Development of new LSM-83177 analogues as anti-tumor agents against colorectal cancer targeting p53-MDM2 interaction

Abstract

LSM-83177, a phenoxy acetic acid derivative, is a small molecule reported for its promising anti-tumor properties. Via inhibiting the interaction between MDM2 and p53, LSM-83177 can elevate the active p53 levels within cells, thereby promoting apoptosis and inhibiting tumor growth. Also, LSM-83177 has been shown to inhibit GST activity in colorectal cancer HT29 cells. In the current work, novel LSM-83177 hydrazone analogs 5a-f, 7a-b, 10a-e, and 13a-b have been designed according to the structure features of LSM-83177 and their binding mode in the active site of MDM2. The anti-cancer activity of the newly synthesized analogs is evaluated against the HT29 cell line. The most potent compounds, 7a and 10a, showed IC₅₀ = 12.48 and 10.44 µg/ml, respectively, when compared with Cisplatin (IC₅₀ = 11.32 µg/ml) as a reference drug. Compounds 7a and 10a were introduced for further inspection for p53-MDM2 protein-protein interaction, where they displayed IC₅₀ values of 3.65 and 11.08 µg/ml, respectively. Furthermore, hydrazones 7a and 10a increased the p-53 expression levels by 3.22- and 4.25-fold, respectively; in addition, they effectively reduced the GST expression levels in HT29 cancer cells with 0.56- and 0.30-fold increments in comparison to the untreated control.

Keywords: Biological evaluation; DFT calculations; Glutathione S-transferases; Molecular modeling; Synthesis.