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Design, synthesis and cytostatic activity of novel pyrazine sorafenib analogues (CROSBI ID 232775)

Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija

Rajić-Džolić, Zrinka ; Perković, Ivana ; Kraljević Pavelić, Sandra ; Sedić, Mirela ; Ilić, Nataša, Schols, Dominique ; Zorc, Branka Design, synthesis and cytostatic activity of novel pyrazine sorafenib analogues // Medicinal chemistry research, 25 (2016), 2729-2741. doi: 10.1007/s00044-016-1667-y

Podaci o odgovornosti

Rajić-Džolić, Zrinka ; Perković, Ivana ; Kraljević Pavelić, Sandra ; Sedić, Mirela ; Ilić, Nataša, Schols, Dominique ; Zorc, Branka

engleski

Design, synthesis and cytostatic activity of novel pyrazine sorafenib analogues

The current study is focused on a series of sorafenib analogues as potential antitumor agents. We have designed and synthesized nine novel pyrazine analogues 6a-i differing in amide and/or urea regions. Two alternative strategies for the preparation of title compounds were applied. The first strategy involved ether formation between 4- hydroxyphenyl urea 3 and 5-chloro-pyrazine-2- carboxamides 4. In the second strategy, ether functionality was introduced in the molecule before urea moiety and included preparation of 5-(4-aminophenoxy)-N-alkylpyrazine-2- carboxamides 5 and their reaction with 4- chloro-3-(fluoromethyl)phenyl isocyanate. Cytostatic activity of the title compounds was evaluated in vitro against a panel of cancer cell lines. Most of the tested compounds showed strong antiproliferative activity in the low micromolar range. 5-/4-[3-(4-Chloro-3- trifluoromethyl-phenyl)-ureido]-phenoxy/- pyrazine-2-carboxylic acid (4-chloro-3- trifluoromethylphenyl)-amide (6g) was the most active compound (IC50 0.9-7.5 μM) and showed comparable or stronger activity than sorafenib, but also similar cytotoxicity to normal human fibroblast cells. Two compounds, namely 5-/4- [3-(4-bromophenyl)-ureido]-phenyloxy/-pyrazine- 2-carboxylic acid cyclopentylamide (6c) and 5-/4-[3-(4-chloro-3-trifluoromethyl-phenyl)- ureido]-phenoxy/-pyrazine-2-carboxylic acid cyclopentylamide (6h), exerted cytostatic activities that surpassed the effects observed with sorafenib in three cancer cell lines (HepG2, HeLa, A549, IC50 0.6-0.9 μM). Similar to sorafenib, compound 6h proved to be cytotoxic to normal human fibroblast cells, whereas compound 6c did not diminish proliferative capacity of these cells and could be regarded as the most promising derivative. Additional biological studies on the c-Raf activity using Western blot method revealed that antiproliferative activity of 6h could be at least partially attributed to its inhibitory effect on c-Raf activation similar to sorafenib. In contrast, 6c did not inhibit the activity of c-Raf, which implies that other cell signalling pathways govern its antiproliferative effects. Taking into account structural differences between compounds 6c and 6h, it is plausible to believe that the substituent in urea part of the molecule is essential for the interaction with c-Raf.

Sorafenib ; Pyrazine ; Synthesis ; Cytostatic activity ; c-Raf ; Western blotting

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Podaci o izdanju

25

2016.

2729-2741

objavljeno

1054-2523

10.1007/s00044-016-1667-y

Povezanost rada

Temeljne medicinske znanosti, Farmacija

Poveznice
Indeksiranost