TY - JOUR

T1 - Design and Synthesis of 3-(N-Substituted)aminocoumarins as Anticancer Agents from 3-Bromopeuruthenicin

AU - Lipeeva, Alla V.

AU - Zakharov, Danila O.

AU - Gatilov, Yurii V.

AU - Pokrovskii, Mikhail A.

AU - Pokrovskii, Andrey G.

AU - Shults, Elvira E.

N1 - Publisher Copyright: © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2019/9/13

Y1 - 2019/9/13

N2 - A convenient protocol for the rapid and efficient synthesis of 3-bromopeuruthenicin 2 from plant coumarin peuruthenicin 1 is described. Coumarin 2 have been successfully reacted with N-methylpiperazine, or 5-aminoisoquinoline under reflux in chloroform with the formation of 3-(N-substituted)aminoumbelliferons. The easiness of formation of the mentioned compounds can be explained by occurring of the tautomerization processes in 3-bromo-7-hydroxycoumarin 2 in the reaction conditions. For obtaining high yields of 3-(arylamino)coumarins in the reaction of 3-bromocoumarin 2 with substituted anilines the palladium-catalyzed C–N coupling reaction was studied. The reaction proceeded cleanly in the presence of the Pd(OAc)2-Xantphos catalytic system with the formation of the corresponding coupling products. The Suzuki cross-coupling reaction of 3-(3-bromophenylamino)coumarin 8 f with aryl- and (hetaryl)boronic acids 11,13 and 14 using PdCl2(dppf) as the catalyst provided the formation of 3-(N-(aryl-hetaryl))aminocoumarins 12, 15 and 16 in good yields. The cytotoxicity of new umbelliferone derivatives was evaluated against human cancer cells using the conventional MTT assays. The data revealed that compounds 12, 15 and 16 possessed most promising cytotoxic potential; aminocoumarins 12 and 16 shown selectivity toward the breast cancer cells MCF-7. The cytotoxicity of 3-(N-substituted)aminocoumarins 12 and 16 on this cell lines was comparable to those of standard drug Doxorubicin.

AB - A convenient protocol for the rapid and efficient synthesis of 3-bromopeuruthenicin 2 from plant coumarin peuruthenicin 1 is described. Coumarin 2 have been successfully reacted with N-methylpiperazine, or 5-aminoisoquinoline under reflux in chloroform with the formation of 3-(N-substituted)aminoumbelliferons. The easiness of formation of the mentioned compounds can be explained by occurring of the tautomerization processes in 3-bromo-7-hydroxycoumarin 2 in the reaction conditions. For obtaining high yields of 3-(arylamino)coumarins in the reaction of 3-bromocoumarin 2 with substituted anilines the palladium-catalyzed C–N coupling reaction was studied. The reaction proceeded cleanly in the presence of the Pd(OAc)2-Xantphos catalytic system with the formation of the corresponding coupling products. The Suzuki cross-coupling reaction of 3-(3-bromophenylamino)coumarin 8 f with aryl- and (hetaryl)boronic acids 11,13 and 14 using PdCl2(dppf) as the catalyst provided the formation of 3-(N-(aryl-hetaryl))aminocoumarins 12, 15 and 16 in good yields. The cytotoxicity of new umbelliferone derivatives was evaluated against human cancer cells using the conventional MTT assays. The data revealed that compounds 12, 15 and 16 possessed most promising cytotoxic potential; aminocoumarins 12 and 16 shown selectivity toward the breast cancer cells MCF-7. The cytotoxicity of 3-(N-substituted)aminocoumarins 12 and 16 on this cell lines was comparable to those of standard drug Doxorubicin.

KW - Bromination

KW - Buchwald amination

KW - Coumarin

KW - Cytotoxicity

KW - Suzuki cross-coupling reaction

UR - http://www.scopus.com/inward/record.url?scp=85073320795&partnerID=8YFLogxK

U2 - 10.1002/slct.201901377

DO - 10.1002/slct.201901377

M3 - Article

AN - SCOPUS:85073320795

VL - 4

SP - 10197

EP - 10201

JO - ChemistrySelect

JF - ChemistrySelect

SN - 2365-6549

IS - 34

ER -