Synthesis and evaluation of the mutagenicity of 3-alkylpyridine marine alkaloid analogues with anticancer potential

•Two new theoneladin C analogues containing thiocyanate group were synthesized.•Compounds were active against P. falciparum clone W2 but were too cytotoxic.•Compounds were mutagenic and cause chromosomal mis-segregation in cancer cells.•Compound 3a was selective to a colon cancer cell line. Theonell...

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Published in:Mutation research. Genetic toxicology and environmental mutagenesis 2018-01, Vol.825, p.31-39
Main Authors: Barbosa, Maria Cristina S., de Souza Barbosa, Camila, de Oliveira, Júlia T., Moreira, Natália Chermont S., de Miranda Martins, Natália Rezende, Alves Gomes, Gabrielle K., Caldeira, Camila A., Alves e Costa, Marília Ladeira, Martins Guimarães, Daniel Silqueira, Guimarães, Luciana, Nascimento, Clebio S., de Pilla Varotti, Fernando, Ribeiro Viana, Gustavo Henrique, Santos, Fabio Vieira dos
Format: Article
Language:English
Subjects:
Aneugen
Antimalarial
Genotoxicity
Thiocyanate group
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Summary:•Two new theoneladin C analogues containing thiocyanate group were synthesized.•Compounds were active against P. falciparum clone W2 but were too cytotoxic.•Compounds were mutagenic and cause chromosomal mis-segregation in cancer cells.•Compound 3a was selective to a colon cancer cell line. Theonella sp is an important source of biologically–active 3-alkylpyridine alkaloids (3-APAs) that has shown a wide variety of promising biological effects. In the present work, two new 3-APAs analogues were synthesized based on molecular modeling studies to act as potential antimalarial agents. These theoneladin C analogues, containing the thiocyanate group in their chemical structures, were synthesized and evaluated against Plasmodium falciparum (IC50 values ranging from 2.3 to 5.5μM). The structural and energetic analysis demonstrated a high chemical affinity of the two analogues for their target, the heme group. However, despite the good antimalarial activity, the compounds exhibited high cytotoxicity and a lack of selectivity for human cell lines. These findings prompted us to evaluate the cytotoxicity of these compounds against human cancer cell lines. In order to better understand the mechanisms responsible for the toxicity, a variety of genotoxicity assays were performed in vitro. One of the compounds assayed presented an interesting selectivity and high toxicity to the human colon cancer cell line RKO-AS45-1. In addition, the results of the micronucleus assay, comet assay, Ames assay and annexin-V/propidium iodide staining showed that the synthetic alkaloids were able to induce chromosomal mis-segregation and trigger cell death by apoptosis. These results demonstrate that the compounds assessed herein may be promising prototypes of anticancer chemotherapeutic agents.
ISSN:1383-5718
1879-3592
DOI:10.1016/j.mrgentox.2017.11.006