New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family

Samson Eugin Simon; Usman Ahmed; Syed Muhammad Saad; Ayaz Anwar; Khalid Mohammed Khan; Ee Wern Tan; Kuan Onn Tan

doi:10.1016/j.bmcl.2022.128731

New synthetic phenylquinazoline derivatives induce apoptosis by targeting the pro-survival members of the BCL-2 family

Bioorg Med Chem Lett. 2022 Jul 1:67:128731. doi: 10.1016/j.bmcl.2022.128731. Epub 2022 Apr 11.

Authors

Samson Eugin Simon¹, Usman Ahmed¹, Syed Muhammad Saad², Ayaz Anwar¹, Khalid Mohammed Khan³, Ee Wern Tan¹, Kuan Onn Tan⁴

Affiliations

¹ Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, No. 5 Jalan Universiti, Bandar Sunway, 47500, Selangor Darul Ehsan, Malaysia.
² Department of Chemistry, University of Karachi, Karachi 75270, Pakistan.
³ H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan; Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
⁴ Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, No. 5 Jalan Universiti, Bandar Sunway, 47500, Selangor Darul Ehsan, Malaysia. Electronic address: jefft@sunway.edu.my.

PMID: 35421577
DOI: 10.1016/j.bmcl.2022.128731

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.

Keywords: Apoptosis; BCL-2; BCL-XL; Mitochondria; Synthesis of Phenylquinazoline derivatives.

MeSH terms

Apoptosis
Apoptosis Regulatory Proteins / metabolism
Breast Neoplasms* / drug therapy
Cell Line, Tumor
Female
Humans
Proto-Oncogene Proteins c-bcl-2* / metabolism
bcl-X Protein / metabolism

Substances

Apoptosis Regulatory Proteins
Proto-Oncogene Proteins c-bcl-2
bcl-X Protein