Unleashing the cytotoxic potential: Synthesis and evaluation of innovative 4-Phenylbutyrate derivatives for the conquest of ovarian, breast, and lung carcinomas

The compound 4-phenylbutyrate (4-PBA) has been identified as a potential anticancer agent due to its favorable safety profile, exhibiting minimal side effects. This makes 4-PBA a promising candidate for further development as an anticancer drug. To develop new and potentially more effective anticancer agents, a series of novel derivatives of 4-PBA were synthesized. The chemical structures of the newly synthesized compounds were confirmed through spectroscopic analyses, including 1 H NMR, 13 C NMR, and FTIR spectra. Furthermore, the cytotoxic activity of all the synthesized compounds was evaluated against three different human cancer cell lines - MCF-7 (breast carcinoma), A549 (lung carcinoma), and SKOV-3 (ovarian carcinoma) – as well as MRC5 (normal lung) using the MTT assay. The results revealed that most of the synthesized compounds exhibited significant cytotoxic effects on the A549 and MCF-7 cell lines, while demonstrating a lesser degree of cytotoxicity against SKOV-3. Compound A4 demonstrated particularly potent anticancer activity across all the studied cancer cell lines. Molecular docking studies revealed that the synthesized compounds could inhibit enzymes, including pyruvate dehydrogenase kinase 2 (PDB ID: 2BU8 ) and histone deacetylase complex (PDB ID: 1C3R ), by forming hydrogen bonds and hydrophobic interactions. In addition, the pharmacokinetic properties, ADME characteristics, of the synthesized compounds were computationally predicted. These predicted ADME profiles further enhanced the potential of these compounds as effective anticancer agents. • Novel derivatives of 4-PBA were synthesized and confirmed using spectroscopic analyses. • Most derivative exhibited significant cytotoxic effects on MCF-7 and A549 cancer cell lines. • Compounds inhibited pyruvate dehydrogenase kinase 2 (PDB ID: 2BU8 ), and histone deacetylase complex (PDB ID: 1C3R ). • Computational predictions of pharmacokinetic support these compounds as effective anticancer agents.