MEDICINAL CHEMISTRY

MEDICINAL CHEMISTRY

Type|Type of Course: YP | BACKGROUND

Teaching Semester: 1st Semester

Hours per Week: 6 Hours

Total Time (Teaching Hours + Student Workload) 149 Hours

Prerequisites: NO

Language of Instruction: Greek

Available for Erasmus: YES

Semester Lectures:Details/Lectures

Teaching Method:

Evaluation Method:

The language of student assessment is English.

Evaluation methods.

A. In the laboratory exercises: Laboratory Work, Reference, Online Exams with multiple choice, true-false, matching, layout questions.

The students' participation in the exercises as well the written report of the results of the exercises, which is done by the students during the workshops, is mandatory. The report includes the measurements (presented in tables and plots), and the conclusions (eg whether the expected results were obtained, if not why not, sources of possible errors in the experiments) as requested by each exercise. At the end of each exercise, the written report is checked by the teachers and signed if it has been filled in correctly. In the event that particularly demanding calculations or diagrams need to be made, it is possible for the report to be completed after the end of the workshop and delivered to the lecturers at a later predetermined date. Successful participation in the exercise is certified by the teacher's signature on the written report of the results.

At the end of the semester, students are examined online in the content of the Workshops. On Laboratory exams material to be examined is the theory, methodology and methods of processing results included in the Laboratory Exercises Guide or developed by the teachers during the laboratories and the corresponding ones tutorials. Only those who successfully participated in the laboratory exercises have the right to participate in the Laboratory exams. Passing the laboratory exams is a necessary condition for participation in the course exams.

B. In theory – lecture material: Written Exams with free development, multiple choice, true-false, matching questions.

Course exams are written, 2 hours long, and consist of free-form, multiple-choice, true-false, matching questions (examples will be available in the course recap tutorials). Examinable material is the material of the lectures as described above.

Only those students who have passed the Laboratory exams have the right to participate in the course exams.

Final grade

The final grade of the course is formed by the grade contribution of the laboratory (20%) and theory (80%) with a prerequisite performance in theory 50%.

All of the above can be accessed by the students as they are contained in the Course Guide that is distributed to all students in print, and is posted in the e-class.

Objective Objectives/Desired Results:

Course URL :https://eclass.uth.gr/courses/MED_U_169/

Course Description:

The content of the "Medicinal Chemistry" course is structured as follows:
A. The lecture material they need to know and the theoretical clinical skills students need to acquire in order to succeed in the course. Each chapter describes the examined material - "what they should "know well" as well as the relevant knowledge aimed at the wider education of the student as a scientist - "what they should have heard".
B. The practical and clinical skills that students must acquire for their attendance to be considered successful.

A. Analytical material and theoretical clinical skills
I. By theory chapter (Lecture material)
Unit 1. PERIODIC TABLE – ELEMENTS OF BIO-INORGANIC CHEMISTRY
What students should know well:
• Periodic properties of the elements and the relationship of these properties with the electronic configuration of the atom: ionization energy, electron affinity, electronegativity, size of atoms, size of ions, redox properties.
• Oxidation-reduction reactions, oxidation state, redox and biological systems, membrane potential.
• Periodic table from a medical point of view: basic and trace elements of the human body. Toxic trace elements and examples of their effect on human health
• Life-giving elements and their selection by nature. Relevance of the biological role and chemical properties of the vital elements.
• Examples of the involvement of trace elements in certain pathological conditions. Element deficiency and excess.
What students should have heard:
• Law of periodicity according to Mendeleev and according to Mosley and its relationship with the electronic structure of the atom.
• Toxic trace elements and environmental contamination problems.

Unit 2. CHEMICAL BONDING AND NON-HOMEPOLAR INTERMOLECULAR INTERACTIONS
What students should know well:
• Chemical bonds – Theory of molecular orbitals. Sigma and pi bonds.
• Hybridization of atomic orbitals and stereochemical structure of molecules.
• Dipole, dipole moment, induction dipole, polarity of the molecule.
• Non-covalent interactions and their nature: Van der Waals forces, London, hydrogen bonding. The role of non-covalent interactions in biomolecules.
What students should have heard:
• Electronic structure for the homonuclear diatomic molecules of the 1st and 2nd periods. Bond class.
• Physico-chemical and pharmaceutical properties of chemical compounds and non-covalent interactions.
• Non-covalent interactions and the action of drugs.

