2,4-dihydroxy benzaldehyde derived Schiff bases as small molecule Hsp90 inhibitors: rational identification of a new anticancer lead.
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, (1)H 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.
Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India; R&D centre, Department of Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Hyderabad, India. Electronic address: sayanduttagupta1@rediffmail.com.
Sayan
S
Dutta Gupta
Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India.
B
B
Revathi
Department of Biological Chemistry, Faculty of Natural Sciences, University of Buenos Aires, Argentina.
Gisela I
GI
Mazaira
Department of Biological Chemistry, Faculty of Natural Sciences, University of Buenos Aires, Argentina; Institute of Experimental Biology and Medicine-CONICET, Argentina.
Mario D
MD
Galigniana
Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India.
C V S
CV
Subrahmanyam
Swami Vivekananda Institute of Pharmaceutical Sciences, Nalgonda, Andhra Pradesh, India.
N L
NL
Gowrishankar
Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India.
N M
NM
Raghavendra
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001547:Benzaldehydes / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012545:Schiff Bases / Q000737:chemistry* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001547:Benzaldehydes; D018841:HSP90 Heat-Shock Proteins; D012545:Schiff Bases; C032175:benzaldehyde
Anticancer; Docking; Hsp90; MTT; Malachite green