Chemistry Program Research Articles

2-(Fluoromethoxy)-4'-(S-methanesulfonimidoyl)-1,1'-biphenyl (UCM-1306), an Orally Bioavailable Positive Allosteric Modulator of the Human Dopamine D1 Receptor for Parkinson's Disease.

Tolerance development caused by dopamine replacement with l-DOPA and therapeutic drawbacks upon activation of dopaminergic receptors with orthosteric agonists reveal a significant unmet need for safe and effective treatment of Parkinson’s disease. In search for selective modulators of the D1 receptor, the screening of a chemical library and subsequent medicinal chemistry program around an identified hit resulted in new synthetic compound 26 [UCM-1306, 2-(fluoromethoxy)-4′-(S-methanesulfonimidoyl)-1,1′-biphenyl] that increases the dopamine maximal effect in a dose-dependent manner in human and mouse D1 receptors, is inactive in the absence of dopamine, modulates dopamine affinity for the receptor, exhibits subtype selectivity, and displays low binding competition with orthosteric ligands. The new allosteric modulator potentiates cocaine-induced locomotion and enhances l-DOPA recovery of decreased locomotor activity in reserpinized mice after oral administration. The behavior of compound 26 supports the interest of a positive allosteric modulator of the D1 receptor as a promising therapeutic approach for Parkinson’s disease.

N → N’ acyl migration in the context of a medicinal chemistry program

A series of tertiary amides was identified as lead matter for a new medicinal chemistry program. Analysis of analogs made for structure activity studies and physicochemical property measurements revealed that some of these tertiary amides were prone to acyl migration. A series of compounds designed to assess the propensity for acyl migration was synthesized. Qualitative time and temperature kinetics were followed up with quantitative kinetic measurements using 1H NMR techniques. Many of the examined tertiary amides from this series were shown to migrate under range of pHs and temperatures. Our finding serves as a cautionary note for others working with amides of a similar nature.

NovoLearning: A strategic response to large class problems in teaching non-English department students

Having English for all non-English department students as a compulsory course in the institution is worthwhile for the improvement of students’ ability in using foreign language; however, practically, the students and the lecturers deal with a lot of issues regarding the implementation of the subject itself. Every English class of non-English department is a large class consisting of more than 50 and even 100 students. Handling large classes constitutes a real challenge to every lecturer that it may hinder greater academic achievement and favorable attitudes toward learning. This study aims to find out how NovoLearning program can be the alternative to cope with large class problems of non-English language students. NovoLearning program is an artificial intelligence-based mobile learning that provides a fully integrated training solution, allowing focused English language instruction, communication preparation and integrated skills training. This study employed descriptive qualitative research involving 356 non-English department students from MIPA major namely Mathematics, Biology, Chemistry, Physics, and Natural Science Education Study Programs. Interview, observation, and documentation were employed to obtain the data of this present study. The results show that NovoLearning program can elevate the efficiency of the teaching and learning level to its best quality. It witnessed several views of students that get advantages from the use of the program such as the interactivity, boost on students’ English proficiency, and high-quality feedback. The practical use of this program makes it potential to be applied not only for today’s learning as an alternative to cope with ineffectiveness of large class but also for more advanced learning in the future.

Evolution of chemistry programme at DAE

Evolution of chemistry programme at DAE

The Structures and Binding Modes of Small-Molecule Inhibitors of Pseudomonas aeruginosa Elastase LasB.

Elastase B (LasB) is a zinc metalloprotease and a crucial virulence factor of Pseudomonas aeruginosa. As the need for new strategies to fight antimicrobial resistance (AMR) constantly rises, this protein has become a key target in the development of novel antivirulence agents. The extensive knowledge of the structure of its active site, containing two subpockets and a zinc atom, led to various structure-based medicinal chemistry programs and the optimization of several chemical classes of inhibitors. This review provides a brief reminder of the structure of the active site and a summary of the disclosed P. aeruginosa LasB inhibitors. We specifically focused on the analysis of their binding modes with a detailed representation of them, hence giving an overview of the strategies aiming at targeting LasB by small molecules.

