Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives
Wafaa S. Ramadan,
Maha M. Saber-Ayad,
Ekram Saleh,
Hajjaj H.M. Abdu-Allah,
Abdel-nasser A. El-Shorbagi,
Varsha Menon,
Hamadeh Tarazi,
Mohammad H. Semreen,
Nelson C. Soares,
Shirin Hafezi,
Thenmozhi Venkatakhalam,
Samrein Ahmed,
Osamu Kanie,
Rifat Hamoudi,
Raafat El-Awady
Affiliations
Wafaa S. Ramadan
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
Maha M. Saber-Ayad
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
Ekram Saleh
Medical Biochemistry and Molecular Biology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 12613, Egypt
Hajjaj H.M. Abdu-Allah
Faculty of Pharmacy, Assiut University, Assiut 16122, Egypt
Abdel-nasser A. El-Shorbagi
College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Faculty of Pharmacy, Assiut University, Assiut 16122, Egypt
Varsha Menon
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
Hamadeh Tarazi
College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
Mohammad H. Semreen
College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
Nelson C. Soares
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
Shirin Hafezi
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
Thenmozhi Venkatakhalam
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
Samrein Ahmed
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Biosciences and Chemistry, College of Health, Wellbeing and Life sciences, University of Sheffield Hallam, Sheffield S1 1WB, United Kingdom
Osamu Kanie
Department of Applied Biochemistry, Tokai University, 4-1-1 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan
Rifat Hamoudi
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; Division of Surgery and Interventional Science, Faculty of Medical Science, University College London, London, United Kingdom
Raafat El-Awady
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Corresponding author
Summary: The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies.
