Medicinal Chemistry

"Medicinal chemists are focused on drug discovery and development and are concerned with the isolation of medicinal agents found in plants, as well as the creation of new synthetic drug compounds. "

American Chemical Society

Medicinal session has been scheduled for Monday Morning.

If you find any errors in our listing please let us know at chemistrybuffalogss@gmail.com

Monday Morning

Session 1B - Room NSC 218 - Moderator: Laura Parisi

9:40 a.m. - 10:00 a.m.

EGFR Targeted Biodegradable Nanoparticles Containing TMZ and Cy5 for Glioblastoma Theranostics

Rebecca Schmitt, Katherine Cwiklinski, Supriya Mahajan, Paras N. Prasad

The State University of New York at Buffalo, Department of Chemistry

Glioblastoma is the most aggressive form of brain cancer. Despite well-established treatment regimens it is associated with low life expectancy, frequent recurrence, and overall poor prognosis. One of the main obstacles in treating glioblastoma is traversing the blood-brain barrier (BBB); a physical barrier that contributes to maintaining brain homeostasis. Nanoparticles can be designed to cross the BBB and have been implemented as delivery systems for therapeutic agents. They also provide the benefit of targeted drug delivery, controlled drug release, and protection of drugs from degradation. The goal of this project is to utilize chitosan coated polylactic-co-glycolic acid (PLGA) nanoparticles to deliver chemotherapeutic temozolomide (TMZ) and near-IR dye Cy-5 across the BBB as a theranostic treatment for glioblastoma. Epidermal growth factor receptor (EGFR) is over expressed in glioblastoma, therefore, targeted drug delivery will be achieved through conjugation of modified gifitinib (an FDA approved small molecule EGFR inhibitor) to the PLGA-chitosan nanoparticles. In-vitro contact co-culture BBB models with normal human astrocytes (NHA) and human brain microvascular endothelial cells (HBMVEC) demonstrate the nanoparticles’ ability to permeate the BBB. Cytotoxicity of the nanoformulation toward HBMVEC and NHA cell lines was evaluated using an MTT assay. Future work will include in-vitro targeting experiments, drug release profiling, and IC-50 determination.

10:00 a.m. - 10:20 a.m.

Single Bacterial Cell Monitoring of Antibiotic Action Using a Fluorescent Redox Sensitive Dye

Louis Ray, Erin M. Merico, Kailey A. Christman, Michael C. Konopka

The University of Akron

An antibiotic crisis is approaching as susceptibility to currently available antibiotics continues to decrease, while discovery of novel antibiotics has nearly ceased. While current methods provide identification, the most commonly used methods remain slow to use relative to the time scale of an aggressive bacterial infection. Here we show that RedoxSensor™ Green dye (RSG) can be used as a rapid indicator of antibiotic susceptibility in bacteria. RSG is a commercially available fluorescent dye marketed for flow cytometry which reports on bacterial reductase activity. We found that cell wall and cell membrane targeting antibiotics result in increased RSG fluorescence upon treatment in both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. RSG fluorescence changes were monitored at the single cell level in real time using fluorescence microscopy and were found to be useful indicators of antibiotic susceptibility for β-lactam antibiotics, polymyxin B and vancomycin. Using our method, identification of antibiotic susceptibility of E. coli to β-lactams using RSG signal takes approximately 50 minutes while susceptibility to polymyxin B takes less than 5 minutes. Our results demonstrate that as few as 100 bacteria could be sufficient for a determination of antibiotic susceptibility for the tested antibiotics.

10:20 a.m. - 10:40 a.m.

Neutral Co(II) complexes as water proton shift or paraCEST agents for cell labeling

Md Saiful Chowdhury, Janet R. Morrow

The State University of New York at Buffalo, Department of Chemistry

Magnetic Resonance Imaging (MRI) has been used to detect both in-vitro labelled cells and in-vivo implanted labelled cells with both relaxation enhancers and lanthanide based paraCEST/paraSHIFT agents. In this study, we have synthesized three amino acid appended cyclam macrocycle-based Co(II) complexes which are overall neutral at physiological pH. These complexes are both paraCEST agents and also shift the proton resonances of bulk water. Exchangeable amide NH protons on these complexes give rise to CEST peaks on z-spectrum which are shifted up to 102 ppm from the bulk water resonance. The properties of these complexes as paraCEST agents will be presented. In addition, Co(II) complexes were loaded in yeast cells (wild-type 538) by means of electroporation and a z-spectrum was measured on a 500Mz (11.7T) NMR spectrometer. Shift of the absorption frequency of the intracellular water resonance (δ) is found in the presence of these paramagnetic Co (II) complexes. Asymmetry of z-spectra generated from the Co(II) complex loaded cells is used to report on the labelled cells. Neutral paraCEST MRI can be used to detect labelled cells as an alternative to lanthanide agents.

10:40 a.m. - 11:00 a.m.

Exploring the Feasibility of Inhibiting the Protein-Protein Interaction between Fatty Acid Binding Protein 4 and Peroxisome Proliferator Activated Receptor gamma

Ndidiamaka Obi, Adrian Whitty

Boston University

Aberrant protein-protein interactions (PPIs) are the underlying cause of many diseases, and their inhibition could potentially lead to new therapeutics. For example, over-expression of FABP4 mediates the down-regulation of PPARgamma, a phenomenon that has been implicated in the development of obesity-linked diabetes. Inhibiting this protein-protein interaction could potentially prevent development of the disease, while sparing other essential functions of these two proteins and thereby reducing the likelihood of on-target toxicity. Such an approach could be advantageous compared to current treatments, which can have serious side-effects. We are characterizing the FABP4/PPARgamma PPI, to establish the feasibility of inhibiting it with a small molecule. Specifically, we are using alanine scanning mutagenesis to identify which regions on each protein form the interaction interface, measuring binding using IP-Western blot and SPR. We are also computationally assessing the presence of druggable sites, using FTMap to identify the locations and strengths of binding energy hot spots. These studies will reveal whether the interaction is likely to be druggable, and will additionally provide guidance as to which approaches are most appropriate (e.g. conventional inhibitor versus a beyond Rule-of-Five compound versus a covalent inhibitor). The binding assays we develop for the alanine scanning study will then be used to pursue inhibitor discovery against this important target.