CHEM 217 - History of Modern Medicinal Chemistry and Drug Development Instructor: Dana Lashley This course was designed to be taught as part of the W&M Study Abroad program at Cambridge University in the United Kingdom. Due to cancellation it is now offered as an on-Campus COLL 300 class. This course can also alternatively satisfy the COLL 200 requirement (NQR looking out to the CSI domain). Class time: MTWRF between July 6th and August 7th. This class is taught synchronously or LIVE at 12.20-1.50pm. There is no class on SOME Fridays. Please see schedule further below! Introduction: It’s not just the Germans! In the early days of the 19th century, many major concepts in the realm of organic chemistry were undoubtedly coined by German scientists. Perhaps the most notable of these was Wöhler’s laboratory synthesis of urea, which disproved the long-standing belief that organic compounds could only be made inside of living organisms. Or maybe it was the spectacular discovery of the structure of benzene by Kekulé, which famously came to him in a dream. In the modern-era organic and medicinal chemistry of the 20th and 21st century however, there have been countless groundbreaking contributions from scientists across the United Kingdom. The discovery of the Citric Acid Cycle by H.A. Krebs at the University of Sheffield, and the discovery of the very first antibiotic drug Penicillin-G by Alexander Fleming in London in the early 20th century are just two examples. The list is as impressive as it is endless, but amongst all of these, what could be more awe-inspiring than the elucidation of the structure of our hereditary material, DNA? This was an achievement that revolutionized the entire field of biochemistry. Furthermore, it is a discovery with a direct connection to the city of Cambridge. Rosalind Franklin was a pioneer female scientist who studied chemistry at the University of Cambridge and received the equivalent of a B.A. in 1941. She went on to work at King’s College in London where she obtained the first X-ray images of DNA. These images were, without her knowledge or permission, used by Watson and Crick in their discovery of the DNA double helix structure in 1953. At the time of this discovery Watson and Crick worked at the Cavendish Laboratory, located in Cambridge. The unraveling of the molecular structure of DNA is considered not only a turning point in biochemistry but also a milestone in the history of mankind. In 1962 Watson and Crick received the Nobel Price in Physiology or Medicine for their work. Franklin died a few years earlier and was not included in the award. Objectives: In this course students will explore modern-era groundbreaking discoveries in the field of Medicinal Chemistry and Drug Development. Highlights will be the discussion of Alkaloid Natural products such as Morphine and Cocaine, Fleming’s discovery of Penicillin G and the elucidation of the structure of DNA as well as the historical and medicinal consequences of these events for mankind. Specifically highlighted, because of timely relevance, will be antiviral drugs and the novel Coronavirus. Students will also become familiar with terminology in the field of medicinal chemistry and pharmacology as they will learn about different classes of drugs and important techniques in toxicology and pharmacology. The course will begin by briefly looking at ancient medicine of the antiquity and middle-ages before highlighting the modern-era discovery of groundbreaking drugs and medicinal practices and culminate with an outlook on both industrial and academic research structure. The processes governing modern day pharmaceutical drug development and the different phases of clinical research will also be discussed in this context. Since the course was supposed to be taught as part of a Study Abroad program in Cambridge, discoveries in the United Kingdom will certainly be emphasized to give students context to their visiting environment. However, drug discovery and development of other leading European countries such as Germany will also be highlighted and explored. Prerequisites: The course has a pre-requisite of Organic Chemistry 1, as this would facilitate students’ understanding of the drug structure and actions. Textbook: none ! Any class readings will be handed out or posted on Blackboard. This will include scientific journal articles that pertain to the NQR domain, as well as book excerpts and articles pertaining to the CSI content. Planned lessons: (this is very ambitious ! In reality, we may not get past topic 15…) 1. Introduction to Medicinal Chemistry: What are Drugs and Natural Products? 2. The drugs of Antiquity: Ancient natural pharmaceuticals from herbs, plants, roots, vines and fungi used in traditional Egyptian, Greek, Roman, Indian and Chinese Medicine (~3000 BC - 19th century) 3. Alkaloids with emphasis on Morphine, Cocaine and Atropine. Also discussion of Opioids (Morphine, Codein and synthetic derivatives such as Heroin). Also: Opioid crisis, Substance Abuse and treatment. 