Anticancer activity of isoquinoline derivatives — products of 3-(2-(thien-2-yl)thiazol-4-yl isocoumarin recyclization

Konovalenko, AS
Shablykin, OV
1Shablykina, OV
1Moskvina, VS
2Brovarets, VS
1Khilya, VP
1Taras Shevchenko National University of Kyiv
2Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv
Dopov. Nac. akad. nauk Ukr. 2019, 12:83-90
https://doi.org/10.15407/dopovidi2019.12.083
Section: Chemistry
Language: Ukrainian
Abstract: 

In order to produce new bioactive derivatives of isoquinoline and to establish correlations between their structure and activity, we used the classic recyclization of isocoumarin into isoquinoline derivatives; this reaction is convenient enough to access certain types of isoquinolines, but was poorly studied for 3-hetaryl substituted derivatives. The purposefully synthesized 3-(2-(thien-2-yl)thiazol-4-yl)isocoumarin was subsequently transformed into isoquinolin-1-(2H)-one (by heating under high pressure in an alcoholic solution of ammonia), 1-chloroisoquinoline (by the prolonged boiling of isoquinolin-1(2H)-one in a large excess of POCl3), and 1-(4- methylpiperazin-1-yl)- and 1-(morpholin-4-yl)isoquinoline with 2-(thien-2-yl)thiazol-4-yl substituent in position 3 (by heating 1-chloroisoquinoline with the corresponding amine in DMF and K2CO3). Studies of 3-(2-(thien-2-yl)thiazol-4-yl)isocoumarin and its isoquinolines derivatives for the anticancer activity, conducted on 60 cancer cell lines at the US National Cancer Institute, showed that 4-(1-(4-methylpiperazin- 1-yl)isoquinolin-3-yl)-2-(thien-2-yl)thiazole inhibits the growth of most of the studied cell lines; in fact, this compound was lethal in some cases, in particular, for the COLO 205, HCC-2998, and HT29 colon cancer lines, as well as for the M14 melanoma line and the K-562 leukemia line. A similar derivative with a morpholine substituent shows, on average, a low activity, but is still quite effective against several cancer lines: melanoma MALME-3M and UACC-257, breast cancer MDA-MB-468 and colon cancer COLO 205. At the same time, the initial isocoumarin, as well as 3-(2-(thien-2-yl)thiazol-4-yl)isoquinolin-1(2H)-one and 1-chloro-3-(2-(thien-2- yl)thiazol-4-yl)isoquinoline have a very low cytotoxicity and can only slightly slow down the growth of some cancer cell lines. The developed approaches to the transformation of 3-hetarylisocoumarin to 1-functionalized isoquinolines use simple techniques and available reagents and provide a wide variety of target products. In fact, they serve as a reliable basis for further biological studies of 1-R-3-hetarylisoquinolines, which demonstrate a clear strong dependence of the antitumor activity on the nature of substituents in the base structure.

Keywords: 1-amino(chloro)-3-hetarylisoquinoline, 3-hetaryl-1H-isochromen-1-ones, 3-hetarylisoquinoline-1(2H)-one, antitumor activity, recyclization
References: 

1. Shepard, E. R. & Noth, J. F. (1950). Preparation of some homologs of papaverine. J. Am. Chem. Soc., 72, Iss. 10, pp. 4364-4366. Doi: https://doi.org/10.1021/ja01166a009
2. He, L.-W., Chen, Y.-Q., Yang, J.-Y., Wang, T.-L., Li, W. & Liu, H.-Q. (2014). Total synthesis and anti-viral activities of an extract of Radix isatidis. Molecules, 19, Iss. 12, pp. 20906-20912. Doi: https://doi.org/10.3390/molecules191220906
3. Prakash, K. S. & Nagarajan, R. (2014). Total synthesis of the marine alkaloid mansouramycin D. Org. Lett., 16, Iss. 1, pp. 244-246. Doi: https://doi.org/10.1021/ol4032396
4. My Van, H. T., Woo, H., Jeong, H. M., Khadka, D. B., Yang, S. H., Zhao, C., Jin, Y., Lee, E.-S., Lee, K. Y., Kwon, Y. & Cho, W.-J. (2014). Design, synthesis and systematic evaluation of cytotoxic 3-heteroarylisoquinolinamines as topoisomerases inhibitors. Eur. J. Med. Chem., 82, pp. 181-194. Doi: https://doi.org/10.1016/j.ejmech.2014.05.047
5. Grethe, G. (Ed.). (2009). Isoquinolines. Pt. 1. John Wiley & Sons.
6. Shablykina, O., Moskvina, V., Savchenko, V. & Khilya, V. (2017). Using of 3-arylisocoumarins in 3-arylisoquino lons synthesis. Visnyk Kyyivs’koho natsional’noho universytetu imeni Tarasa Shevchenka. Khimiya, Iss. 2, pp. 18-30 (in Ukrainian). Doi: https://doi.org/10.17721/1728-2209.2017.2(54).2
7. Moskvina, V. S., Shablykina, O. V. & Khilya, V. P. (2017). Reactions of 3-arylisocoumarins with N-nucleophiles — a route to novel azaheterocycles. Curr. Top. Med. Chem., 17, No. 29, pp. 3199—3212. Doi: https://doi.org/10.2174/1568026618666171227124212
8. Shablykina, O. V., Shablykin, O. V., Ishchenko, V. V. Voronaya, A. V. & Khilya, V. P. (2013). Synthesis of 3-hetaryl-1H-isochromen-1-ones based on 3-(2-bromoacetyl)-1H-isochromen-1-one. Chem. Heterocycl. Compd., 48, Iss. 11, pp. 1621-1627. Doi: https://doi.org/10.1007/s10593-013-1183-7
9. Sarangi, P. K. N., Sahoo, J., Swain, B. D., Paidesetty, S. K. & Mohanta, G. P. (2016). Thiazoles as potent anticancer agents: a review. Indian Drugs, 53, Iss. 11, pp. 5-11.
10. National Cancer Institute. Division of Cancer Treatment and Diagnosis. Retrieved from https://dtp.cancer.gov
11. NCI-60 Human Tumor Cell Lines Screen. Retrieved from https://dtp.cancer.gov/discovery_development/nci-60/default.htm