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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Assembly Of Human C-Terminal Binding Protein (Ctbp) Into Tetramers, Andrew G. Bellesis, Anne M. Jecrois, Janelle A. Hayes, Celia A. Schiffer, William E. Royer Jun 2018

Assembly Of Human C-Terminal Binding Protein (Ctbp) Into Tetramers, Andrew G. Bellesis, Anne M. Jecrois, Janelle A. Hayes, Celia A. Schiffer, William E. Royer

Schiffer Lab Publications

C-terminal binding protein 1 (CtBP1) and CtBP2 are transcriptional coregulators that repress numerous cellular processes, such as apoptosis, by binding transcription factors and recruiting chromatin-remodeling enzymes to gene promoters. The NAD(H)-linked oligomerization of human CtBP is coupled to its co-transcriptional activity, which is implicated in cancer progression. However, the biologically relevant level of CtBP assembly has not been firmly established; nor has the stereochemical arrangement of the subunits above that of a dimer. Here, multi-angle light scattering (MALS) data established the NAD(+)- and NADH-dependent assembly of CtBP1 and CtBP2 into tetramers. An examination of subunit interactions within CtBP1 ...


Cytotoxicity Of Platinum Anticancer Drugs In Mammalian Cell Lines Of Metastatic Cancer, Hosannah Evie Jun 2017

Cytotoxicity Of Platinum Anticancer Drugs In Mammalian Cell Lines Of Metastatic Cancer, Hosannah Evie

Honors College Capstone Experience/Thesis Projects

With the invention of advanced technology, focus has been put on understanding and looking for potential cures for many diseases, one of which is cancer. The difference in the leaving and non-leaving ligands of the FDA approved cancer drugs contributes to the differential cell specific cytotoxic effects. These drugs such as oxaliplatin approved for colorectal cancer, cisplatin approved for testicular cancer, and their analogs were used to treat different cancer cell lines in an MTT assay. This project aims to determine how changing the molecular shape of these compounds affects their uptake and toxicity into different cell lines. The assay ...


Synthesis And In-Vitro Cell Viability/Cytotoxicity Studies Of Novel Pyrrolobenzodiazepine Derivatives, John M. Jarrett May 2017

Synthesis And In-Vitro Cell Viability/Cytotoxicity Studies Of Novel Pyrrolobenzodiazepine Derivatives, John M. Jarrett

Undergraduate Honors Theses

Pyrrolobenzodiazepines (PBDs) are a group of naturally occurring compounds that were discovered in the cultures of Streptomyces in the 1960s. Some natural PBDs discovered in these cultures, such as anthramycin and sibiromycin, were shown to possess a broad spectrum of anti-tumor activity. Since cancer is still a leading cause of death globally, the development of novel anti-proliferative derivatives of PBDs is essential for human welfare worldwide. Further synthesis and structure-activity relationship (SAR) studies of the parent natural products and their tetracyclic analogs will lead to the discovery of drug candidates. In this work, thirteen PBD analogues were synthesized using no ...


Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith Jul 2016

Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith

Chemistry Articles

We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ.


Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue Feb 2016

Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue

Thompson Lab Publications

Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to ...


Synthesis And Characterization Of Imidazolium Salt Derivatives For Anti-Tumor Activity, Ryan W. Pearce Jan 2015

Synthesis And Characterization Of Imidazolium Salt Derivatives For Anti-Tumor Activity, Ryan W. Pearce

Williams Honors College, Honors Research Projects

Several aldehydes (butanal, pentanal, hexanal, 4-hydroxybenzaldehyde) were reacted with 1,3-bis(naphthalen-2-ylmethyl)-imidazolium bromide (1) to produce novel C2 substituted imidazolium salts for the potential use against non-small cell lung cancer in humans. Compounds 2-(1-hydroxypentyl)-1,3-bis(naphthalen-2-ylmethyl)-imidazolium bromide (3) and 2-(1-hydroxyhexyl)-1,3-bis(naphthalen-2-ylmethyl)-imidazolium bromide (5) were successfully synthesized with structures supported by NMR and mass spectrometry. Characterization by 1H NMR showed evidence of 1 in both compounds. The tumor cell growth inhibition of 3 against non-small cell lung cancer lines NCI-A549, NCI-H460, HCC827, and NCI-H1975 was tested and found to be comparable ...


Inhibition Of The Thioesterase Activity Of Human Fatty Acid Synthase By 1,4- And 9,10-Diones, Herman H. Odens Sep 2014

Inhibition Of The Thioesterase Activity Of Human Fatty Acid Synthase By 1,4- And 9,10-Diones, Herman H. Odens

Faculty Works

Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widely recognized as a valuable therapeutic target. In this report, we describe a variety of 1,4-quinones and 9,10- anthraquinones, including several natural compounds and some newly synthesized compounds, that potently inhibit the ...


Functionalization And Modification Of Naphthaquinone Analogs As Her2 Kinase Inhibitors, Divya Jyothi Lella May 2014

Functionalization And Modification Of Naphthaquinone Analogs As Her2 Kinase Inhibitors, Divya Jyothi Lella

Masters Theses & Specialist Projects

HER2 overexpression in breast cancer tumors predicts lower overall survival. Because of the aggressive nature of HER2 tumors and the association with metastatic disease, the HER2 receptor holds great promise as a therapeutic target in metastatic breast cancer. We are developing small molecule inhibitors that bind to the ATP binding site of the tyrosine kinase domain in order to inhibit tyrosine auto-phosphorylation. This process controls biological pathways that mediate the cell growth. In normal cells this process is highly controlled. We are targeting the modification of the side chain of the hydroxy methyl group of 2-Hydroxy methyl-5,8-dimethoxy-1,4-naphthaquinone. These ...