ЦИТОТОКСИЧНОСТЬ ПИРАНОПИРИДОНОВ С ТРИПТАМИНОВЫМ ФРАГМЕНТОМ

Abstract

New derivatives of pyrano[3,2-c]pyridones III 5, 10, 15, 18 were synthesised by threecomponent reaction of pyridonotryptamines I, aromatic aldehydes II and malononitril. Pyridonotryptamines I were synthesised by reaction of tryptamines (these compounds were obtained by Grandberg reaction of arylhydrazines with γ-halogencarbonyl compounds) with 4-hydroxy- 6-methyl-2H-pyran- 2-on. The aromatic aldehydes II 1, 5, 6, 9 are commercially available compounds. Boiling a mixture of compounds I, II and malononitril (molar ratio 1:1.1:1.1) in ethyl alcohol in the presence of triethylamine gives the target compounds III 5, 10, 15, 18. The product yields 44–75%. The structure of pyrano[3,2-c]pyridones with tryptamine fragment III (four compounds) was proved by 1H NMR and confirmed by elemental analysis. Compounds III 1–4, 6–9, 11–14, 16 and 17 were synthesised earlier by a similar procedure. The cytotoxicity of the synthesised compounds III 1–18 was determined in vitro using the MTT test on human cell cultures A549 (lung carcinoma) and HCT116 (colorectal carcinoma). Camptothecin and daunorubicin were used as reference drugs. The value of the concentration inducing 50% inhibition of the cell growth (IC50, μM) was determined from the dose-response curves using GraphPad Prism 9 software. Compounds III 3 (R1=R2=Br, Ar=2,5-di-OMe-С6Н3,) III 4 (R1=R2=Br, Ar=4-F-С6Н4), III 6 (R1=Ме, R2=Н, Ar=2,4,5-tris-OMe-С6Н2), III 13 (R1=R2=Br, Ar=Ph), III 14 (R1=R2=Br, Ar=2,3-di-OMe-С6Н3) and III 16 (R1=R2=Br, Ar=Py) showed the best results for A549 and HCT116 cultures. The effect of the most active compounds III 3 and III 4 on the cell cycle and apoptosis was studied on Jurkat cell culture (human acute T-cell leukemia). Compounds III 3 and III 4 showed significant cytotoxicity against the Jurkat line in the resazurin test – 1.47 ± 0.06 and 4.56 ± 0.19 μM, respectively, comparable to the cytotoxicity of the reference drug camptothecin of 1.24 ± 0.05 μM. Based on the flow cytometry results, it is suggested that the effect is manifested by some (possibly reversible) cell cycle arrest in the presynthetic phase.