Unit 3. COMPLEX ASSOCIATIONS AND COMPLEX THERAPY
What students should know well:
• Definition of complex compounds or splicing compounds.
• Substituents (ligands), polyactive/ monoactive/ chelating substituent and chelating complexes.
• Stability of complexes. Stability of complexes based on the theory of hard and soft acids and bases.
• Stability of chelate compounds.
• Examples of biologically important complexes: iron complexed to heme, carbonic anhydrase.
• Complex therapy (chelation therapy) and the pathological conditions applied. Complexing agents used in complex therapy and corresponding pharmaceutical preparations.
What students should have heard:
• Nature of bonding in complexes: bond-valence theory, crystal field theory.
• Spectroscopic and magnetic properties of the complexes and their interpretation based on bond-valence and crystal field theories.
• Stereochemical structure of the complexes

Unit 4. ACID-BASE BALANCE AND REGULATORY SYSTEMS OF THE BODY
What students should know well:
• Properties of electrolytic solutions.
• Electrolytes of the extracellular and intracellular fluid.
• Lewis acid-bases.
• Blood pH and its fluctuations.
• Buffers, buffer capacity.
• Henderson-Hasselbalch equation and preparation of the buffer solutions.
• Blood regulatory systems.
• Effects of CO2, HCO-3 and H2CO3 on blood pH.
What students should have heard:
• Ionization and absorption of drugs

Section 5. DISTRIBUTION SYSTEMS
What students should know well:
• Dispersion systems: mixtures, colloidal systems, solutions.
• Solubility, unsaturated, saturated and supersaturated solutions. Ways of expressing concentration.
• Hydrophilicity / hydrophobicity / lipophilicity of chemical compounds and prediction of these properties from the study of the chemical structure of the compound. Hydrophilic functional groups.
• Additive properties of solutions: osmosis. Hypotonic, isotonic and hypertonic solutions. Plasmolysis and hemolysis.
• Colloid systems: aerosol, emulsion, suspension.
• Colloid systems in water: hydrophobic and hydrophilic colloids. Colloid thrombosis and its mechanisms.
• Increasing water solubility of a xenobiotic substance as a way to detoxify the body.

Unit 6. INTRODUCTION TO ORGANIC CHEMISTRY
What students should know well:
• Marital systems.
• Electronic phenomena and distribution of the electronic cloud in molecules: Inductive (I) and conjugate (R) effect. Coordination.
• Classification of reactions and reagents in organic chemistry. Nucleophilic and electrophilic reagents, free radicals.
• Reactive oxygen compounds, oxidative stress and human health.
• Functional groups of organic compounds and their role in the design of new drugs.
What students should have heard:
• Carbanions and carbocations
• Basic steps in the development of new drugs: identification of initial bioactive structures (hit compounds), transition to lead compounds

Section 7. STEREOCHEMISTRY OF ORGANIC COMPOUNDS
What students should know well:
• Stereochemistry and stereoisomerism.
• Mirror image isomers / enantiomers / optical antipodes
• Chiral/ achiral compounds
• Asymmetric (chiral, stereogenic) center
• Optical activity, (+) – right-handed and (-) – left-handed enantiomer.
• Racemic mixture, racemization.
• Views against Fischer
• Description of the absolute stereochemical structure of the enantiomers with symbols D,L.
• Stereotype description of the chiral centers of the molecule according to the CHAN-INGOLD-PRELOG rules and RS symbols.
• Diastereoisomerism, mesoforms.
• Geometric isomerism : CIS – TRANS, ZE, priority of substituents.
• Mechanisms of SN1, SN2 nucleophilic substitution reactions.
What students should have heard:
• Special rotational capacity.
• Separation and isolation of enantiomers.
• Thalidomide case – typical example of a substance whose two enantiomers exhibit completely different pharmacological activity.
• Stereoselectivity of enzymes.

Section 8. HYDROCARBONS-AROMATIC COMPOUNDS-STEROIDS
What students should know well:
• General properties and most important reactions of hydrocarbons. Electrophilic addition reactions, hydrogenation, hydrogenation, hydration of unsaturated hydrocarbons.
• Aromatic hydrocarbons: aromatic character, HUCKEL's rule. Electrophilic substitution – characteristic reaction of aromatic hydrocarbons.
• Examples of hydrocarbons in biological systems.
• Resonance energy, aromatic stabilization.

