Chemistry 6310 Advanced Topics In Organic Chemistry: The Organic Chemistry

Chemistry 6310 Advanced Topics in Organic Chemistry: The Organic Chemistry of Drug Development Fall Quarter 2009 Instructor: Dr. Anne Kotchevar Lectures: T, Th 6:00 – 7:15 PM Office: SC S 407 Phone: 885-3478 E-mail: [email protected] Office hours: M,W 9:30 – 10:30 AM, Th 2:00 – 3:00 PM Required Text: The Organic Chemistry of Drug Design and Drug Action 2nd Ed, Richard B. Silverman, Elsevier Academic Press, 2004. ISBN 0-12-643732-7 Course Objective: The goal of this course is to give you an insight into the various principles involved in modern drug design. Upon completion you should have a better understanding of how and why certain chemicals interact at biological targets and how to exploit these interactions to design better medicines. Prerequisite: It is assumed that you know all the material covered in a full year undergraduate organic chemistry course. As a result, things like stereochemistry, electron pushing, etc. will not be re-taught. You should refer to your organic text to review background aspects. Some background in biochemistry is helpful though not a necessity. It is also assumed that your course in organic chemistry covered the bioorganic compounds – amino acids, proteins, nucleic acids, and carbohydrates. It is highly encouraged that you review the following concepts from your undergraduate organic chemistry courses: Stereoisomerism Charge stabilization by both inductive and resonance effects The language of electron movement in describing chemical transformations The hydrogen bond, dipole-dipole, dipole-ion and van der Waals interactions The physical properties of the functional groups with special attention to their polarity and aqueous solubility The chemical definition of oxidation and reduction of alkanes, alkenes, alcohols, carbonyls and aromatic compounds The definition and role of a catalyst in terms of its effect on the reaction coordinate chemistry of a chemical transformation Acid-base chemistry and leaving groups The chemistry of carboxylic acids and their derivatives such as esters and amides The chemistry of amines and imines

If you have a documented disability and wish to discuss academic accommodations, or if you would need assistance in the event of an emergency, please contact me within the first week of class.

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Grading The grading for the course is based on an accumulation of points based on the exams and final paper as follows: Exams, 3@120 pts. each Final Paper

= 360 pts = 60 pts

Total

= 420 pts

Grades will be assigned such that students who earn approximately the same number of points earn the same letter grade. End-of-the-chapter questions and supplemental problem sets are suggested for you to practice your comprehension of the chapter material. They will not be graded or collected. Attendance will not be taken. However, you are responsible for all material discussed during lecture in addition to the readings assigned. There are no make-up exams. Documentation of a verifiable medical emergency must be provided to change a zero grade (missed exam). Late papers will have points deducted. You may not turn papers into the chemistry office. Exam and Assignments Schedule Exam 1:

Th 10/19 6:00 – 7:15 PM

Exam 2:

T 11/5

6:00 – 7:15 PM

Exam 3:

Th 12/3

6:00 – 7:15 PM

Final Paper:

Th 12/3

in class

The three exams are not cumulative although some concepts from the initial part of the course are needed to understand later concepts. A hard copy of the final paper is due on the last day of class. An electronic copy must also be submitted through Blackboard. Papers may not be turned into the Department Office. Grades for late papers will be deducted 10% per day. Alternative times to turn in papers should be arranged in advance. Important note on plagiarism/cheating: Students are expected to know and abide by the section on Academic Dishonesty in the University Catalog. In accordance with the policies outlined in the CSUEB University Catalog, plagiarism or cheating will result in an ‘F’ for the assignment or exam and the filing of an Academic Dishonesty Report (no exceptions).