Aspectos de Alfabetização Científica e Tecnológica presentes em projetos pedagógicos de cursos brasileiros de Química-Licenciatura

Scientific and technological literacy is one of the main objectives of scientific education, however, there are arguments about its definition and possibilities of implementation. There is, though, the consensus that Science teachers (Chemistry, Physics and Biology) have an important role in its promotion. Thus, the present article aimes to analyse elements of Scientifical and Technological Literacy, its concepts and dimensions, in the Pedagogical Projects of Chemistry programs offered on various Brazilian institutions. For such, it was performed a mixed methods research, in which the Pedagogical Projects of 15 Chemistry courses of different institutions from the five Brazilian regions were analyzed in the software Iramuteq 0.7 alpha 2. The results show that the programs indicate the importance of the three dimensions of the STL analyzed in this study, which configures as an argument in favor of further investigations about the implementation of these concepts in the day-to-day practice of these programs.

Field-Based Environmental Chemistry Course for Interdisciplinary, Project-Based Learning

Faculty in the Chemistry and Environmental Science programs at St. Mary’s University in San Antonio, Texas, collaborated to develop an undergraduate course in Field-Based Environmental Chemistry. The course was developed and implemented as a 2-semester, 1-semester, and online, synchronous course offered during the 2020/21 COVID-19 pandemic. As part of the course, chemistry and environmental science majors designed and executed a sampling and laboratory analysis plan for monitoring the physical and chemical conditions of soil and/or water in a local, urban setting. As part of a goal to help students develop communication skills, they presented their work to stakeholders from the local community. Through participation in an active learning model, students demonstrated significant gains in the student learning outcomes. Students in the 2-semester sequence showed gains in their understanding of the scientific process, more comfort with the uncertainty and the ambiguity of natural environments, and appreciation for the importance of statistics in data analysis. The online course and COVID-19 pandemic restrictions did not allow for student field or laboratory work but did engage students in a project typical of a work environment.

Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones.

As saturated heterocyclic building blocks become increasingly popular in medicinal chemistry and drug discovery programs, expansion of the synthetic toolkit to novel stereofunctionalized heterocycles is a priority. Herein, we report the development of a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to access a broad range of enantioenriched α-difunctionalized 5- and 6-membered sulfones from easily accessible racemic starting materials. The allylic alkylation step was found to occur with high levels of enantioselectivity as a result of a palladium-mediated dynamic kinetic resolution of E/Z enolate intermediates. This methodology paves the way to hitherto unexplored stereodefined cyclic sulfones for medicinal chemistry applications.

Integration and differentiation in the STEM education subject with the development of problem-solving capacity of students

The renovation of current teaching methods aims to achieve two important goals: Firstly, equip students with the ability to synthesize knowledge, skills, etc. in many different fields to solve problems. Secondly, from the requirement of educational socialization, it is necessary to fulfill the teaching purposes for all students, that is, to ensure that each individual student is trained to improve knowledge and develop capacity. STEM education is one of the solutions to meet the above goals. STEM education demonstrates integration and differentiation in teaching content and organization to equip learners with necessary knowledge and skills, thereby developing problem-solving abilities for all learners. This article deeply explores the integration and differentiation in the topic of STEM education with the development of problem - solving capacity for students through the topic: Chemical fertilizers in high school grade 11 chemistry program.

Abstract 5977: Discovery and preclinical validation of [11C]AZ3391: A first in class blood-brain barrier permeable, subtype selective PARP-1 PET radioligand