Section 9. SIMPLE OXYGEN, SULFUR & NITROGEN COMPOUNDS
What students should know well:
• Alcohols: properties (water solubility, acidity), production (by reduction of aldehydes, ketones, by hydration of alkenes), reactions (oxidation, dehydration, esterification, nucleophilic substitution).
• Phenols: Properties: water solubility, acidity
• Thiols: properties (water solubility, acidity), reactions (mild and strong oxidation), disulfide bond and its biological importance.
• Sulfonic acids and the derivatives of 4-aminobenzenesulfonic acid – the sulfonamide drugs.
• Aliphatic amines: primary, secondary, tertiary. General properties – their basic character. Characteristic reactions.
• Aromatic amines: general properties and the comparison of their properties with the properties of aliphatic amines.
• Aliphatic quaternary ammonium salts.
• Amides. Imines, amino alcohols.

Section 10. CARBONYL COMPOUNDS & CARBOXYLIC ACIDS
What students should know well:
• Carbonyl physicochemical properties, polarizability, electrophilic and nucleophilic attack
• Enol – ketone tautomerism, tautomers.
• Nucleophilic addition reactions. Hemiacetals, hemiketals, acetals, ketals. Condensation reactions with amines (R-NH2). Imines – Schiff's bases.
• Aldol condensation.
• Ketoacids, urinary ketones, ketoacidosis. Causes of ketoacidosis and ketonuria.
• General properties of carboxyl group: ionization, coordination.
• Acyl derivatives of acids: acyl halides, anhydrides, esters, amides.
• Mechanism of formation and hydrolysis of carboxylic acid esters.
• Dicarboxylic acids, hydroxy acids, ketone acids and unsaturated acids: Special properties and members of biological interest.
What students should have heard:
• Toxic effect of formaldehyde and acetaldehyde, treatment of poisoning with methanol (wood alcohol).

Section 11. HETEROCYCLIC COMPOUNDS – NUCLEOTIDES
• Definition of heterocyclic compounds.
• Five-membered heterocyclic compounds with one heteroatom and their derivatives: pyrrole (proline, porphyrin), imidazole (histidine), thiophene (biotin). Chemical properties: aromaticity, participation in nucleophilic or electrophilic substitution reactions, acid-base properties.
• Five-membered heterocyclic compounds with two heteroatoms: imidazole and its derivatives histidine and histamine, thiazole (thiamine – vitamin B1)
• Heterocyclic compounds with one heteroatom and their derivatives: pyridine (NAD+, NADP+, pyridoxal). Chemical properties of pyridine: aromaticity, participation in nucleophilic or electrophilic substitution reactions, acid-base properties.
• Heterocyclic compounds with two heteroatoms and their pyrimidine derivatives (uracil, thymine, cytosine).
• Condensed heterocyclic rings and their derivatives: indole (tryptophan), purine (adenine, guanine), isoalloxazine (riboflavin, FAD, FMN), pteridine (folic acid).
• Structure and properties of nucleosides and nucleotides

Unit 12. STRUCTURE AND BIOLOGICAL ROLE OF AMINO ACIDS AND PEPTIDES
What students should know well:
• Biological functions of amino acids
• Common chemical structure, stereochemistry, common chemical properties, ionization
• Chemical structure of the 20 proteinogenic amino acids: Hydrophobic, Polar, Charged
• Essential amino acids, amino acid modifications & derivatives
• Spectroscopic properties and biologically important reactions
• Detection & analysis
• Peptides & peptide bond, important peptides
What students should have heard:
• Diagnostic value of amino acid analysis

