Summer Research in Physical Sciences: Chemistry

Malignant brain cancers such as glioblastoma are notoriously difficult to treat, with a median patient survival time of less than 16 months. Treatment is complicated by the blood-brain barrier (BBB) which presents a challenge in transporting larger compounds, such as therapeutic drugs, to the brain to treat tumors and other diseases. Recently, tumor-targeting drug delivery systems have been created by conjugating carbon dots, a type of carbon nanoparticle, to fatty acids and arranging them into a vesicle. However, these systems cannot bypass the BBB due to their size. A proposed solution to this problem is menthol, a compound that disrupts tight junction proteins in the BBB and increases its permeability. This research aims to modify carbon dots with menthol and form them into vesicle nanoparticles to increase their BBB permeability and treatment efficiency. The carbon dots were synthesized in a microwave irradiator, both with and without menthol. The presence of menthol moieties on the surface of the carbon dots was examined using FTIR. Oleic acid was then conjugated to the carbon dots to mimic the structure of conventional phospholipids, creating carbon dot-fatty acids (CD-FAs). These CD-FAs were purified using rotary evaporation. The CD-FAs were then arranged into a vesicle and loaded with fluorescent dye, which was then used to evaluate and visualize the drug release characteristics of the vesicles. Future directions include testing the BBB permeability of these vesicles in vivo using zebrafish embryos as a model organism.

Polyethylene terephthalate (PET) is one of the most common thermoplastics in the world, with increasing demand. Its accumulation in the environment has many negative effects including depletion of soil nutrients, contamination of groundwater, and marine aquatic ecotoxicity. Additionally, the production and recycling of PET consume significant energy while emitting greenhouse gases. Biodegradation techniques are being explored for a more sustainable and efficient method to recycle PET. Advances in enzymatic recycling have successfully degraded amorphous PET, but these enzymes can't efficiently degrade crystalline PET. Enzymatic recycling will only be feasible at an industrial scale once effective crystalline PET degrading enzymes are developed, which will eliminate extra steps and reduce harmful environmental impacts. This project aims to design, express, and evaluate a PET hydrolase with stronger crystalline degradation activity. Several promising mutants with optimal characteristics were engineered using computational software, sharing a structure similar to a previously described hydrolase. Residue modifications were implemented to optimize interactions at the active site while conserving the catalytic triad (specifically Ser132) and to achieve characteristics that are ideal for degrading the crystalline form. Additionally, several disulfide bonds were introduced to increase the overall enzyme stability. These mutants will be tested to determine their stability and affinity for degradation, and the most promising will be expressed in E. coli and tested on crystalline PET.

Five to thirteen percent of reported broken bones result in a case of delayed or non-union (no sign of site-healing 3 months post-trauma). The standard treatment procedure for these sites are autografts or xenografts followed by antibiotic treatment. These treatments come with several issues: autografts require two invasive surgeries and an adequate amount of non-essential bone stock, and xenografts have the risk of site-rejection. The surgeries required for both open the site up for microbial infections, and the typical antibiotic treatment results in high concentrations of antibiotic for short periods of time between redosing. This project aims to solve these issues through the design and formulation of antimicrobial bone scaffolds. The scaffolds were composed of varying ratios of chitosan (Ch) and hydroxyapatite (HAp), which was selected due to chitosan’s well-studied degradation profile and hydroxyapatite’s osteoconductive properties and mechanical performance. The scaffolds were formed through a free radical cross-linking mechanism in which two cross-linkers were tested at varying ratios; azobisisobutyronitrile (AIBN) and benzophenone (Bp). Analysis of the Young’s Modulus indicate similar mechanical performance between the AIBN and Bp cross-linked scaffolds, with superior performance by the AIBN scaffolds. Between the various ratios of the Ch to HAp, the 2:1 ratio had the best mechanical performance across both cross-linkers. Swelling tests were performed in both 1% v/v acetic acid solution and a pH 7.4 phosphate-buffer solution to calculate the gel fraction and analyze the level of cross-linking. Future directions include continued mechanical testing of the scaffolds, and the synthesis of vancomycin encapsulated β-cyclodextrin nanoparticles for their incorporation into the scaffolds.

Plastic pollution has been a leading cause of environmental distress in the last two decades. Since its invention in 1907, the amount of plastic consumed per year has increased exponentially, as have the applications for plastics. The United Nations estimates that 430 million tons of plastic are produced yearly, of which two-thirds end up as waste. Plastic pollution causes environmental degradation and ecological harm. Moreover, the non-renewable nature of plastic and the increase in plastic production is depleting natural resources such as oil. To combat this, alternatives to synthetic plastics are now being developed. This research aims to investigate agricultural-sourced, corn-starch-based bioplastics. Without modification, corn-starch-based plastics are universally flawed in their mechanical properties, including their tensile strengths and hydrophobicity. To remediate these issues, this research uses pecan shells as fillers and citric acid as a cross-linking agent to increase tensile strength and hydrophobicity, respectively. Testing of these plastics has shown that the inclusion of pecan shells drastically increases the tensile strength of the plastic. The plastic was tested in three compositions of pecan shells in order to determine the optimal amount of reinforcer. The plastics demonstrated up to a 477% increase in ultimate tensile strengths with fillers. Testing demonstrates that such modified plastics could be promising alternatives to many petroleum-based plastics on the market as they demonstrate similar mechanical properties. Future assays will evaluate the hydrophobic properties of the respective plastics in addition to biodegradability. Additionally, the structures of the plastics will be analyzed using FTIR and SEM.