Abstract Positron emission tomography (PET) is a molecular imaging technique used to study the distribution of radiolabeled tracer molecules in vivo in a non-invasive fashion. We here report the discovery and preclinical validation of a novel PET tracer for PARP1. Its exquisite selectivity and high contrast in vivo opens up unique opportunities for exploring target engagement and relationships between drug exposure in plasma and PARP1 occupancy during clinical development of PARP1 inhibitors. AZ3391 was identified as a PET radioligand candidate from our medicinal chemistry program investigating novel PARP1 selective inhibitors and radiolabeled with carbon-11 (t1/2=20.4 min) for a series of in vitro and in vivo imaging experiments. Using in vitro autoradiography, dense binding of [11C]AZ3391 was observed in tissues known to be rich in PARP1 (eg tumour xenograft; NHP and human brain cerebellum). [11C]AZ3391 binding was completely abolished by the inclusion of a high concentration of Olaparib or AZD5305 in the incubate, thus demonstrating specific binding to PARP1 in vitro. Following intravenous injection of [11C]AZ3391 in non-human primates, high binding was observed in organs known to express PARP1, eg brain, spleen and bone marrow. The radioactivity in these organs could be blocked in a dose-dependent manner after pre-treatment with increasing doses of AZD9574 (up to 0.05 mg/kg), thus demonstrating specific binding to PARP1 in vivo. This set of preclinical data supports further development of [11C]AZ3391 as a tool to assess drug induced PARP1 engagement in patients. Citation Format: Peter Johnström, Jeffrey Johannes, Andy Pike, Zsolt Cselényi, Magnus Schou. Discovery and preclinical validation of [11C]AZ3391: A first in class blood-brain barrier permeable, subtype selective PARP-1 PET radioligand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5977.

Continuous Flow Technology as an Enabler for Innovative Transformations Exploiting Carbenes, Nitrenes, and Benzynes.

Miniaturization offered by microreactors provides for superb reaction control as well as excellent heat and mass transfer. By performing chemical reactions in microreactors or tubular systems under continuous flow conditions, increased safety can be harnessed which allows exploitation of these technologies for the generation and immediate consumption of high-energy intermediates. This Synopsis demonstrates the use of flow technology to effectively exploit benzynes, carbenes, and nitrenes in synthetic chemistry programs.

Silver Ion-Induced Formation of Unprecedented Thorium Nonamer Clusters via Lacuna-Construction Strategy

Silver Ion-Induced Formation of Unprecedented Thorium Nonamer Clusters via Lacuna-Construction Strategy

Graduate Student Women's Perceptions of Faculty Careers: The Critical Role of Departmental Values and Support in Career Choice.

While the number of women in undergraduate and graduate chemistry programs has increased in recent years, women remain under-represented and excluded in the ranks of faculty in chemistry higher education. This marginalization results from not only fewer women being offered faculty positions but also fewer women applying for these positions. To investigate the reasons why faculty positions are causing so many women to turn elsewhere for employment, a survey was designed based on the literature themes surrounding women’s career choices, interviews with the current graduate student women in chemistry programs, and our previous work. The survey was grounded in social cognitive career theory (SCCT), and data were analyzed through a QuantCrit lens. Despite the existing literature focusing on the impact of having children on women’s career decisions, the desire to have children did not appear among either the top priorities or the most important factors in predicting whether any of the 130 survey respondents were interested in a faculty career. Instead, faculty career interest was related to themes of overwork, high expectations from departments, and expected department emphasis on research despite an individual’s interest in teaching and mentoring. Furthermore, women expressed a strong interest in maintaining work–life balance but low expectations for their ability to obtain a position that would allow it. They also reported a desire to work for a department that values mental health and diversity and supports its community members but similarly low expectations for their ability to find a department that shares these values. These themes suggest that chemistry departments must make fundamental changes regarding what is tangibly valued and rewarded within their systems if they wish to reduce the exclusion of women in faculty positions.

Can the GRE predict valued outcomes? Dropout and writing skill.

Graduate school programs that are considering dropping the GRE as an admissions tool often focus on claims that the test is biased and does not predict valued outcomes. This paper addresses the bias issue and provides evidence related to the prediction of valued outcomes. Two studies are included. The first study used data from chemistry (N = 315) and computer engineering (N = 389) programs from a flagship state university and an Ivy League university to demonstrate the ability of the GRE to predict dropout. Dropout prediction for the chemistry programs was both statistically and practically significant for the GRE quantitative (GRE-Q) scores, but not for the verbal or analytical writing scores. In the computer engineering programs, significant dropout prediction by GRE-Q was evident only for domestic students. In the second study, GRE Analytical Writing scores for 217 students were related to writing produced as part of graduate school coursework and relationships were noted that were both practically and statistically significant.