Section 13. STRUCTURE AND BIOLOGICAL ROLE OF PROTEINS
What students should know well:
• General functions of proteins
• Molecular interactions that determine protein structure and function
• Levels of molecular organization
• Primary structure
• Physicochemical properties – Solubility
• 3D Structure – Limitations
• Secondary structure: α-helix, β-fold, turns & loops
• Tertiary structure
The role of hydrophobic interactions
The example of myoglobin
The role of disulfide bonds
• Quaternary structure
• Protein structure representation
• Experimental determination of protein structure
• Protein folding
The experiment of C. Anfinsen
The role of amino acids, Cumulative selection, Molecular chaperones
Fatal errors: Amyloidosis, encephalopathies, prion diseases
The student who will attend the course should have heard
• for the Rachamandran diagram and the possible values of the angles φ and ψ of the peptide bond
• for the super-secondary structures (motifs) and structural domains of proteins
• for intrinsically unstructured & metamorphic proteins
• for protein information banks
• for protein folding models and computational methods

Unit 14. STRUCTURE AND BIOLOGICAL ROLE OF CARBOHYDRATES & LIPIDS
What students should know well:
• Basic chemical structure, functions, classes and stereo-isomerism of carbohydrates
• Common monosaccharides:
Circular structures & polystorfism
Reducing sugars, Glycated hemoglobin
Exogenous derivatives
• Glycosidic bond
• Common disaccharides
• Polysaccharides: Starch/Glycogen, Cellulose, Chitin
• Glycoproteins, Proteoglycans, Glycosaminoglycans, Glycolipids
• Biological role & Classes of lipids
• Fatty acids: Chemical structure, properties, Nomenclature
• Triacylglycerols: Chemical structure, properties
• Phospholipids: Chemical structure, properties of Phosphoglycerides & Sphingolipids
• Glycolipids & Ethereal lipids
• Steroids: Cholesterol & derivatives, Vitamin D
The student who will attend the course should have heard
• for lectins
• for blood groups

Unit 15. CHEMICAL THERMODYNAMICS AND CHEMICAL EQUILIBRIUM
What students should know well:
• What questions does chemical thermodynamics answer?
• Enthalpy, entropy and free energy of a chemical or biochemical reaction. Work and free energy. Standard free energy. Exothermic / endothermic reaction. Exergonic / endergonic reactions
• Equilibrium constants of a reaction. Factors affecting the equilibrium constant – VAN'T HOFF equation.
• Free energy and equilibrium constant ΔGo = – RT ln Kequor
• HESS's law, LE CHATELIER's principle.
• Coupling of chemical and biochemical reactions. What is a chemical intermediate and its role in coupling?
• Experimental determination of enthalpy, entropy and free energy
The student who will attend the course should have heard
• Open, closed and isolated thermodynamic system.
• Statistical interpretation of entropy.
• Chemical potential.

Unit 16. CHEMICAL KINETICS – MECHANISMS OF CHEMICAL REACTIONS
What students should know well:
• Rate of chemical reactions, rate law, order of the reaction.
• Zero, first and second order reactions and their mathematical description with differential or integral equations. Half-life (double doubling) time and initial concentration dependence.
• Molecularity of chemical reactions.
• Theory of molecular collisions. Activation energy of a reaction. Arrhenius equation. Examples of nucleophilic - electrophilic reactions.
What they must have heard:
• Experimental determination of velocity law. Relationship between rate law and mechanism of a chemical reaction.
• Experimental determination of activation energy and the rate constant of a chemical reaction.
• Parallels of chemical kinetics and pharmacokinetics.

Unit 17. ENZYMES AND KINETICS OF ENZYME REACTIONS
What students should know well:
• General characteristics, clinical applications, function, enzyme cofactors
• Classification & Nomenclature of enzymes
• Thermodynamics & Transition state Enzyme reaction
• Enzyme Active Center: Characteristics, Models, Binding Energy
• The steady state model in enzyme kinetics
• The Michaelis-Menten equation
• The importance of Vmax, KM and the Michaelis-Menten curve
• Vmax and KM values, Conversion number, Specificity constant
• Experimental determination of Vmax and KM
• Double inverse chart
• Physiological Significance of Vmax and KM: Alcohol Sensitivity, Fate of Glucose, Diagnosis – Treatment

Section 18. REGULATION OF ENZYMES
What students should know well:
• Basic principles of enzyme activity regulation:
• Allosteric regulation:
Characteristics of allosteric enzymes
V vs [S] sigmoid curve, Two forms (R and T), Models
Allosteric modifiers
Synergistic properties
Feedback inhibition
Catalytic/Regulatory subunits
• Isoenzymes
• Regulation by covalent modification
• Proteolytic cleavage – Zymogens

