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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Antitumor Properties Of Imidazolium Salts, Jenna Frantz Jan 2019

Antitumor Properties Of Imidazolium Salts, Jenna Frantz

Williams Honors College, Honors Research Projects

This is the final write-up for an honors research project for the University of Akron Williams Honors College. Synthesis of novel imidazolium salts was conducted. Following synthesis of imidazolium salts, the stability of the compound was tested at 37°C over a 72-hour period to give preliminary information about drug stability in vivo. 2D NMR was also conducted to confirm the structure of TPP-1. The student wrote an experimental protocol for the use of C57BL/6 mice and performed the online CITI training by the IRB to prepare to work with animals in a study of the antitumor properties of ...


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 ...


Development Of Neurotensin-Based Radiopharmaceuticals For Neurotensin-Receptor-1-Positive Tumors Targeting, Yinnong Jia May 2017

Development Of Neurotensin-Based Radiopharmaceuticals For Neurotensin-Receptor-1-Positive Tumors Targeting, Yinnong Jia

Theses & Dissertations

The neurotensin receptor 1 (NTR1) is overexpressed in many cancers, due to its role as a growth pathway. These NTR1-positive cancers include pancreatic, colon, prostate and breast cancers. In the radiopharmaceutical field, the overexpression of NTR1 in cancer has prompted the development of NTR1-targeted diagnostics and therapeutics. The neurotensin (NT) peptide exhibits low nanomolar affinity for NTR1 and has been the paradigm for NTR1-targeted agents. Since the 1980’s, radiolabeled NT analogs have been developed and evaluated for targeting NTR1-positive cancers. Since native NT is rapidly degraded in vivo by a variety of peptidases, a tremendous amount of effort has ...


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 ...


Ligands Of Therapeutic Utility For The Liver X Receptors., Rajesh Komati, Dominick Spadoni, Shilong Zheng, Jayalakshmi Sridhar Jan 2017

Ligands Of Therapeutic Utility For The Liver X Receptors., Rajesh Komati, Dominick Spadoni, Shilong Zheng, Jayalakshmi Sridhar

Faculty and Staff Publications

Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism ...


Improving Binding Affinity Through Cyclization, Kaylee M. Newcomb, Nicolas Abrigo Jan 2017

Improving Binding Affinity Through Cyclization, Kaylee M. Newcomb, Nicolas Abrigo

Undergraduate Research Posters

Cancer chemotherapy results in systematic damage as the drugs used are also toxic to benign tissue. Sensitizing a cancer cell to therapy by interfering with the DNA repair mechanisms would decrease overall toxicity, as the necessary dosage of chemotherapy drugs would be lowered. The Hartman lab developed a peptide (8.6) that binds with a KD of 1 μM to the C-terminal domain of breast cancer associated protein (BRCA1), blocking homologous recombination. The crystal structure of the peptide shows the tyrosine and threonine residues are close together, suggesting that by cyclizing these positions, the peptide may already be constrained into ...


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.


Binding Of Oxaliplatin And Its Analogs With Dna Nucleotides At Variable Ph And Concentration Levels, Rippa Sehgal Apr 2016

Binding Of Oxaliplatin And Its Analogs With Dna Nucleotides At Variable Ph And Concentration Levels, Rippa Sehgal

Masters Theses & Specialist Projects

Oxaliplatin is one of the three FDA-approved platinum anticancer drugs and considered a third generation drug, discovered after the first generation drug cisplatin and second generation drug carboplatin. It is known to react with proteins and DNA nucleotides in the body. Reaction with DNA occurs primarily at guanosine residues and secondarily at adenine residues for oxaliplatin and other platinum drugs. We have previously studied oxaliplatin and an analog with additional steric hindrance in the amine ligand and found that the analog had different reactivity with methionine. Now, we have prepared oxaliplatin and its three analogs Pt(Me2dach)(ox), Pt(en ...


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 ...


