2,4-dihydroxy benzaldehyde derived Schiff bases as small molecule Hsp90 inhibitors: Rational identification of a new anticancer lead |
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| Affiliation: | 1. Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India;2. R&D centre, Department of Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Hyderabad, India;3. Swami Vivekananda Institute of Pharmaceutical Sciences, Nalgonda, Andhra Pradesh, India;4. Department of Biological Chemistry, Faculty of Natural Sciences, University of Buenos Aires, Argentina;5. Institute of Experimental Biology and Medicine-CONICET, Argentina;1. University School of Basic and Applied Sciences, Guru Gobind Singh Indraprastha University, Sector 16-C, Dwarka, New Delhi, 110078, India;2. Department of Chemistry, Acharya Narendra Dev College, University of Delhi, Kalkaji, New Delhi, 110019, India;1. The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550002, Guizhou, China;2. Guizhou University, Guiyang 550025, Guizhou, China;3. The Second Affiliated Hospital of Guiyang College of Traditional Chinese Medicine, Guiyang 550003, Guizhou, China;1. Department of Chemistry, Qeshm Branch, Islamic Azad University, Qeshm, Iran;2. Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran;1. School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, South Africa;2. Department of Chemistry, Ekiti State University, Ado-Ekiti, Nigeria;3. Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007, Porto, Portugal |
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| Abstract: | Hsp90 is a molecular chaperone that heals diverse array of biomolecules ranging from multiple oncogenic proteins to the ones responsible for development of resistance to chemotherapeutic agents. Moreover they are over-expressed in cancer cells as a complex with co-chaperones and under-expressed in normal cells as a single free entity. Hence inhibitors of Hsp90 will be more effective and selective in destroying cancer cells with minimum chances of acquiring resistance to them. In continuation of our goal to rationally develop effective small molecule azomethines against Hsp90, we designed few more compounds belonging to the class of 2,4-dihydroxy benzaldehyde derived imines (1–13) with our validated docking protocol. The molecules exhibiting good docking score were synthesized and their structures were confirmed by IR, 1H NMR and mass spectral analysis. Subsequently, they were evaluated for their potential to suppress Hsp90 ATPase activity by Malachite green assay. The antiproliferative effect of the molecules were examined on PC3 prostate cancer cell lines by adopting 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay methodology. Finally, schiff base 13 emerged as the lead molecule for future design and development of Hsp90 inhibitors as anticancer agents. |
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| Keywords: | Hsp90 Anticancer Docking Malachite green MTT |
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