resumo
Chromones and triazoles are groups of heterocyclic compounds widely known to exhibit a broad spectrum of biological activities. The combination of these two pharmacophores could result in multiple mechanisms of action to increase the potency of anticancer drugs and reduce their side effects. The in vitro antitumor effect of eight chromone-based compounds was evaluated in breast (T-47D and MDA-MB-231) and prostate (PC3) cancer cell lines, and in non-cancerous human mammary epithelial cells (HuMEC) using a resazurin-based method. Flow cytometry was used to evaluate the cell cycle and cell death, and gamma-H2AX detection to identify DNA damage. The compounds showed selective cytotoxicity against cancer cell lines, with (E)-2-(2-(5-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl)vinyl)-4H-chro-men-4-one (compound 2a) being more potent in non-metastatic T-47D cells (IC50 0.65 mu M). Replacing the hydrogen by a methyl group on the triazole ring in compound 2b enhanced the cytotoxic activity up to IC50 0.24 mu M in PC3, 0.32 mu M in MDA-MB-231 and 0.52 mu M in T-47D. Compound 2b was 3-fold more potent than doxorubicin in PC3 (IC50 0.73 mu M) and 4-fold in MDA-MB-231 (IC50 1.51 mu M). The addition of tetrahydroisoindole-1,3-dione moiety in compound 5 did not improve its effectiveness in any of the cell lines but it exerted the lowest cytotoxic effect in HuMEC (IC50 221.35 mu M). The compounds revealed different cytotoxic mechanisms: 2a and 2b induced G2/M arrest, and compound 5 did not affect the cell cycle.
palavras-chave
DRUG DISCOVERY; PRIVILEGED SCAFFOLD; DESIGN; INHIBITORS; HYBRIDS; AGENTS; DEATH
categoria
Biochemistry & Molecular Biology; Chemistry
autores
Saher, L; Monteiro, FL; Rocha, DHA; Albuquerque, HMT; Silva, AMS; Helguero, LA
Grupos
Projectos
Collaboratory for Emerging Technologies, CoLab (EMERGING TECHNOLOGIES)
CICECO - Aveiro Institute of Materials (UIDB/50011/2020)
CICECO - Aveiro Institute of Materials (UIDP/50011/2020)
Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)
agradecimentos
This work was financed by Portugal 2020 through FEDER in the frame of POCI and in the scope of the projects: CICECO - Aveiro Institute of Materials (UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020), and LAQV-REQUIMTE (UIDB/50006/2020), and EpigenGlicON (POCI-01-0145-FEDER-029767) and Portuguese-Algerian collaborative projects (PT-DZ-005-2015), iBiMED - Aveiro Institute of Biomedicine (UIDB/04501/2020 & UIDP/04501/2020). Liza Saher would like to acknowledge LAQV-REQUIMTE (UIDB/50006/2020) and FCT/MEC (FCT UID/QUI/00062/2013) projects for her research fellowship. Helio M. T. Albuquerque also acknowledges EpigenGlicON project (POCI-01-0145-FEDER-029767) for his research contract. Liliana Monteiro is supported by the FCT Ph.D. fellowship (SFRH/BD/117818/2016).