As plastic production continues to increase, the amount of plastic cycled into the environment has presented a crisis that must be addressed.

Polyolefins, a group of thermoplastics derived from simple olefin (alkene) groups, have widespread usage due to their chemical resistance and durability. As polyolefins have strong chemical resistance, new means of recycling must be considered to tackle polyolefins found in the environment. Currently, many studies focus on different chemical recycling methods as a means of combatting pollution. Cross-metathesis, which rearranges alkene groups to perform scissions in polymer chains, has been researched to recycle polyolefin. Though current research has proven the effectiveness of cross-metathesis in olefin recycling, materials such as expensive transition-metal-centered catalysts and dangerous solvents are needed to perform this procedure. This research aims to develop a method that avoids using dangerous solvents and expensive catalysts, by synthesizing a catalyst with a more abundant and stable transition-metal-center to reduce cost and make this type of chemical processing more accessible. As a result of this manganese two PNP pincer ligand-coordinated Mn(I) complexes were synthesized to perform cross-metathesis. Two PNP pincer ligand-coordinated Mn(I) complexes were synthesized to perform cross-metathesis. The two synthesized complexes, (tBuPNHP)Mn(CO)2Br (C1) and (tBuPNHP)Mn(CO)2(NO2) (C2) were chosen according to previous works using similar ligand complexes and were synthesized in one-pot processes. So far, C1 has undergone preliminary testing using small alkenes to perform cross-metathesis in which C1 has demonstrated suitable properties for conducting cross-metathesis. 

Breast cancer is the most common cancer affecting women and is the leading cause of cancer-related deaths in females worldwide. The Fanconi anemia (FA) pathway has recently become an attractive therapeutic target as the breast cancer susceptibility genes BRCA1 and BRCA2 are involved in ubiquitination as part of the DNA damage response network in this pathway. Ubiquitination is a post-translational modification of proteins that regulates several cell processes such as DNA repair. In the FA pathway, proteins undergo ubiquitination through a series of enzymatic steps involving the E2 enzyme Ube2T which is responsible for processing damage after exposure to interstrand cross-links (ICLs) and has thus been linked to chemotherapy resistance. The inhibition of this pathway would restore sensitivity to ICL-inducing chemotherapeutic agents. However, there are currently very few selective inhibitors of ubiquitin conjugation pathways. This project aims to computationally design novel small molecule drugs with the ability to bind to and prevent the expression of the Ube2T enzyme complex. Using known fragment binders as template structures, the drug discovery platform Schrödinger Maestro was utilized to make modifications to these structures and computationally model them. Over 100 potential candidates were tested for binding and the best performing compound was selected to be tested. Future work includes testing the identified Ube2T inhibitor with a gel-based ubiquitination assay in order to further characterize it.

Over eight million people worldwide are affected by Sickle Cell Disease (SCD), a genetic disorder affecting adult hemoglobin (HbA), the oxygen-carrying component of red blood cells. SCD mutates HbA, structurally compromising red blood cells and dramatically reducing their efficacy. This introduces an elevated risk of clotting, which can lead to dangerous major cardiac events. The small-molecule drug hydroxyurea is the most common treatment for SCD. Treatment with hydroxyurea results in increased levels of nitric oxide and fetal hemoglobin (HbF), a type of hemoglobin that does not carry the SCD mutation. These effects are proposed to result from the interaction between hydroxyurea and Hb’s heme. Despite its positive effects on SCD, hydroxyurea treatment has an unfavorable side-effect profile due to its chemotherapeutic effects. Hydroxyurea stops cell replication by inhibiting ribonucleotide reductase I (RNR I). These side effects can deter patients from starting or continuing hydroxyurea treatment. This research aims to computationally design and synthesize a novel drug that retains hydroxyurea’s nitric oxide donor and HbF stimulating effects while minimizing adverse effects. Using computational software, a variant of hydroxyurea, 1-pentyl-3-hydroxyurea, was identified as an ideal candidate due to its decreased RNR I inhibition, similar Hb affinity, and favorable pharmacological properties. This candidate was successfully synthesized as determined by NMR. Future directions include in-vitro testing of cytotoxicity and nitric oxide donation.

