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

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-JúniorMaria C.F. de Oliveira, Leslie Gunatilaka

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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).

Original languageEnglish (US)
Pages (from-to)156-166
Number of pages11
JournalJournal of Photochemistry and Photobiology B: Biology
Volume179
DOIs
StatePublished - Feb 1 2018

Fingerprint

deoxyribonucleic acid
DNA
Abietane Diterpenes
cancer
interactions
leukemias
Ethidium
fibroblasts
Glioblastoma
Tumor Cell Line
Fluorescent Dyes
cultured cells
macromolecules
intercalation
Antineoplastic Agents
Colonic Neoplasms
mice
bromides
Prostate
Hepatocellular Carcinoma

Keywords

  • Annonalide
  • Casimirella ampla
  • Cytotoxic activity
  • DNA interaction
  • Pimarane diterpene
  • Semisynthesis

ASJC Scopus subject areas

  • Radiation
  • Radiological and Ultrasound Technology
  • Biophysics
  • Radiology Nuclear Medicine and imaging

Cite this

Annonalide and derivatives : Semisynthesis, cytotoxic activities and studies on interaction of annonalide with DNA. / Marques, Ricardo A.; Gomes, Akenaton O.C.V.; de Brito, Maria V.; dos Santos, Ana L.P.; da Silva, Gladyane S.; de Lima, Leandro B.; Nunes, Fátima M.; de Mattos, Marcos C.; de Oliveira, Fátima C.E.; do Ó Pessoa, Cláudia; de Moraes, Manoel O.; de Fátima, Ângelo; Franco, Lucas L.; Silva, Marina de M.; Dantas, Maria Dayanne de A.; Santos, Josué C.C.; Figueiredo, Isis M.; da Silva-Júnior, Edeíldo F.; de Aquino, Thiago M.; de Araújo-Júnior, João X.; de Oliveira, Maria C.F.; Gunatilaka, Leslie.

In: Journal of Photochemistry and Photobiology B: Biology, Vol. 179, 01.02.2018, p. 156-166.

Research output: Contribution to journalArticle

Marques, RA, Gomes, AOCV, de Brito, MV, dos Santos, ALP, da Silva, GS, de Lima, LB, Nunes, FM, de Mattos, MC, de Oliveira, FCE, do Ó Pessoa, C, de Moraes, MO, de Fátima, Â, Franco, LL, Silva, MDM, Dantas, MDDA, Santos, JCC, Figueiredo, IM, da Silva-Júnior, EF, de Aquino, TM, de Araújo-Júnior, JX, de Oliveira, MCF & Gunatilaka, L 2018, 'Annonalide and derivatives: Semisynthesis, cytotoxic activities and studies on interaction of annonalide with DNA', Journal of Photochemistry and Photobiology B: Biology, vol. 179, pp. 156-166. https://doi.org/10.1016/j.jphotobiol.2018.01.016
Marques, Ricardo A. ; Gomes, Akenaton O.C.V. ; de Brito, Maria V. ; dos Santos, Ana L.P. ; da Silva, Gladyane S. ; de Lima, Leandro B. ; Nunes, Fátima M. ; de Mattos, Marcos C. ; de Oliveira, Fátima C.E. ; do Ó Pessoa, Cláudia ; de Moraes, Manoel O. ; de Fátima, Ângelo ; Franco, Lucas L. ; Silva, Marina de M. ; Dantas, Maria Dayanne de A. ; Santos, Josué C.C. ; Figueiredo, Isis M. ; da Silva-Júnior, Edeíldo F. ; de Aquino, Thiago M. ; de Araújo-Júnior, João X. ; de Oliveira, Maria C.F. ; Gunatilaka, Leslie. / Annonalide and derivatives : Semisynthesis, cytotoxic activities and studies on interaction of annonalide with DNA. In: Journal of Photochemistry and Photobiology B: Biology. 2018 ; Vol. 179. pp. 156-166.
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abstract = "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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AU - de Brito, Maria V.

AU - dos Santos, Ana L.P.

AU - da Silva, Gladyane S.

AU - de Lima, Leandro B.

AU - Nunes, Fátima M.

AU - de Mattos, Marcos C.

AU - de Oliveira, Fátima C.E.

AU - do Ó Pessoa, Cláudia

AU - de Moraes, Manoel O.

AU - de Fátima, Ângelo

AU - Franco, Lucas L.

AU - Silva, Marina de M.

AU - Dantas, Maria Dayanne de A.

AU - Santos, Josué C.C.

AU - Figueiredo, Isis M.

AU - da Silva-Júnior, Edeíldo F.

AU - de Aquino, Thiago M.

AU - de Araújo-Júnior, João X.

AU - de Oliveira, Maria C.F.

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N2 - 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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