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Organic Chemistry and Medicine A Sample Lecture from an Organic Chemistry Course Designed for Pre-Med, Nursing, and BiologyStudents Jason Dinsmore, Ph.D Facebook.com/OrganicChemistOnCall Design of Course A Few Common Observations… Organic chemistry is typically taught from a chemical point of view Organic chemistry is the one course EVERYONE has heard of and many DREAD taking Organic chemistry is usually a “make it or break it” class for pre-med students Does it have to be this way? ABSOLUTELY NOT!!! You can learn the same material that has been taught semester after semester at universities around the world but from a medical/biological point of view Organic Chemistry and Medicine Or·gan·ic \ȯr-ˈga-nik\ adj : 1. of, relating to, or arising in a bodily organ; 2. of, relating to, or containing carbon compounds; 3. relating to, being, or dealt with by a branch of chemistry concerned with the carbon compounds of living beings and most other carbon compounds Chem·is·try \ˈke-mə-strē\ n : a science that deals with the composition, structure, and properties of substances and with the transformations that they undergo Med·i·cine \ˈme-də-sən\ n : 1. a substance or preparation used in treating disease; 2. the science and art dealing with the maintenance of health and the prevention, alleviation, or cure of disease Organic Chemistry and Medicine MEDICINE ORGANIC CHEMISTRY History and Physical Exam Review Literature Differential Diagnosis Synthetic Strategy Order labs and Procedures Run Model Reactions Diagnose and Treat Synthesize Molecule Organic Chemistry and Medicine The format of the lectures will be as follows: Presentation of Case Study - Ex. 24 year old female presents to the ED with… Discuss Functional Group(s)/Reaction(s) - How this functional group/reaction(s) relates to the disease Organic Chemistry and Medicine Medicine Organic Chemistry and Medicine Biology Organic Chemistry and Medicine Organic Chemistry Organic Chemistry and Medicine Medicine Organic Chemistry Case 1 A 30-year-old man is evaluated in the emergency department for complications of difficulty breathing, chills, and chest pain for the past 24 hours. He denies any previous history of medical problems. On physical examination, he appears ill. His temperature is 40°C (104°F), his blood pressure is 90/50 mm Hg, and his heart rate is 110/min. Cardiac examination reveals a 3/6 diastolic murmur; however, the patient denies any history of a murmur. ECG results are normal. Diagnosis: Acute Endocarditis How does this case relate to organic chemistry? Treatment of Endocarditis PENICILLIN CEFTRIAXONE VANCOMYCIN AMPICILLIN GENTAMICIN NAFCILLIN OXACILLIN Penicillin R H N O O S N O OH b-lactam structure is involved in the mechanism of action Penicillin Mechanism of Action Penicillin Binding Protein - PBPs are all involved in the final stages of the synthesis of peptidoglycan, which is the major component of bacterial cell walls. - Bacterial cell wall synthesis is essential to growth, cell division (thus reproduction) and maintaining the cellular structure in bacteria. - Inhibition of PBPs leads to irregularities in cell wall structure such as elongation, lesions, loss of selective permeability, and eventual cell death and lysis. Penicillin Mechanism of Action H2N H N R O OH S O N O OH O H H N N O O R R H H N N O O OH OH R R S S OH OH Ser Ser NH NH SS O O O O N N O OO O O O O O R R H H N N O O N N OH O O OH OH Ser Ser Nucleophilic Attack on the Cyclic Amide Carbonyl Carbon SS HN HN O O O O OH OH The Chemistry of Amides R R O O O O H H R R H H N N O O H H O O NH NH O O O O S S N N O O OH OH Ser Ser S S HN HN O O O O OH OH NH22 NH O O Biology sets the reaction up perfectly; however, this is not the case in a chemistry laboratory…. The Chemistry of Amides R R H H N N O O O O S S N N O O OH OH O O O R Cl O O R O R R Formation Formation R O O R R OH OH Reactions Reactions NH22 NH R NH NH22 R O R R C C N N R OR' OR' 11H 13 NMR, 13 C NMR, NMR, IR, IR, MS MS H NMR, C The Formation of Amides H++ R C N + H22O OH R C NH O R C NH22 Nitrile CH33 O C Cl + 2 NH33 CH33 O C NH22 CH33 O C NH22 + CH33 CH33 O C NH22 + HO CH2CH33 + NH44+ Cl-- Acid Chloride CH33 O C O O C CH33 + 2 NH33 O + C O-- NH4 Anhydride CH33 O C O CH22CH33 + Ester NH33 Mechanisms CH CH33 O O NH33 C C Cl Cl ++ 22 NH CH CH33 O O C C NH NH22 ++ NH NH44++ Cl Cl-- NH NH33 CH CH33 O O C C Cl Cl H H CH CH33 NH NH33 O O C C Cl Cl NH NH22 CH CH33 NH3 H CH3 C NH3 H O Cl NH22 H O H O C NH33++ Cl Cl-C NH NH22 ++ NH CH3 O C Cl NH 2 Halides are great leaving groups Mechanisms H++ R C N + H22O OH R C NH O R C NH2 H++ R C N H2O H+ R C N H O H H R C N H O H H++ R C N H O H H H R C N H H O H Regenerated acid catalyst H R C N H O 13C NMR and IR 13C NMR spectra Carbonyl carbon: 180 ppm Alkyl carbon: 20 ppm of Amide IR spectra Carbonyl group: 1700 cm-1 N-H group: 3200 cm-1 - Physicians obtain laboratory values and perform diagnostic tests - Organic chemists obtain spectroscopic data and perform model reactions The Chemistry of Amides What compounds can we make from the amide functional group? The Chemistry of Amides CH33 O C NH22 HCl + CH3 H22O O C OH + NH4++ Cl- Carboxylic acid CH33 O C NH22 CH33 O C NH22 + 1. LiAlH4, Et22O 2. H22O Br2 CH33 CH22 NH22 Amine + 2NaOH CH33 NH22 + Amine CO2 Stability of Amides O O R R O O N N H H H H O O H H H H R R O O R R R R NH NH NH22 NH H H NH2 NH Less electrophilic that other carbonyl functional group Amides and Amino Acids O H2N CHC OH R O H22N CHC OH CH33 Alanine O H2N O H22N CHC OH CH22 CH22 CH22 NH C NH NH22 Arginine OH R O H22N CHC OH CH22 CH22 CH22 CH22 NH22 Lysine Amides and Amino Acids Penicillin Binding Protein O O O O O O N CH C NH CHC NHCH C OH OH H22N CH33 CH22 CH22 CH22 CH22 CH22 CH22 NH NH CH22 NH NH NH22 C NH NH NH22 G-coupled Protein Receptor Na/K Channel