2. Academic Validation
  3. From triazolophthalazines to triazoloquinazolines: A bioisosterism-guided approach toward the identification of novel PCAF inhibitors with potential anticancer activity

From triazolophthalazines to triazoloquinazolines: A bioisosterism-guided approach toward the identification of novel PCAF inhibitors with potential anticancer activity

  • Bioorg Med Chem. 2021 Jul 15;42:116266. doi: 10.1016/j.bmc.2021.116266.
Mohamed H El-Shershaby 1,  Adel Ghiaty 1,  Ashraf H Bayoumi 1,  Ahmed A Al-Karmalawy 2,  Ebtehal M Husseiny 3,  Mona S El-Zoghbi 4,  Hamada S Abulkhair 5
Affiliations

Affiliations

  • 1 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University - Egypt, International Coastal Road, 34518 New Damietta, Egypt.
  • 3 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo, Egypt.
  • 4 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Gamal Abd El-Nasir Street, Shebin El-Koum, Egypt.
  • 5 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Horus University - Egypt, International Coastal Road, 34518 New Damietta, Egypt. Electronic address: [email protected].
PMID: 34126285 DOI: 10.1016/j.bmc.2021.116266
Abstract

Inhibition of PCAF bromodomain has been validated as a promising strategy for the treatment of Cancer. In this study, we report the bioisosteric modification of the first reported potent PCAF bromodomain inhibitor, L-45 to its triazoloquinazoline bioisosteres. Accordingly, three new series of triazoloquinazoline derivatives were designed, synthesized, and assessed for their Anticancer activity against a panel of four human Cancer cells. Three derivatives demonstrated comparable cytotoxic activity with the reference drug doxorubicin. Among them, compound 22 showed the most potent activity with IC50 values of 15.07, 9.86, 5.75, and 10.79 µM against Hep-G2, MCF-7, PC3, and HCT-116 respectively. Also, compound 24 exhibited remarkable cytotoxicity effects against the selected Cancer cell lines with IC50 values of 20.49, 12.56, 17.18, and 11.50 µM. Compounds 22 and 25 were the most potent PCAF inhibitors (IC50, 2.88 and 3.19 μM, respectively) compared with bromosporine (IC50, 2.10 μM). Follow up Apoptosis induction and cell cycle analysis studies revealed that the bioisostere 22 could induce apoptotic cell death and arrest the cell cycle of PC3 at the G2/M phase. The in silico molecular docking studies were additionally performed to rationalize the PCAF inhibitory effects of new triazoloquinazoline bioisosteres.

Keywords

Anticancer; Apoptosis; Bioisosterism; PCAF; Synthesis; Triazoloquinazoline.

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