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1.
Int J Biol Macromol ; 161: 1086-1098, 2020 Oct 15.
Article in English | MEDLINE | ID: mdl-32561284

ABSTRACT

Hsp90 chaperone is an encouraging target for the development of novel anticancer agents. The failure of Hsp90 inhibitors to get regulatory approval for the treatment of cancer is hindered due to toxicity, cost involved in their development and formulation issues. The inhibitors against this chaperone are also being evaluated in pre-clinical models for the treatment of diseases other than cancer (Alzheimer, malaria, AIDS, etc.). Recently, Hsp90 inhibitors have shown promising senolytic effect that is helpful in increasing the health and life span of mice. The senolytic property of Hsp90 inhibitors will make them less toxic for use in humans. The review focuses on Hsp90 inhibitors discovered till date as senolytic agents along with their future prospects. Further, the various models used for the evaluation of senolytic effect are also discussed.


Subject(s)
Drug Development , Drug Discovery , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Apoptosis/genetics , Cellular Senescence/drug effects , Cellular Senescence/genetics , Clinical Studies as Topic , Drug Design , Drug Development/methods , Drug Discovery/methods , Drug Evaluation, Preclinical , HSP90 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/metabolism , Humans , Molecular Targeted Therapy , Protein Isoforms , Signal Transduction/drug effects , Structure-Activity Relationship
2.
Eur J Med Chem ; 178: 48-63, 2019 Sep 15.
Article in English | MEDLINE | ID: mdl-31176095

ABSTRACT

The ninety kilo Dalton molecular weight heat shock protein (Hsp90) is an attractive target for the discovery of novel anticancer agents. Several strategies have been employed for the development of inhibitors against this polypeptide. The most successful strategy is targeting the N-terminal ATP binding region of the chaperone. However, till date not a single molecule reached Phase-IV of clinical trials from this class of Hsp90 inhibitors. The other approach is to target the Cterminal region of the protein. The success with this approach has been limited due to lack of well-defined ligand binding pocket in this terminal. The other promising strategy is to prevent the interaction of client proteins/co-chaperones with Hsp90 protein, i.e., protein-protein interaction inhibitors of Hsp90. The review focuses on advantage of this approach along with the recent advances in the discovery of inhibitors by following this strategy. Additionally, the biology of the client protein/co-chaperone binding site of Hsp90 is also discussed.


Subject(s)
Antineoplastic Agents/therapeutic use , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Neoplasms/drug therapy , Protein Binding/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , HSP90 Heat-Shock Proteins/chemistry , Humans
3.
Med Chem ; 14(1): 44-52, 2018.
Article in English | MEDLINE | ID: mdl-28641528

ABSTRACT

BACKGROUND: Heat shock protein 90 is a molecular chaperone required for the stability and function of several client proteins that promote cancer cell growth and/or survival. Discovery of Hsp90 inhibitors has emerged as an attractive target of research in cancer therapeutics. Natural products like geldanamycin and radicicol are established Hsp90 inhibitors, but face limitations with toxicity and inactivity, by in vivo studies respectively. However, they lay the logical starting point for the design of novel synthetic or semi-synthetic congeners as Hsp90 inhibitors. OBJECTIVE: In this article, the structure based drug design of substituted 2-aryl/heteroarylidene-6- hydroxybenzofuran-3(2H)-one analogues to optimize and mimic the pharmacophoric interactions of the valid Hsp90 inhibitor radicicolis focused. METHOD: In silico docking study was performed by Surflex dock-Geom (SYBYL- X 1.2 drug discovery suite) and the designed ligands were chemically synthesized by conventional method using resorcinol and chlororesorcinol as starting materials. Two dimensional chemical similarity search was carried out to identify the chemical space of 'SY' series in comparison with reported Hsp90 inhibitors. The in vitro cell proliferation assay (resazurin reduction method) and proteomic investigation (DARTS) was carried out on whole cell lysate to evaluate anticancer activity. RESULTS: The chemical structures of all the synthesized compounds were confirmed by IR, 1H-NMR and Mass spectral analysis. The results of chemical similarity search show that SY series fit it in the chemical space defined by existing Hsp90 inhibitors. In vitro cell proliferation assay, against human melanoma and breast cancer cell lines, identified 'SY3' as the promising anticancer agent amongst the series. CONCLUSION: Docking studies, 2D chemical similarity search, resazurin reduction assay and qualitative proteomic analysis identify 'SY3'as a promising Hsp90 inhibitor amongst the series.


Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Drug Design , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship
4.
Biomed Pharmacother ; 86: 662-668, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28033583

ABSTRACT

The antibacterial and antioxidant potential of Tiliacora racemosa leaf extracts in various solvents (methanolic, hexane, chloroform and ethyl acetate) was determined. Additionally, the presence of bisbenzylisoquinoline alkaloids in the plant prompted us to evaluate the nootropic activity of the methanolic extract in mice. Further, we seek to verify the nootropic effect by examining the anticholinesterase inhibition potential of the methanolic extract. The leaf extracts in various solvents were evaluated for their antibacterial and antioxidant activity by agar diffusion technique and α, α-diphenyl-ß-picrylhydrazyl (DPPH) free radical scavenging method, respectively. The ex vivo acetylcholine esterase inhibitory activity of the methanolic extract was carried out by Ellman's method in male Wistar rats. The nootropic capacity of the methanolic extract was examined in Swiss albino mice by utilizing the diazepam induced acute amnesic model. The chloroform/n-hexane and ethyl acetate fraction showed promising antioxidant and antibacterial (Gram positive and Gram negative bacteria) property, respectively. The methanolic extract was able to diminish the amnesic effect induced by diazepam (1mg/kg i.p.) in mice. The extract also showed significant acetyl cholinesterase inhibition in rats. The findings prove that the memory enhancing capability is due to increased acetyl choline level at the nerve endings. The strong antioxidant nature and potential nootropic activity shown by the extract suggests its future usage in the treatment of neurodegenerative disorders such as dementia and Alzheimer.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antioxidants/pharmacology , Menispermaceae/chemistry , Nootropic Agents/pharmacology , Plant Leaves/chemistry , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Free Radical Scavengers/chemistry , Free Radical Scavengers/pharmacology , Hexanes/chemistry , Male , Mice , Plant Extracts/chemistry , Plant Extracts/pharmacology , Rats , Rats, Wistar
5.
Int J Biol Macromol ; 80: 253-9, 2015 09.
Article in English | MEDLINE | ID: mdl-26116388

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Molecular Docking Simulation , Acetophenones/chemistry , Adenosine Triphosphatases/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , HSP90 Heat-Shock Proteins/chemistry , Humans , Mannich Bases/chemical synthesis , Mannich Bases/chemistry , Mannich Bases/metabolism , Mannich Bases/pharmacology , Protein Conformation , Water/chemistry
6.
Bioorg Chem ; 59: 97-105, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25727264

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, (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.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzaldehydes/chemistry , Benzaldehydes/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Schiff Bases/chemistry , Schiff Bases/pharmacology , Cell Line, Tumor , Drug Design , HSP90 Heat-Shock Proteins/metabolism , Humans , Male , Models, Molecular , Prostate/drug effects , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology
7.
Biomed Pharmacother ; 68(3): 369-76, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24486109

ABSTRACT

Heat shock protein 90 (Hsp90) is an emerging attractive target for the discovery of novel cancer therapeutic agents. Docking methods are powerful in silico tools for lead generation and optimization. In our mission to rationally develop novel effective small molecules against Hsp90, we predicted the potency of our designed compounds by Sybyl surflex Geom X docking method. The results of the above studies revealed that Schiff bases derived from 2,4-dihydroxy benzaldehyde/5-chloro-2,4-dihydroxy benzaldehyde demonstrated effective binding with the protein. Subsequently, a few of them were synthesized (1-10) and characterized by IR, (1)HNMR and mass spectral analysis. The synthesized molecules were evaluated for their potential to suppress Hsp90 ATPase activity by Malachite green assay. The anticancer studies were performed by 3-(4,5-dimethythiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. The software generated results was in satisfactory agreement with the evaluated biological activity.


Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Design , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/chemistry , Molecular Docking Simulation , Schiff Bases/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Humans , Hydrogen Bonding , Molecular Structure , Protein Binding , Schiff Bases/chemistry , Schiff Bases/pharmacology
8.
Chem Biol Drug Des ; 82(3): 351-60, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23758794

ABSTRACT

In our lead finding program, a series of 1,2,4-triazolo[1,5-a][1,3,5]triazine derivatives were synthesized, and their in vitro thymidine phosphorylase inhibitory potential was explored. Among the different derivatives, compounds having keto group (C = O) at C7 and thioketo group (C = S) at C5 positions showed varying degrees of TP inhibitory activity comparable with positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 µm). Enzyme inhibition kinetics study suggested that compound IVn behaved as a mixed-type inhibitor of the enzyme with respect to thymidine (dThd) as a variable substrate. Compound IVn was also found to inhibit PMA-induced MMP-9 expression in MDA-MB-231 cells at sublethal concentrations. Computational docking study was performed to illustrate the enzyme inhibition kinetics and to explore the ligand-enzyme interactions.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Thymidine Phosphorylase/antagonists & inhibitors , Triazines/chemistry , Triazoles/chemical synthesis , Binding Sites , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Gene Expression/drug effects , Humans , Kinetics , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Molecular Docking Simulation , Protein Structure, Tertiary , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/analogs & derivatives , Tetradecanoylphorbol Acetate/pharmacology , Thermodynamics , Thymidine/metabolism , Thymidine Phosphorylase/metabolism , Triazines/chemical synthesis , Triazines/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Xanthines/pharmacology
9.
Chem Pharm Bull (Tokyo) ; 54(10): 1384-90, 2006 10.
Article in English | MEDLINE | ID: mdl-17015974

ABSTRACT

Flavones chemically are anthoxanthins, occur either in the free state or as glycosides associated with tannins (flavanoids). Flavanoids (derivatives of flavone) possess various pharmacological activities and due to its xanthine-oxidase enzyme inhibitory effect it also has superoxide-scavenging activities. A series of 2-phenyl-2,3-dihydrochromon-4-one derivatives (flavanone derivatives) were synthesized from chalcones by cyclization method and their activities were evaluated against some gram positive and gram-negative bacteria. IR, NMR and CHN analysis confirmed the structure of the synthesized compounds. The results of the antibacterial studies shows that compounds 2b, 2e, 2f and 2h possess activity against many bacterial strains. Among that the compound (2h) has remarkable activity against all strains viz. 25 microg/ml inhibitory concentration against S. aureus, S. sonnei, E. coli, S. typhimurium and V. cholerae. Compound 2f possess minimum inhibitory concentration of 200 microg/ml against E. coli and S. typhimurium and 25 microg/ml against S. sonnei, S. dysenteriae and V. cholerae. In silico metabolic and toxicity study of the synthesized compounds were performed and the predicted result showed that the compound having hydroxyl functional group undergo sulfate and O-glucuronide conjugation reaction and methoxy derivatives undergo demethylation reaction. The biologically active compounds are free of toxicity in oncogene, teratogen, sensitivity and immunotoxicity.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Computational Biology/methods , Flavanones/chemical synthesis , Flavanones/pharmacology , Anti-Bacterial Agents/chemistry , Cyclization , Flavanones/chemistry , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Microbial Sensitivity Tests , Molecular Structure , Reference Standards , Sensitivity and Specificity , Stereoisomerism , Structure-Activity Relationship
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