Acute Ischemic Stroke (AIS) is one of the leading causes of death and long-term disability in adults around the world. Approximately 795,000 Americans suffer from new or recurrent AIS each year and 1 in 4 of those affected by AIS have recurrent strokes. AIS occurs when a blood vessel in the brain is blocked by a thrombus, cutting off blood supply to the brain. When this occurs, an influx of oxidative stress releases free radicals that attack neurons leading to their malformation and death. Current stroke treatments focus on breaking up the blood clot within 1 to 3 hours post-stroke. Despite this, there are no available treatments that target oxidative stress to prevent neurodegeneration. Recently, the functional group nitrones have been explored for their neuroprotective properties as free radical scavengers. This work aims to computationally design, synthesize, and evaluate a drug that functions as both a platelet aggregation inhibitor and free radical scavenger. Using computational modeling, several promising drug candidates were identified that maintain platelet aggregation inhibitory properties, show antioxidant potential, and exhibit favorable pharmacological properties. The identified drug candidates used a factor Xa inhibitor as a chemical scaffold with the addition of nitrone moieties to introduce antioxidant properties. Future work will include synthesizing the drug candidates via an eco-friendly procedure and in-vitro testing of this compound’s factor Xa inhibition and antioxidant activity to determine its potential as an AIS treatment option. 

Over 55 million people worldwide are living with dementia according to Alzheimer's Disease International. Numbers are projected to nearly double every 20 years, reaching 78 million in 2030 and 139 million in 2050, with a larger burden expected in developing countries. Two of the proposed causes of dementia are low acetylcholine levels and oxidative stress. Given the significant burden of dementias like Alzheimer's on patients' quality of life, there is a pressing need to explore treatment options. A current treatment, acetylcholinesterase (AChE) inhibitors, often come with concerning side effects ranging from gastrointestinal distress to cholinergic toxicity. This research aims to investigate the potential of modifying natural compounds found in plants to produce an AChE inhibitor that is more accessible, bioavailable, and has antioxidant properties in order to mitigate side effects. Using computational software, several promising drug scaffolds were identified with optimized protein interaction scores, pharmacological properties, and oxidation potentials. Modifications included the addition of aldehyde functional groups with the duff reaction and conversion of alcohol groups to aldehyde groups with (phenyliodine(III) diacetate and lithiated geminal-(Bpin) on the starting compounds of epicatechin, 2-epigallocatechin-gallate, and resveratrol. In the future, the compounds will be characterized using NMR and FTIR. The modified compounds will then be tested for their free radical scavenging capacity and their inhibitory effects on the acetylcholinesterase enzyme to evaluate their therapeutic potential for dementias.

Despite many effective modern treatments, HIV deaths remain high worldwide, primarily in sub-Saharan Africa and other areas with limited access to healthcare. As a result, effective, inexpensive, and accessible drugs are needed. An attractive target for HIV treatment is the attachment of HIV’s gp120 spike protein to the CD4 protein on human immune cells which initiates the cell infection process. For this study, the gp120 spike protein was targeted to inhibit its binding to human CD4. Drug candidates were screened computationally to model the binding of a candidate to the target protein and potential toxicity. Chalcones were selected as a chemical scaffold due to their facile synthesis and promising prescreening results. Systematic alterations were made to the chalcone pharmacore and promising candidates were identified based on synthetic feasibility and favorable pharmacological properties. Once a final candidate had been identified, synthesis procedures were planned and the first steps toward synthesis were completed. Protection of a starting compound was successfully performed for a Friedel crafts acylation to be conducted on that compound. In the future, the final synthesis steps will be completed and the product will be characterized via NMR and FTIR.

Approximately 3.5 million people die each year due to inadequate water supply, sanitation, and hygiene according to the United Nations. More than 90% of pollution-related deaths occurred in low-income and middle-income countries. While scientists have developed various nanomaterials to contribute to the study of wastewater remediation, expensive equipment and costly chemical treatments will only continue burdening developing countries facing heavy metal water pollution. This research aims to investigate the applicability of functionalized multi-walled carbon nanotubes (MWCNTs) decorated with cobalt ferrite nanoparticles for the adsorptive removal of Pb2+ and Cu2+ from synthetic wastewater. Cobalt ferrite (CoFe2O4) nanoparticles could be a promising nanomaterial for both lead and copper removal from wastewater due to the oxygen atoms of iron oxide, which will increase the absorption sites. MWCNTs have shown impressive results in removal efficiency and absorption capacity in a minimal amount of contact time. To synthesize the decorated MWCNTs, MWCNTs were commercially obtained and were then coated with synthesized cobalt ferrite nanoparticles. The synthesized CoFe2O4/MWCNTs were evaluated in synthetic wastewater, including water containing lead, copper, both lead and copper, and a mix of lead, copper, and calcium. The experimental trials demonstrated the nanocomposite’s adept ability to absorb lead and steadily absorb copper within the synthetic wastewater containing lead, copper, and a mix of lead and copper. The results of this research offer a highly eco-friendly and cost-effective device for removing lead and copper pollutants from wastewater. If implemented, this nanocomposite would provide an innovative solution for metal-rich wastewater remediation.