2. Academic Validation
  3. Development of new LSM-83177 analogues as anti-tumor agents against colorectal cancer targeting p53-MDM2 interaction

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

  • Bioorg Chem. 2024 Aug 28:153:107766. doi: 10.1016/j.bioorg.2024.107766.
Mohamed K Elgohary 1,  Mahmoud S Elkotamy 2,  Tarfah Al-Warhi 3,  Wagdy M Eldehna 4,  Hatem A Abdel-Aziz 5
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo, 11829, Egypt. Electronic address: mohamed-elgohary@eru.edu.eg.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian-Russian University, Badr City, Cairo, 11829, Egypt.
  • 3 Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. Electronic address: tarfah-w@hotmail.com.
  • 4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com.
  • 5 Applied Organic Chemistry Department, National Research Center, Dokki, Cairo, 12622, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt. Electronic address: hatem_741@yahoo.com.
PMID: 39244969 DOI: 10.1016/j.bioorg.2024.107766
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.

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