The Preparation And Characterization Of Cyclodextrin:Sterol Inclusion Complexes As Anti-Tumor Therapeutics, Janet V. Cowins Dec 2015

The Preparation And Characterization Of Cyclodextrin:Sterol Inclusion Complexes As Anti-Tumor Therapeutics, Janet V. Cowins

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

An inclusion complex between β-cyclodextrin and insoluble guest compounds has been reported by several researchers. The main purpose of forming an inclusion complex between β-CD and sparingly soluble guests is to enhance the guest’s solubility and mask its undesirable properties. Preliminary studies have shown that when conjugated with target-specific moieties, these inclusion complexes can be used in pharmaceutical applications for drug delivery. β-Sitosterol, a plant sterol, has been well documented to reduce tumor cell growth and migration as well as exhibit apoptotic characteristics. An issue with this plant sterol and most pharmaceutical compounds is their lack of solubility. In ...


Synthesis And Anti-Proliferative Activity Of N,N’-Bis(Arylmethyl)Benzimidazolium Salts, Travis M. Williams Jan 2015

Synthesis And Anti-Proliferative Activity Of N,N’-Bis(Arylmethyl)Benzimidazolium Salts, Travis M. Williams

Williams Honors College, Honors Research Projects

A series of N,N’-bis(arylmethyl)benzimidazolium salts with hydrophilic and lipophilic substituents have been synthesized, characterized, and tested against select non-small cell cancer cell lines. Substituent variations on the imidazole ring have shown that lipophilicity and hydrophilicity can influence the imidazolium salts’ anti-proliferative activity and aqueous solubility.


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 ...


Interesting Properties Of P-, D-, And F-Block Elements When Coordinated With Dipicolinic Acid And Its Derivatives As Ligands: Their Use As Inorganic Pharmaceuticals, Michael J. Celestine, Jimmie L. Bullock, Shivani Boodram, Varma H. Rambaran, Alvin A. Holder Jan 2015

Interesting Properties Of P-, D-, And F-Block Elements When Coordinated With Dipicolinic Acid And Its Derivatives As Ligands: Their Use As Inorganic Pharmaceuticals, Michael J. Celestine, Jimmie L. Bullock, Shivani Boodram, Varma H. Rambaran, Alvin A. Holder

Chemistry & Biochemistry Faculty Publications

This is a review of the literature concerning the interesting properties of p-, d-, and f-block elements when coordinated with 2,6-pyridinedicarboxylic acid (dipicolinic acid, H2dipic) and its derivatives as ligands, with a focus on their use as inorganic pharmaceuticals. Some of the complexes reported were used as insulin-like, bioimaging contrasting agents, antimicrobial agents, and anticancer agents.


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 ...


Lead Optimization Of Dual Tubulin And Hsp27 Inhibitors, Bo Zhong, Rati Lama, Daniel G. Kulman, Bibo Li Ph.D., Bin Su Ph.D. Jun 2014

Lead Optimization Of Dual Tubulin And Hsp27 Inhibitors, Bo Zhong, Rati Lama, Daniel G. Kulman, Bibo Li Ph.D., Bin Su Ph.D.

Chemistry Faculty Publications

Tubulin and heat shock protein 27 (Hsp27) are well-characterized molecular targets for anti-cancer drug development. We previously identified lead compounds that inhibited both Hsp27 and tubulin. These compounds exhibited extensive anti-cancer activities against the proliferation of various human cancer cell lines. In the current study, a systematic ligand based structural optimization led to new analogs that significantly inhibited the growth of a panel of breast cancer cell lines. Furthermore, the most potent compounds were examined with tubulin polymerization assay and Hsp27 chaperone activity assay. The compounds showed potent tubulin polymerization inhibition but no Hsp27 inhibitory effect. The structural optimization dissected ...


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 ...


Reactions Of Platinum(Ii) Compounds With Selenium Containing Amino Acids, Stephanie Robey May 2013

Reactions Of Platinum(Ii) Compounds With Selenium Containing Amino Acids, Stephanie Robey

Masters Theses & Specialist Projects

Platinum(II) anticancer medications essentially react with DNA forming kinks in
the double helix of DNA and causing apoptosis. It has also been noted that these
anticancer medications react with methionine and cysteine in the body. With the new discoveries of selenium containing amino acids including selenomethionine and selenocysteine, new research is ongoing to see what types of products can be formed from these amino acids. Our research reacts [Pt(Met-S,N)Cl2] 2+ with selenomethionine to determine what types of products are produced. Monochelates including [Pt(SeMet-Se,N)Cl2] 2+ have formed two isomers, as ...