Abstract
Cancer is a multifaceted disease. With the development of multi drug resistance, the need for the arousal of novel targets in order to avoid these drawbacks increased. A new series of acrylamide derivatives was synthesized from starting material 4-(furan-2-ylmethylene)-2-(3,4,5-trimethoxyphenyl)oxazol-5(4H)–one (1), and they are evaluated for their inhibitory activity against β-tubulin polymerization. The target molecules 2–5 d were screened for their cytotoxic activity against breast cancer MCF-7 cell line. The results of cytotoxicity screening revealed that compounds 4e and 5d showed good cytotoxic profile against MCF-7 cells. Compounds 4e produced significant reduction in cellular tubulin with excellent β-tubulin polymerization inhibition activity. In addition, compound 4e exhibited cytotoxic activity against MCF-7 cells by cell cycle arrest at pre-G1 and G2/M phases, as shown by DNA flow cytometry assay. Aiming to enhance the limited aqueous solubility and, hence, poor oral bioavailability of the prepared lead acrylamide molecule, 4e-charged PEGylated bilosomes were successfully fabricated via thin film hydration techniques as an attempt to improve these pitfalls. 23 full factorial designs were manipulated to examine the influence of formulation variables: types of bile salt including either sodium deoxy cholate (SDC) or sodium tauro cholate (STC), amount of bile salt (15 mg or 30 mg) and amount of DSPE–mPEG-2000 amount (25 mg or 50 mg) on the characteristics of the nanosystem. The F7 formula of entrapment efficiency (E.E% = 100 ± 5.6%), particle size (PS = 280.3 ± 15.4 nm) and zeta potential (ZP = −22.5 ± 3.4 mv) was picked as an optimum formula with a desirability value of 0.868. Moreover, prominent enhancement was observed at the compound’s cytotoxic activity (IC50 = 0.75 ± 0.03 µM) instead of (IC50 = 2.11 ± 0.19 µM) for the unformulated 4e after being included in the nano-PEGylated bilosomal system.
Highlights
Microtubules are one of the most important cellular protein scaffolds [1,2]
The capability of compound 4e in the induction of apoptosis in MCF-7 cells was superior over that of PTX. These results suggested that compound 4e induced cancer cell death via G2/M phase arrest with apoptosis inducing activity marked by the presence pre-G1 peak in the cell cycle profile of MCF-7 cells, and it is in line with the previously discussed data
4e upregulated the expression of active caspase 3/7 percentages, as revealed by green flow cytometry analysis
Summary
Microtubules are one of the most important cellular protein scaffolds [1,2]. Microtubules along with actin and intermediate filaments are major cell building blocks and, play an integral role in cell reproductive processes during mitosis [3,4]. Microtubules are crucial for a variety of fundamental cell processes, including cell proliferation, sustained cell shape and structure, intracellular transport of vesicles and protein complexes and motility regulation [5,6,7]. The importance of microtubules in mitosis and cell division makes them an attractive target for the development of anticancer drugs. Breast cancer characteristically displays uncontrolled or abnormal cell proliferation due to excessive microtubule synthesis [11,12]. Knowledge and understanding of this intrinsic property have resulted in the development of chemotherapeutic regimens that act by interfering with the microtubule assembly or disassembly [13]
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