4. The rise of the Pharmaceutical Chemistry and Pharmacology and the first synthetic drugs (1869 onward). Chloroform, chloral hydrate, bromide salts, paraldehyde and urethanes 5. Barbiturates (1903 onward) with focus on Veronal, Luminal, Vesparax and Thiopental. Use as sedatives, hypnotics, sleeping aids, anesthesia and use in capital punishment. 6. Introduction to FDA law: Controlled substance laws for Narcotics and other drugs. 7. Introduction to pharmacology and toxicology. Determination of the median lethal dose LD50 and the median effective dose ED50 8. The first Analgesics and Antipyretics and the role of synthetic dyes such as mauveine by British chemist Henry Perkin (1838-1907). Emphasis on Acetaminophen (Tylenol) and Aspirin 9. Discovery of the Structure of DNA (Watson, Crick and Franklin 1953). Nucleoside and Nucleotide nomenclature. 10. Viruses and Nucleosidic Anti-Viral Drugs – Highlighting the novel Coronavirus and Covid-19 as well as Ebola. 11. Discovery of Penicillin (Alexander Fleming 1929) and other classes of Antibiotics 12. Depression and anti-Depressive drugs. 13. Schizophrenia and Anti-Psychotic drugs (Neuroleptics) 14. Steroids and the development of the Contraceptive Pill (1950s Carl Djerassi) 15. Student Presentations on select topics Potential additional lessons if we have time: 16. Peptide drugs with focus on Oxytocin and Insulin. Intro to Bioengineering. 17. Modern rationale design drug development and clinical trials 18. Ethics of Animal testing 19. Blockbuster drugs and Pharmaceutical companies Week 1: Intro on Monday. Lectures Tue-Thu. Friday: intro to literature research and scientific citations. Week 2: Lectures Mon-Thu. Friday: individual discussion of Natural Product Paper or Student Presentation ideas. By appointment only. No traditional class is held Friday! Week 3: MUST HAVE PRESENTATION TOPIC PICKED AND APPROVED BY Monday July 20th! Lectures Mon-Thu. Friday: individual discussion of Natural Product Paper or Student Presentation content! By appointment only. No traditional class is held Friday! Week 4: Student presentations Mon-Fri. Natural Product paper due on Friday, July 31st! Week 5: Student presentations continued Mon&Tue. Lectures Wed&Thu. FINAL EXAM Fri, Aug 7th. Assessments Students final grades will be determined according to the below assessments: 30% (Group or Solo) Presentation on Select Med. Chem Topic 25% Natural Product Paper 25% Final exam 20% Participation (Group or Solo) Presentation. Students will prepare a 15 minute presentation on a select medicinal chemistry topic in the last two weeks of the semester. Topic choices must be made by mid-semester and the selected topics must be approved by the instructor. Optionally you may decide to work in groups of two and present on the same topic. In that case each student should present for 15 minutes. The presentation should capture both the scientific importance (NQR) and the historical and cultural context of the topic, thereby integrating the CSI domain. Natural Product Paper. Students will select a Natural Product of choice and write a literature review through researching and critically evaluating of primary literature. Detailed criteria and instructions for the paper will be posted on BB and also handed out on the first day of class. This paper is due by July 31st on 23.59pm (electronic submission on Blackboard). You may turn the paper in at any time during the semester and do not have to wait until the deadline. Final exam. The cumulative final exam will assess the students understanding of lecture and reading topics. This exam will be the major means of assessment for the NQR domain and will include drug structure, nomenclature, mechanism of action and pharmacological calculations. The historical and cultural contexts (CSI) of drug discovery as highlighted in lecture will also be subject to the exam. The Final exam is on Friday, August 7th. The Final Exam will be proctored using Honor Lock. Participation. Students are expected to attend class and actively participate by engaging in discussions. Moreover, students are expected to apply their critical thinking skills when presented information and ask questions to seek clarification. This goes both for lectures as well as after student presentations. During group presentations students will be asked to assess their peers’ presentations based on a set of given criteria on a handed out form. Final Grades: A-/A 90-100% Excellent performance and mastery of the material B-/B/B+ 80-89.99% Very good understanding of the material C-/C/C+ 70-79.99% Adequate performance D-/D/D+ 60-69.99% Poor performance F below 60% Unsatisfactory performance Inclusion and Diversity: I value all students regardless of their background, country of origin, race, religion, ethnicity, disability status, sexual orientation or gender identity. I am committed to providing a climate of excellence and inclusiveness within all aspects of this course. If there are aspects of your culture or identity that you would like to share with me as they relate to your success in this class, I am happy to meet to discuss.