Synthesis of steroidal imidazolidinthiones as potential apoptotic agents: Investigation by theoretical and experimental studies |
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| Affiliation: | 1. Department of Chemistry, Aligarh Muslim University, Aligarh 202 002, India;2. Department of Chemistry, Govt Degree College Kulgam, Kashmir 192231, India;3. Department of Chemistry, Indian Institute of Technology Powai, Mumbai 400076, India;4. Department of Chemistry, OPJS University, Churu 331001, Rajasthan, India;5. Department of Biochemistry JNMC, Aligarh Muslim University, Aligarh 202 002, India;6. Department of Chemistry, Govt Degree College Anantnag, Kashmir 192101, India;1. College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea;2. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea;1. Laboratory of Neuropharmacology, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure 737-0112, Japan;2. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan;3. Department of Pharmacotherapy, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan;1. Applied Organic Chemistry Department, National Research Centre, Cairo, Egypt;2. Faculty of Science and Arts, Mohail Asser, King Khalid University, Saudi Arabia;3. Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt;4. Chemistry Department, Faculty of Science, Al-Azhar University (Boys), Cairo, Egypt;5. Department of Chemistry, College of Science, United Arab Emirates University, P.O. Box 15551, Al-Ain, United Arab Emirates;6. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;7. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;8. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt;1. Department of Chemistry, Faculty of Science, Taibah University, Almadinah Almunawarrah, Saudi Arabia;2. Applied Organic Chemistry Department, National Research Centre, Cairo, Egypt;3. Faculty of Science and Arts, Mohail Asser, King Khalid University, Saudi Arabia;4. Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt;1. School of Studies in Chemistry, Jiwaji University, Gwalior, 474011, India;2. Department of Chemistry, Islamic University of Science and Technology, Awantipora, Kashmir, 192122, India;3. Department of Chemistry, Govt Degree College, Khanabal, Anantnag, Kashmir, 192101, India;4. Department of Chemistry, Howard University, Washington DC 20059, USA |
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| Abstract: | New steroidal imidazolidinthione derivatives (4–6) were synthesized from steroidal thiosemicarbazones and dichloroethane. The synthesized compounds were characterized using spectral data analysis. Theoretical DFT involving B3LYP/6-31G7 level of theory was employed to gain insights into the molecular structure of the target compounds. MEPS and FMO analysis were carried out. HOMO-LUMO energy gap was determined which helped to evaluate various global descriptors like hardness, chemical potential, electronegativity, nucleophilicity and electrophilicity index, etc. The calculated properties established that the synthesized products are more or less similar in their reactivity behaviour. To explore their biological potential, interaction studies of compounds (4–6) with DNA were carried out using various biophysical techniques. The compounds bind DNA preferentially through electrostatic and hydrophobic interactions with Kb of 3.21 × 103 M−1, 2.79 × 103 M−1 and 2.26 × 103 M−1, respectively indicating the higher binding affinity of compound 4 towards DNA. Gel electrophoresis of compound 4 demonstrated strong interaction during the concentration dependent cleavage activity with pBR322 DNA. It was observed that these steroidal imidazolidinthiones are minor groove binders of DNA which was validated using molecular docking studies. An in vitro cytotoxicity screening using MTT assay revealed that the compounds (4–6) exhibit potential toxicity against different human cancer cells. Highest antiproliferative effect was observed on HeLa cells by compound 4. The results suggested that compounds 4–6 cause apoptotic cell death by cleaving apoptotic protein caspase-3 and suppress anti-apoptotic protein Bcl-2 in HeLa cancer cells. |
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| Keywords: | Synthesis Computational Docking Fluorescence DNA binding Apoptosis |
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