Synthesis and Evaluation of the Cytotoxicity of Indeno[1,2- c ]Isoquinoline Derivatives Bearing Ester Functional Group a

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Synthesis and evaluation of the cytotoxicity of indeno[1,2-c]isoquinoline derivatives bearing ester functional group and 1,2,3-triazole moiety Hoai Thu Pham1, Giang Le-Nhat-Thuy1,2, Tuyet Anh Dang Thi1,2, Phuong Hoang Thi1, Tuan Anh Nguyen1, Thanh Ha Nguyen1, Tien Dung Nguyen3, Hanh Thuong Ngo3, Tuan Anh Le4, Tuyen Van Nguyen1,2* 1

Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet St., Cau Giay, Hanoi 100000, Vietnam; e-mail: [email protected] 2 Graduate University of Science and Technology, VAST, 18 Hoang Quoc Viet St., Cau Giay, Hanoi 100000, Vietnam; email: [email protected] 3 Vietnam University of Traditional Medicine, Ha Dong, Hanoi 100000, Vietnam; e-mail: [email protected] 4 VNU University of Science, 19 Le Thanh Tong, Hoan Kiem, Hanoi 100000, Vietnam; e-mail: [email protected] Submitted March 27, 2020 Accepted May 20, 2020

Published in Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(9), 1167–1172

Synthesis of novel indeno[1,2-c]isoquinoline derivatives, functionalized at the D ring and bearing 1,2,3-triazole unit, has been reported. These hybrid compounds display cytotoxic activity against two human cancer cell lines – KB and HepG2 with half maximal inhibitory concentration (IC50) values in a range of 20–40 µM. Keywords: indenoisoquinoline, 1,2,3-triazole, click chemistry, cytotoxicity, pharmacophore hybridization.

1,2,3-Triazoles, one of the most promising classes of nitrogen-containing heterocycles, may be successfully used in structural modifications and have an important effect on biological interactions between the modified compounds and their targets. Triazoles can be used as linkers and can show bioisosteric effects on peptide linkage, aromatic rings, including imidazole ring, and double bonds.1 Attachment of pharmacophores with a 1,2,3-triazole backbone is a promising strategy for developing anticancer drug candidates, which are highly effective against both drug-sensitive and drug-resistant cancer cells due to their specific mechanisms of action. Obviously, it can be assumed that hybridization of 1,2,3-triazole scaffold with pharmacophores that ensure anticancer properties, such as quinazoline,2 quinone,3 triterpenoids,4 etc., has the potential to provide novel biologically active hybrid compounds with low toxicity against normal cells and high efficacy against drug-resistant cancer cells. 0009-3122/20/56(9)-1167©2020 Springer Science+Business Media, LLC

On the other hand, indenoisoquinolines are one of the key structural units, which have been attracting considerable interest because of their various biological activities.5 Combination of triazole and indenoisoquinoline rings into a single molecule is an interesting strategy used in anticancer drug design. However, data on the synthesis of 1,2,3triazole and indenoisoquinoline adducts are limited despite the fact that a wide range of indenoisoquinoline derivatives have been synthesized previously.6 In this work, we present the design and synthesis of novel hybrid compounds