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

• Published in: ChemistrySelect (Weinheim) Vol. 4; no. 34; pp. 10197 - 10201
• Main Authors: Lipeeva, Alla V., Zakharov, Danila O., Gatilov, Yurii V., Pokrovskii, Mikhail A., Pokrovskii, Andrey G., Shults, Elvira E.
• Format: Journal Article
• Language: English
• Published: 13-09-2019
• Subjects: Bromination; Buchwald amination; Coumarin; Cytotoxicity; Suzuki cross-coupling reaction
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.201901377

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.
Selective synthesis of 6,7‐disubstituted 3‐bromocoumarins from the plant coumarin peuruthenicin are reported. The reaction of 3‐bromocoumarin with a variety of 1‐aminoazoles and anilines is described. The Suzuki coupling of privileged structures resulted in functionally advantageous compounds. Their cytotoxicity was tested against human cancer cell lines. The introduction of an additional aryl(hetaryl) moiety turned some compounds into cytotoxic agents, and one of the hybrid azole‐coumarin derivatives exhibited cytotoxicity on the cancer cell lines comparable to those of Doxorubicin.