to: 85.88%, 84.95%, 42.10% and 36.82% correspondingly. Towards CCRF-CEM cells, this compound not only inhibits cell growth and division, but also destroys them by 20.34%.

Thus conducted studies confirm perceptivity of search for compounds with antitumor action on the basis of [4-(41-chlorophenyl)-5,6,7,8-tetrahydro-2,2а,8а-triazacyclopenta[c,d]azulen-1-yl­methyl]-para-tolylamin.

References

Hostri leikemii. Rezhym dostupu: http://www.all-blood.ru/ua/gostri-leikemiyi.html

Hemoblastozy. Rezhym dostupu: http://www.all-blood.ru/ua/gemoblastozi.html

Buss E. C., Ho A. D. Leukemia stem cells // Int. J. Cancer. – 2011. – V. 129. – P. 2328–2336. http://dx.doi.org/10.1002/ijc.26318

Sviezhentseva I. O. Rol leikoznoi stovburovoi klityny u patohenezi khronichnoi miieloidnoi leikemii // Annals of Mechnikov Institute. – 2016. – N 3. – S. 15–21. Rezhym dostupu: www.imiamn.org.ua /journal.htm

Likarski zasobi dlya likuvannya lejkemiyi. Rezhуm dostupu: http://mediclab.com.ua/index.php?newsid=7461

Imatinib. Rezhym dostupu: https://uk.wikipedia.org/wiki/Іматиніб

Interferony. Rezhym dostupu: https://uk.wikipedia.org/wiki/Інтерферони

Letrozol (Letrozolum). Rezhym dostupu: https://compendium.com.ua/akt/76/55/letrozolum/

[4-(41-Khlorfenil)-5,6,7,8-tetrahidro-2,2a,8a-tryazatsyklopenta[cd]azulen-1-il-metyl]-para-tolilamin, yakyi maie protypukhlynnu aktyvnist shchodo rakovykh klitynnykh linii leikemii / Patent Ukrainy na korysnu model №136968, MPK : S07D 487/00, A61P 35/00. zaiavka № u 2019 01414. Demchenko S. A., Sukhovieiev V. V., Shvydko O. V., Demchenko A. M. – Zaiavl. 12. 02. 2019; Opubl. 25. 09. 2019, Biul. № 18.

Rohlmann R., Stopka T., Richter H. et al. Iron-catalyzed oxidative tandem reactions with TEMPO oxoammonium salts: Synthesis of dihydroquinazolines and quinolines // J. Organic Chem. – 2013. – V. 78, N 12. – Р. 6050–6064. https://doi.org/10.1021/jo4007199

Bonacorso H., Pittaluga E., Alves S. et al. Regioselective synthesis and antimicrobial evaluation of new 1-aryloxyacetyl-, 1-thiophenoxyacetyl- and 1-phenylaminoacetylsubstituted 3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazoles // Arkivoc. – 2012. – V. 2012, N 8. – Р. 62–75.

Granik V. G., ZHidkova A. M., Kuryatov N. S. i dr. Acetali laktamov. VII. Issledovanie alkilirovaniya N-metillaktamov i laktimnyh efirov dimetilsul'fatom // HGS. – 1973. – № 11. – S. 1532–1535.

Demchenko S. A., Єr'omіna G. O., Perekhoda L. O. ta іn. Sintez ta anal'gezuyuchі vlastivostі pohіdnih (3-allіl-4-aril-3N-tіazol-2-іlіden)-[4-(6,7,8,9-tetragіdro-5N[1,2,4]triazolo[4,3-a]azepіn-3-їl)fenіl]amіnіv // Farmac. zh. – 2017. – N 1. – S. 67–73. https://doi.org/10.32352/0367-3057.1.17.09

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

Published
2020-07-30
How to Cite
Demchenko, S. A., Sukhoveev, V. V., МоsкаlеnкоО. V., Fedchenkova, Y. A., Potebnia, G. P., & Demchenko, A. M. (2020). Synthesis and anti-tumor properties of derivatives [4- (41-chlorophenyl)-5,6,7,8-tetrahydro-2,2a,8a-triazacyclopenta[c,d]azulen-1-yl-metil]-para-tolylamine. Farmatsevtychnyi Zhurnal, (4), 69-77. https://doi.org/10.32352/0367-3057.4.20.07
Section
Synthesis and analysis of biologically active compounds