title: Molecular docking study, synthesis and biological evaluation of Mannich bases as Hsp90 inhibitors.
abstract: The ubiquitously expressed heat shock protein 90 is an encouraging target for the development of novel anticancer agents. In a program directed towards uncovering novel chemical scaffolds against Hsp90, we performed molecular docking studies using Tripos-Sybyl drug designing software by including the required conserved water molecules. The results of the docking studies predicted Mannich bases derived from 2,4-dihydroxy acetophenone/5-chloro 2,4-dihydroxy acetophenone as potential Hsp90 inhibitors. Subsequently, a few of them were synthesized (1-6) and characterized by IR, (1)H NMR, (13)C NMR and mass spectral analysis. The synthesized Mannich compounds were evaluated for their potential to suppress Hsp90 ATPase activity by the colorimetric Malachite green assay. Subsequently, the molecules were screened for their antiproilferative effect against PC3 pancreatic carcinoma cells by adopting the 3-(4,5-dimethythiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. The activity profile of the identified derivatives correlated well with their docking results.
authors.affiliation: 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.
authors.forename: Sayan
authors.initials: S
authors.lastname: Dutta Gupta
authors.affiliation: Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India.
authors.forename: Manish Kumar
authors.initials: MK
authors.lastname: Bommaka
authors.affiliation: Department of Biological Chemistry, Faculty of Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Gisela I
authors.initials: GI
authors.lastname: Mazaira
authors.affiliation: Department of Biological Chemistry, Faculty of Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina; Institute of Experimental Biology and Medicine-CONICET, Buenos Aires, Argentina.
authors.forename: Mario D
authors.initials: MD
authors.lastname: Galigniana
authors.affiliation: Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India.
authors.forename: Chavali Venkata Satya
authors.initials: CV
authors.lastname: Subrahmanyam
authors.affiliation: Swami Vivekananda Institute of Pharmaceutical Sciences, Nalgonda, Andhra Pradesh, India.
authors.forename: Naryanasamy Lachmana
authors.initials: NL
authors.lastname: Gowrishankar
authors.affiliation: Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Osmania University, Hyderabad, India.
authors.forename: Nulgumnalli Manjunathaiah
authors.initials: NM
authors.lastname: Raghavendra
mesh_terms: D000098:Acetophenones / Q000737:chemistry; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008352:Mannich Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D014867:Water / Q000737:chemistry
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D008352:Mannich Bases; D014867:Water; C107067:2,4,6-trihydroxyacetophenone; D000251:Adenosine Triphosphatases
keywords: Docking; Hsp90; Mannich base