Annonalide and derivatives: Semisynthesis, cytotoxic activities and studies on interaction of annonalide with DNA

Publication date: February 2018
Source:Journal of Photochemistry and Photobiology B: Biology, Volume 179
Author(s): Ricardo A. Marques, Akenaton O.C.V. Gomes, Maria V. de Brito, Ana L.P. dos Santos, Gladyane S. da Silva, Leandro B. de Lima, Fátima M. Nunes, Marcos C. de Mattos, Fátima C.E. de Oliveira, Cláudia do Ó Pessoa, Manoel O. de Moraes, Ângelo de Fátima, Lucas L. Franco, Marina de M. Silva, Maria Dayanne de A. Dantas, Josué C.C. Santos, Isis M. Figueiredo, Edeíldo F. da Silva-Júnior, Thiago M. de Aquino, João X. de Araújo-Júnior, Maria C.F. de Oliveira, A.A. Leslie Gunatilaka
The cytotoxic activity of the pimarane diterpene annonalide (1) and nine of its semisynthetic derivatives (2–10) was investigated against the human tumor cell lines HL-60 (leukemia), PC-3 (prostate adenocarcinoma), HepG2 (hepatocellular carcinoma), SF-295 (glioblastoma) and HCT-116 (colon cancer), and normal mouse fibroblast (L929) cells. The preparation of 2–10 involved derivatization of the side chain of 1 at C-13. Except for 2, all derivatives are being reported for the first time. Most of the tested compounds presented IC50s below 4.0 μM, being considered potential antitumor agents. The structures of all new compounds were elucidated by spectroscopic analyses including 2D NMR and HRMS. Additionally, the interaction of annonalide (1) with ctDNA was evaluated using spectroscopic techniques, and the formation of a supramolecular complex with the macromolecule was confirmed. Competition assays with fluorescent probes (Hoechst and ethidium bromide) and theoretical studies confirmed that 1 interacts preferentially via DNA intercalation with stoichiometric ratio of 1:1 (1:ctDNA). The ΔG value was calculated as −28.24 kJ mol⁻¹, and indicated that the interaction process occurs spontaneously. Docking studies revealed that van der Walls is the most important interaction in 1-DNA and EB-DNA complexes, and that both ligands (1 and EB) interact with the same DNA residues (DA6, DA17 and DT19).

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