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A series of novel pyrazolyl 2-aminopyrimidine derivatives (7a-t) were designed based on scaffold hopping techniques, synthesized and biologically evaluated for their HSP90 inhibition and anticancer activity. Several compounds exhibited potent HSP90 inhibition with IC values less than that of the reference standard 17-AAG (1.25 µM). The most potent compound 7t displayed excellent HSP90 inhibition with an IC of 20 nM and in vitro antiproliferative potential against three cancer cell lines (IC < 5 µM). 7t also induced dose dependent degradation of client proteins (pHER2 and pERK1/2) in Western blot analysis. Several structural features of 7p-t oriented the molecules to retain all the essential binding interactions with HSP90, as observed by rationalized docking studies. Therefore, the para-nitrophenyl ring on the central pyrazole ring along with the 2-amino group on the pyrimidine ring are the crucial features in the development of novel HSP90 inhibitors based on this scaffold for targeted anticancer therapy.
This article was published in the following journal.
Name: Archiv der Pharmazie
SHP2 phosphatase, encoded by the PTPN11 gene, is a non-receptor PTP, which plays an important role in growth factor, cytokine, integrin, hormone signaling pathways, and regulates cellular responses, s...
An efficient, one-pot and four-component synthesis of a new series of 2,3-disubstituted isoindolin-1-ones is described and their Jack bean urease inhibitory activities are evaluated. Heating a mixture...
A series of new urea derivatives (3a-p) have been synthesized from readily available isocyanates and amines in good to high yields. All synthesized compounds were fully characterized using H NMR, C NM...
An efficient and convenient Meglumine catalyzed procedure for the synthesis of bis(indolyl) methanes at ambient temperature under aqueous conditions in high yields. The catalytic reaction proceeds ver...
Herein we report the design, synthesis, molecular docking study and evaluation of antimicrobial activity of ten new dithioloquinolinethiones. The structures of compounds were confirmed by H NMR, C NMR...
Cholesterol is the precursor of glucocorticoids, mineralocorticoids and sex steroids. Both adrenal and non-adrenal (ovarian + testicular) all steroid hormones are primarily synthesized usi...
To establish a serial ascertainement of specimens from patients with bone sarcomas to be used in ongoing cytogenetic and molecular genetic analyses. These data will be integrated and corre...
Collagen synthesis is depressed systemically in the immediate postoperative period. Arginine, zinc and vitamin C impact collagen synthesis. The aim of this study is to investigate the eff...
Biobank is a program which collects biological samples, health information and imaging data from consented patients and stored them at the core facility. These information would be used to...
The present proposal is designed to examine the effect of carbohydrate and protein co-ingestion on muscle protein synthesis during endurance type exercise activities. We hypothesize that m...
A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein.
The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis.
Procedures by which protein structure and function are changed or created in vitro by altering existing or synthesizing new structural genes that direct the synthesis of proteins with sought-after properties. Such procedures may include the design of MOLECULAR MODELS of proteins using COMPUTER GRAPHICS or other molecular modeling techniques; site-specific mutagenesis (MUTAGENESIS, SITE-SPECIFIC) of existing genes; and DIRECTED MOLECULAR EVOLUTION techniques to create new genes.
An approach, process, or methodology which emphasizes credible evidence and the best available scientific knowledge, judiciously integrated to achieve the best possible outcomes in structural design. For example, the design of a new OUTPATIENT CLINIC might incorporate a review of published research on outpatient clinic design, decisions on similar past projects, along with interviews with staff and consumers.
Studies comparing two or more treatments or interventions in which the subjects or patients, upon completion of the course of one treatment, are switched to another. In the case of two treatments, A and B, half the subjects are randomly allocated to receive these in the order A, B and half to receive them in the order B, A. A criticism of this design is that effects of the first treatment may carry over into the period when the second is given. (Last, A Dictionary of Epidemiology, 2d ed)
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...