Visualizing the school organic chemistry course with augmented reality

Nowadays, studying natural sciences, as well as chemistry, is impossible without good-quality visualization of the theoretic data. Supplying mobile apps with augmented reality give the opportunity to visualize the study information for the students and make its perception and learning easier. The paper is dedicated to developing a lap book and mobile app LiCo.STEAM Sugar with augmented reality and studying the “Carbohydrates” topic according to the 10 th grade chemistry program, and also to investigate it’s effciency within the chemistry lessons. The developed lap book includes the theories with carbohydrate molecules’ images, an experimental part designed for performing chemical experiments and studying properties of organic compounds, and also tasks of different levels. Molecules of carbohydrates, their structure can be visualized with AR, and also video-experiments on this subjets can be played. Using the lap book “Carbohydrates” with augmented reality together with LiCo.STEAM Sugar mobile app allows to upgrade the content and the volumes of the theories, apply modern ICT within the study in order to build students’ skills of a new level. Applying educational data with augmented reality give students the ability to memorize the theories in a better way, which is shown with the increased results of educational achievements of students in chemistry.

Developing a skills-based practical chemistry programme: an integrated, spiral curriculum approach

Abstract Teaching practical laboratory skills is a key component of preparing undergraduate students for future careers in chemistry and elsewhere. In this paper, we present our new strategy to teach practical skills to undergraduate chemistry students. We report a Skills Inventory, a list of the suggested practical skills a graduate chemist should possess; this list was compiled by chemists across the UK. In our new practical course we begin by decoupling the practical skill from the theoretical background, compelling students to first master the basic processes needed to carry out a specific technique. In what we have termed a ‘spiral curriculum’ approach, skills are revisited on multiple occasions, with increasing complexity and greater emphasis on underlying theory. The new course makes links across traditional subdisciplines of chemistry to avoid compartmentalisation of ideas.

Reverse-Design toward Optimized Labeled Chemical Probes – Examples from the Endocannabinoid System

Labeled chemical probes are of utmost importance to bring drugs from the laboratory through the clinic and ultimately to market. They support and impact all research and discovery phases: target verification and validation; assay development; lead optimization; and biomarker engagement in the context of preclinical studies and human trials. Probes should display high potency and selectivity as well as fulfill specific criteria in connection with absorption, distribution, metabolism, excretion and toxicology (ADMET) profile. Progress in fields such as imaging and proteomics increased the need for specialized probes to support drug discovery. Labeled probes carrying an additional reporter group are valuable tools to meet specific application requirements, but pose significant challenges in design and construction. In the reverse-design approach, small molecules previously optimized in medicinal chemistry programs form the basis for the generation of such high-quality probes. We discuss the reverse design concept for the generation of labeled probes targeting the endocannabinoid system (ECS), a complex lipid signaling network that plays a key role in many human health and disease conditions. The examples highlighted include diverse reporter units for a range of applications. In several cases the reported probes were the product of mutually rewarding and highly cross-fertilizing collaborations among academic and industry research programs, a strategy that can serve as a blueprint for future probe generation efforts.

Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors.

The use of peptides as therapeutics has often been associated with several drawbacks such as poor absorption, low stability to proteolytic digestion, and fast clearance. Peptidomimetics are developed by modifications of native peptides with the aim of obtaining molecules that are more suitable for clinical development and, for this reason, are widely used as tools in medicinal chemistry programs. The effort to disclose innovative peptidomimetic therapies is recurrent and constantly evolving as demonstrated by the new lead compounds in clinical trials. Synthetic strategies for the development of peptidomimetics have also been implemented with time. This perspective highlights some of the most recent efforts for the design and synthesis of peptidomimetic agents together with their biological evaluation toward a panel of targets.

