|Konovalenko, AS |
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|
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|
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