Section 19. CATALYTIC MECHANISMS AND ENZYME INHIBITORS
What students should know well:
• Basic principles of catalysis
Equivalent, General acid-base, metal ion, with approx
• Effect of temperature and pH
• Enzyme inhibitors
Types of inhibition and motor discrimination
Inhibitors as tools to study enzymes
Inhibitors as drugs
• Serine protease catalysis strategies
Chymotrypsin, Trypsin, Elastase
Specificity, Role of active center serine, Catalytic triad
Tetrahedral transition state
• Catalysis strategies of other proteases
• High speed enzymes: Carbonic anhydrases
• Enzymes with high specificity: Restriction endonucleases

II. In compulsory schools: example-based learning

Section Φ1. INSTRUMENTAL ANALYSIS
What students should know well:
• Visible and ultraviolet spectroscopy – physicochemical basis of the method. LAMBERT – BEER law. Molar absorption coefficient. Principles of qualitative and quantitative analysis using visible and ultraviolet spectroscopy: standard solutions, instrument calibration, reference curve.
• Chromatography – physicochemical basis of the method. Gas and liquid chromatography. Distribution, ion exchange, gel chromatography. Examples of applications in clinical chemistry and the study of proteins.
• Mass spectroscopy – physicochemical basis of the method, its role in combined chromatography-mass spectroscopy techniques. Examples of applications in clinical chemistry/biochemistry and toxicology.
• Evaluation of measurements and results: precision, repeatability, random and systematic errors.

Section Φ2. PROTEIN ANALYSIS METHODOLOGY
What students should know well:
• the basic principles of protein isolation, purification and analysis methods: differential centrifugation, fractional sedimentation, dialysis, thin layer chromatography, column chromatography, electrophoresis, isoelectric focusing, ultracentrifugation, mass spectroscopy.
• Electrophoresis, physicochemical basis of the method and application examples.
• the basic principles of amino acid sequencing methodology
• the basic principles of immunological techniques used in protein analysis (ELISA, immunoblotting, immuno-fluorescence microscopy).
The student who will attend the course should have heard
o for the definition and importance of the proteome and its relationship with the genome
o about the basic structure and properties of antibodies
o on the importance and method of preparation of monoclonal antibodies
o for the methodology of structure determination by X-ray crystallography and NMR.

B. Practical and clinical skills
In compulsory workshops: learning based on practical experience
Acquisition of general and specific practical skills by the medical students during the preparation
of laboratory exercises:
1. General skills
• observation of phenomena in the laboratory, recording and analysis of data
• drawing conclusions from data
• solving practical problems
• building graphs from data
• extracting information from graphs
• handling basic equipment of Medical Chemistry laboratories
• effective team work
• safe work in a laboratory environment
• receiving and following instructions
• perception of laboratory errors and identification of their sources
2. Special skills
Exercise 1: Spectroscopy – UV-Vis Spectrophotometry
Quantification and analysis of substances by spectrophotometry
Exercise 2nd: Buffer solutions – Titration
Quantification and analysis of substances by titration, Preparation and evaluation of buffer solution
Exercise 3rd: Chromatography-Chromatographic analysis of proteins and amino acids
Separation and analysis of protein and amino acid samples by chromatography
Exercise 4th: Analysis of amino acids & proteins
Analysis of protein samples by SDS-PAGE electrophoresis, study of the effect of pH and temperature on protein solubility.

Recommended reading:

A. COURSE THEORY

Recommended books:

• Berg JL, Tymoczko JM & L. Stryer: BASIC PRINCIPLES OF BIOCHEMISTRY, PASCHALIDIS PUBLICATIONS.
• Karen Timberlake: "Chemistry - An Introduction to General, Organic, and Biological Chemistry" Key Editions.

Other writings:

• Notes from deliveries – Posted on e-class.
• A. Tsakalov "Medicinal Chemistry in questions and answers" - Posted on the Kallipos platform (https://www.kallipos.gr/el/).
• Varvoglis A. G. Epitomized organic chemistry, Ziti Publications.
• GA TAYLOR Organic Chemistry for Medical and Biological Sciences.

B. LABORATORIES

Guide to Laboratory Exercises in MEDICINAL CHEMISTRY, H. Mylonis, A. Tsakalov, S. Bonanou-Tzedakis, G. Simos