Pharmacokinetic Profile Evaluation of Novel Combretastatin Derivative, LASSBio-1920, as a Promising Colorectal Anticancer Agent
Celina de Jesus Guimarães,
Teiliane Rodrigues Carneiro,
Marisa Jadna Silva Frederico,
Guilherme G. C. de Carvalho,
Matthew Little,
Valder N. Freire,
Victor L. B. França,
Daniel Nascimento do Amaral,
Jéssica de Siqueira Guedes,
Eliezer J. Barreiro,
Lídia Moreira Lima,
Francisco W. A. Barros-Nepomuceno,
Claudia Pessoa
Affiliations
Celina de Jesus Guimarães
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceara (UFC), Fortaleza 60430-275, CE, Brazil
Teiliane Rodrigues Carneiro
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceara (UFC), Fortaleza 60430-275, CE, Brazil
Marisa Jadna Silva Frederico
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceara (UFC), Fortaleza 60430-275, CE, Brazil
Guilherme G. C. de Carvalho
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceara (UFC), Fortaleza 60430-275, CE, Brazil
Matthew Little
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceara (UFC), Fortaleza 60430-275, CE, Brazil
Valder N. Freire
Department of Physics, Federal University of Ceara (UFC), Fortaleza 60440-900, CE, Brazil
Victor L. B. França
Department of Physics, Federal University of Ceara (UFC), Fortaleza 60440-900, CE, Brazil
Daniel Nascimento do Amaral
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-590, RJ, Brazil
Jéssica de Siqueira Guedes
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-590, RJ, Brazil
Eliezer J. Barreiro
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-590, RJ, Brazil
Lídia Moreira Lima
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-590, RJ, Brazil
Francisco W. A. Barros-Nepomuceno
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceara (UFC), Fortaleza 60430-275, CE, Brazil
Claudia Pessoa
Department of Physiology and Pharmacology, Drug Research and Development Center, Federal University of Ceara (UFC), Fortaleza 60430-275, CE, Brazil
LASSBio-1920 was synthesized due to the poor solubility of its natural precursor, combretastatin A4 (CA4). The cytotoxic potential of the compound against human colorectal cancer cells (HCT-116) and non-small cell lung cancer cells (PC-9) was evaluated, yielding IC50 values of 0.06 and 0.07 μM, respectively. Its mechanism of action was analyzed by microscopy and flow cytometry, where LASSBio-1920 was found to induce apoptosis. Molecular docking simulations and the enzymatic inhibition study with wild-type (wt) EGFR indicated enzyme-substrate interactions similar to other tyrosine kinase inhibitors. We suggest that LASSBio-1920 is metabolized by O-demethylation and NADPH generation. LASSBio-1920 demonstrated excellent absorption in the gastrointestinal tract and high central nervous system (CNS) permeability. The pharmacokinetic parameters obtained by predictions indicated that the compound presents zero-order kinetics and, in a human module simulation, accumulates in the liver, heart, gut, and spleen. The pharmacokinetic parameters obtained will serve as the basis to initiate in vivo studies regarding LASSBio-1920’s antitumor potential.
