The Conjugates of Indolo[2,3-b]quinoline as Anti-Pancreatic Cancer Agents: Design, Synthesis, Molecular Docking and Biological Evaluations

Abstract

New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5H-indolo[2,3-b]quinoline (2), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC50 values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate 2 did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA–topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II–DNA complex compared to DiMIQ. Conjugate 2 was predicted to have the strongest binding to the enzyme–DNA complex, with a Ki value of 2.8 nM.

Special Issue “Development and Synthesis of Biologically Active Compounds”

“…In addition, Cybulski et al [17] synthesized five new amide conjugates of hydroxycinnamic acids with the known analog of the naturally occurring alkaloid neocryptolepine, i.e., antitumor 5,11-dimethyl-5H-indolo[2,3-b]quinoline [18,19]. Three conjugates demonstrated significant antiproliferative effect on pancreatic cancer (BxPC-3 and metastatic AsPC-1), breast cancer (MCF-7), and cervical cancer cells (HeLa).…”