New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family. (1st July 2022)

• Record Type: Journal Article
• Authors: Eugin Simon, Samson; Ahmed, Usman; Saad, Syed Muhammad; Anwar, Ayaz; Khan, Khalid Mohammed; Tan, Ee Wern; Tan, Kuan Onn
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 67(2022)
• Publication Date: 2022-07-01
• Subjects: Synthesis of Phenylquinazoline derivatives -- BCL-2 -- BCL-XL -- Mitochondria -- Apoptosis; BAX BCL-2 Associated X Protein -- BAK BCL-2 Homologous Antagonist Killer -- BCL-2 B-Cell Lymphoma 2 -- BCL-XL B-Cell Lymphoma-Extra Large -- BSA Bovine Serum Albumin -- CuCl2.2H2O Copper (II) Chloride Dihydrate -- DAPI 4′, 6-diamidino-2-phenylindole -- DMEM Dulbecco's Modified Eagle Medium -- DMSO Dimethyl Sulfoxide -- EC50 Half Maximal Effective Concentration -- ECL Enhanced Chemiluminescence -- EDTA Ethylenediaminetetraacetic Acid -- FBS Fetal Bovine Serum -- MCF-7 Human Breast Cancer Cell Line -- MCF-7-CR Cisplatin Resistant Human Breast Cancer Cell Line -- MOAP-1 Modulator of Apoptosis 1 -- RASSF1a Ras Association Domain Family Member 1 A -- MTT (3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyl tetrazolium bromide) -- PVDF Polyvinylidene Fluoride or Polyvinylidene Difluoride Membrane -- RIPA Radioimmunoprecipitation Assay Buffer -- SDS-PAGE Sodium Dodecyl-Sulfate Polyacrylamide Gel Electrophoresis -- SMS Small Molecules Synthesized -- TBST Tris-buffered Saline and Tween 20 Buffer -- EGFR Epidermal Growth Factor Receptor -- AKT/mTOR Protein Kinase B/Mammalian Target of Rapamycin; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128731
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: SMS-IV-20 and SMS-IV-40 potently induce apoptosis in MCF-7 and MCF-7-CR cells. The compounds chemo-sensitize MCF-7 and MCF-7-CR cells expressing MOAP-1, Bax, and RASSF1a. When combine with ABT-737, both compounds enhance apoptotic cell death in MCF-7-CR cells. The compounds down-regulate the expression of BCl-2, BCL-XL, or both in MCF-7-CR cells. Abstract: Chemo-resistant cancer cells acquire robust growth potential through cell signaling mechanisms such as the down-regulation of tumor suppressors and the up-regulation of pro-survival proteins, respectively. To overcome chemo-resistance of cancer, small molecule drugs that interact with the cell signaling proteins to enhance sensitization of cancer cells toward cancer therapies are likely to be effective for the treatment of chemo-drug resistant cancer. To identify high potency small molecules, a series of ten novel phenylquinazoline derivatives were synthesized to determine their cellular effects in MCF-7 and MCF-7- cisplatin-resistant (CR) human breast cancer cells which led to the identification of two bioactive compounds, SMS-IV-20 and SMS-IV-40, that exhibited an elevated level of cytotoxicity against the human breast cancer cells and spheroid cells. In addition, both compounds enhanced chemo-sensitization of the human breast cancer cells that were genetically engineered to express the tumor suppressor and pro-apoptotic proteins, MOAP-1, Bax, and RASSF1a (MBR), suggesting that the compounds interact with the MBR signaling pathway. Furthermore, when MCF-7-CR cells were treated with SMS-IV-20 and SMS-IV-40 in the presence of ABT-737, a BCL-XL and BCL-2 inhibitor, enhanced chemo-sensitization was observed, suggesting SMS-IV-20 and SMS-IV-40 exert antagonistic activity to regulate the functional activity of BCL-2 and BCL-XL. Western blot analysis showed that both SMS-IV-20 and SMS-IV-40 induced down-regulation of BCL-2 or both BCl-2 and BCL-XL expression, respectively while promoting the release of mitochondrial Cytochrome C . Taken together, the data showed that SMS-IV-20 and SMS-IV-40 are potent activators of apoptosis that enhance chemo-sensitization through their antagonistic actions on the pro-survival activity of the BCl-2 family in human cancer cells.