Teaching Collaboration Skills to Undergraduate Biochemistry and Chemistry Students

We want our students to develop effective collaboration skills, but how do we intentionally teach teamwork and assess it? The Department of Chemistry and Biochemistry at St. Mary’s College of Maryland has scaffolded collaboration skills throughout the curriculum for the chemistry and biochemistry programs at three levels, foundational, developing, and capstone. The skills are tied to signature assignments at each level. In Biochemistry I and II, we are using a team contract at the beginning of semester‐long team projects (a bioinformatics project and a grant proposal project) where students identify their strengths, review expectations, and make plans for group communication. At the end of the semester, each student assesses their own contributions and those of their team members for various parts of the project. In addition, this academic year we started using a common collaboration rubric in multiple courses for students to evaluate self and team members using the following subcategories: quality of work, commitment, leadership, communication, and analysis. In Biochemistry I and II, we used this rubric for multiple assignments that are part of the semester long projects. In the General Chemistry lab, we modified this rubric to fit into a form that reflects these same collaboration attributes after each lab experience, so students can assess and report privately on their experiences as part of their collaboration grade for the course. A similar collaboration rubric is completed by students for each of five team‐based laboratories in Physical Chemistry I, enabling us to obtain honest feedback and assign a collaboration grade. We will discuss how the use of these forms has affected collaborative projects in our courses.

In Vitro Pharmacological Characterization of CRN04894: The First Reported Oral, Selective Nonpeptide Melanocortin 2 Receptor Antagonist Evaluated in Phase 1 First‐in‐Human Clinical Trials

Adrenocorticotropic hormone (ACTH) is secreted from the pituitary gland and selectively activates the melanocortin type 2 receptor (MC2R) in the adrenal glands, where it modulates steroidal hormone (e.g., cortisol) synthesis and secretion. Excess ACTH contributes to the pathophysiology of Cushing’s disease (CD), ectopic ACTH syndrome (EAS), and congenital adrenal hyperplasia (CAH). ACTH‐secreting tumors cause CD (in pituitary) and EAS (outside pituitary) and lead to hypercortisolemia and various metabolic comorbidities. CAH is caused by inactivating mutations in adrenal steroid synthesis pathway proteins leading to low levels of cortisol that are insufficient to provide negative feedback on ACTH production. Chronic ACTH elevation can lead to life‐threatening salt wasting and significant virilization. We hypothesize that blocking the ACTH‐MC2R interaction with a selective MC2R antagonist may provide a key new therapeutic option for these patients.We initiated an iterative medicinal chemistry program to identify potent and selective nonpeptide MC2R antagonists suitable for evaluation in clinical trials. Initial assessment consisted of equilibrium radioligand binding competition assays using [125I]ACTH(1‐39) to determine Ki and EC50 shift functional assays using ACTH(1‐24) to determine ΔpEC50 values. Select compounds were then characterized using a full Schild regression analysis to determine KB values and gain insight into mechanism. There was a strong correlation between the Ki and KB values for this class of small molecule.Our efforts identified CRN04894 as a highly potent MC2R antagonist (Ki = 2.1 nM, KB = 0.34 nM). The Schild regression data for CRN04894 was consistent with a competitive, orthosteric interaction with ACTH. The individual ACTH dose‐response curves with the addition of different concentrations of CRN04894 showed the same maximum response and slopes near unity, and the Schild plot had a slope not statistically different than unity. Furthermore, CRN04894 did not affect the dissociation rate of [125I]ACTH(1‐39) initiated by a saturating concentration of ACTH(1‐39), also consistent with an orthosteric interaction. Because CRN04894 appeared to bind the orthosteric site on MC2R, it was further tested in a kinetic radioligand binding competition assay using [125I]ACTH(1‐39) to determine its binding rate constants. CRN04894 rate constants are comparable to published values for other GPCR ligands with kon = 1.2 e7 M‐1 min‐1 and koff = 0.018 min‐1, corresponding to a dissociation t1/2of 39 min. The kinetic Ki (1.5 nM) calculated from the kon and koff is in accordance with the equilibrium competition binding Ki and Schild analysis KB. In addition, CRN04894 selectively blocks the ACTH‐MC2R interaction, showing no binding to MC1R, MC3R, MC4R, and MC5R at concentrations ≥ 1 µM. To our knowledge, this class of molecule represents the first reported potent nonpeptide MC2R antagonists, and CRN04894 is currently being evaluated in a first‐in‐human phase 1 clinical trial evaluating pharmacokinetics, pharmacodynamics, and tolerability in healthy subjects.