Please login first

5-aminosalicylate–4-thiazolinone hybrid derivatives: A potent modulator of DNA damage response and G2/M cell cycle arrest via ATM/ATR pathway and Cyclin-CDK complex
Wafaa S Ramadan * 1 , Maha Saber Ayad * 2 , Rifat Hamoudi * 2 , Amina Laham * 1 , Varsha Menon * 3 , Lama Lozon * 1 , Hajjaj Abdu-Allah * 4 , Abdel-Nasser El-Shorbagi * 5 , Hamadeh Tarazi * 6 , Raafat El-Awady * 6
1  Sharjah Institute for Medical Research and college of Medicine, University of Sharjah, Sharjah, United Arab Emirates
2  College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
3  Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
4  Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt
5  College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates
6  Sharjah Institute for Medical Research and college of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates

10.3390/IECC2021-09188
Abstract:

The last several years have witnessed a tremendous advance in the knowledge of DNA repair and cell cycle mechanisms for the purpose of increasing the treatment efficacy of radiotherapy and DNA damaging agents. Thereby, targeting DNA damage and repair pathways and cell cycle checkpoints become an attractive rationale to optimize treatment strategies through identifying new targets. However, the improved knowledge has increased the complexity of DNA damage response (DDR) and checkpoint pathways which extremely proved challenges in the development of cell cycle and DNA repair targeting drugs. To this end, a novel approach of synthesizing new compounds has been recently introduced which involved accommodating two chemical entities that target several molecules into a single structure. Here we combined 5-aminosalicylic acid and 4-thiazolinone, which both reported to affect DDR and cell cycle progression, in a single structural framework to generate two derivatives named HH32 and HH33. The transcriptomic, in silico, and in vitro analysis has been used to uncover the anti-cancer potential of these two compounds. Both compounds exhibited a high cytotoxic effect against a panel of eight cancer cell lines from different tissue origins and showed a low toxicity profile on normal cells compared to Doxorubicin. The in-silico molecular docking predicts a strong binding of the HH32 and HH33 to cell cycle regulators like CDC2-cyclin B, CDK2-cyclin A complexes, and retinoblastoma. Interestingly, the transcriptomic analysis revealed that DNA double-strand repair and cell cycle are the most affected pathways by HH33 compound. These findings were validated using in vitro models and demonstrated the induction of DNA double-strand breaks and the stimulation of ATM/ATR signaling pathway by HH32 and HH33. In addition to the potent effect of HH compounds on cell cycle progression mediated through upregulation of cyclin-dependent kinase inhibitors and downregulation of G2/M phase cell cycle markers which ultimately arrest the cells at G2/M phase and promote apoptosis. In conclusion, the pleiotropic biological effect of HH32 and HH33 compounds on cancer cells suggests the requirement for assessing their anti-cancer activities in preclinical models which may lead to a new area in the development of potentially therapeutic drugs.

Keywords: 5-aminosalicylate–4-thiazolinone; DNA damage; ATM/ATR; Cell cycle; Cyclin-CDKs, Apoptosis
Top