Synthesis, Molecular Docking, and Cytotoxic Evaluation of Fluorinated Podophyllotoxin Derivatives

Abstract

Objective: The study was conducted to evaluate the in vitro and in silico anticancer activity of fluorinated podophyllotoxin derivatives. Methods: Microwave-assisted multicomponent reactions were carried out in an Anton Paar Microwave Synthetic Reactor Monowave 400 in order to synthesize fluorinated podophyllotoxin derivatives. These products were identified by spectral analysis and evaluated for their cytotoxicity against 4 types of human cancer cell lines (KB, HepG2, A549, and MCF7), as well as human embryonic kidney (Hek) 293 cells using MTT protocol. Molecular docking was conducted using 2 crystal structures of tubulin—colchicine (PDB ID: 4O2B) and topoisomerase II—etoposide (PDB ID: 3QX3) complexes. Results: Two potent cytotoxic fluorinated podophyllotoxin–naphthoquinone compounds were synthesized in good yields. They displayed high cytotoxic activity against all the tested cell lines, with IC50 values ranging from 0.58 to 3.17 µM. Notably, product 8a showed low toxicity against the Hek-293 cell line. Molecular docking results showed that products 8a and 8b participated in the same key interactions provided by etoposide with both topoisomerase and DNA chain domains. The binding energy values calculated for 8a and 8b are acceptable. Conclusion: This study revealed that products 8a and 8b exhibited promising in vitro and in silico anticancer activity and could be recognized as promising anticancer agents.

Synthesis and Evaluation of Acetylcholinesterase Inhibitory and Cytotoxic Activities of Pyrano[2,3-d]pyrimidines

“…Besides that, all synthesized compounds were also evaluated for their cytotoxic activities against human cancer cell lines, namely human epidermoid carcinoma cancer cell line (KB), human lung cancer cell line (A549) and human hepatoma carcinoma cancer cell line (HepG2) by MTT (3-[4,5-di-methylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, 71,72 with ellipticine as a reference. The results indicated that all synthesized products have shown no cytotoxic activity against selected cancer cell lines with IC 50 > 32 µg/mL (Table 1).…”

Synthesis, molecular docking analysis and in vitro evaluation of new heterocyclic hybrids of 4-aza-podophyllotoxin as potent cytotoxic agents

“…37 Several hybrid compounds of 4-aza-podophyllotoxin with heterocycles have been developed and evaluated the anticancer activity. [38][39][40][41] For instance, Kamal et al, has prepared a series of 4-azapodophyllotoxin with heterocycles including benzothiazole-podophyllotoxin hybrids 6, pyrimidine-podophyllotoxin hybrids 7, and, indole-podophyllotoxin hybrids 8 which have inhibited tubulin polymerization, induced cell cycle arrest at G2/M phase and caspase-3 dependent apoptotic cell death in non-small lung A549 cell line. 33 Pyrazole-podophyllotoxin hybrids which have been synthesized by Magedov et al, have showed apoptosis induction in cancerous Jurkat cells even aer a short 24 h exposure.…”