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Final Paper The Final for this class will be a comprehensive paper in which you incorporate the concepts of drug design covered during the quarter. For your paper, you will choose a drug (not a drug class). Once you have chosen your drug, you must contact me. As you select your drugs, I will post your selection on Blackboard – no one else may then select your drug. If you wish to change your drug you must also contact me. You may not choose a drug already chosen by someone else, so check the list on Blackboard before spending too much time researching your topic. The following information should be included (use these as separate headings): Common name(s) and IUPAC name Therapeutic use (very brief) - What disease is the drug used for? Chemical structure and physical properties of the compound Mechanism of action - Does it bind to a receptor, an enzyme, or DNA? How does it bind? Metabolism - How is it broken down? What metabolites are formed? Your Future Plans - If you were given the job to make a series of modifications, what would you do? To do this you must identify the pharmacophore. This may be speculation but it should be supported with literature references. Draw three modified structures using ChemDraw and explain what affect you would expect each of the modifications to have using the principles we learned in class. Start by choosing a drug that you are genuinely interested in – for example: a drug you take or have taken, a drug a family member takes, a drug you have seen advertised, a drug targeting a disease you are interested in, etc. Then go to the reference section of the library. Look up your choice in drug reference books like the Physician’s Desk Reference or the Merck Index. This will give you some basic information and will make sure you know all the various names for the compound. You might also want to try the Internet for information to get you going. Then go to online databases like Medline or Web of Science and look up literature in scientific journals about your drug. Check under all the various names that you have for the compound. Compile promising citations to the primary literature (scientific journals), look them up, read them, and find the information you seek. All structures must be drawn using scientific software (i.e. ChemDraw). The paper should be about 6 - 8 pages, double-spaced, 1 in margins, 12 pt. font. About 10 references should be cited and the references must be journal articles, scientific publications, news publications, company publications, government documents, or reference books. Citation must follow the format of a standard American Chemical Society journal. No Web references allowed. Although this is not a class in English, I expect the papers to be written using correct grammar, spelling and punctuation. If you have difficulty with this, I suggest you make an appointment with the Writing Center (Student Center for Academic Achievement, LI 2550) on campus for help. Points will be deducted if the papers are not clearly and correctly written. The papers must be turned in as a hard copy to me in person on the last day of class (12/3) and as an electronic copy to the course Blackboard site.

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Tentative Schedule Date

Topic

Chapter

Th 9/24

Introduction, Lead Discovery, Design Approaches

1,2

T 9/29

Structure Modification

2

Th 10/1

Quantitative Structure-Activity Relationships (QSAR)

2

T 10/6

Lipinski’s Rules, Acid/Base Chemistry

2

Th 10/8

Combinatorial and Computational Approaches

2

T 10/13

Receptor-Drug Interactions

3

Th 10/15

Exam 1 (Chapters 1-2)

T 10/20

Drug-Receptor Binding Theories

3

Th 10/22

Drug Topography and Stereochemistry

3

T 10/27

Enzyme Background

4

Th 10/29

Drug Resistance, Drug Synergism

5

T 11/3

Reversible and Irreversible Inhibitors, DNA Background

5,6

Th 11/5

Exam 2 (Chapters 3-5)

6

T 11/10

DNA-Drug Interactions

Th 11/12

No Class

T 11/17

Phase I Metabolism – Oxidative Reactions

7

Th 11/19

Phase I Metabolism – Reductive Reactions

7

T 11/24

Phase II Metabolism

7

Th 11/26

No Class: Thanksgiving Holiday

T 12/1

Prodrugs Overview

Th 12/3

Exam 3 (Chapters 6-8), Final Paper Due

8

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Suggested Problems The end of the chapter problems are recommended to test your comprehension of the material and as a guide to study for the exams. They will not be collected, the answers can be found at the end of the book. Supplemental problem sets (also not collected) and their solutions will be posted on Blackboard. When working the problems you should avoid looking at the solution before trying to solve the problem yourself. Part 1 Chapter 2: 1, 3, 5, 6, 7, 8, 13, 15, 16, 17, 18 Supplemental Acid-Base Problems Supplemental QSAR and Hammett Equation Problems Part 2 Chapter 3: 1, 3, 4, 5, 6, 7, 8 Supplemental Stereochemistry Problems Chapter 4: 1, 2, 5, 7 Chapter 5: 1, 2, 3, 4, 7, 10 Part 3 Chapter 6: 2, 3, 4, 11, 12, 15 Chapter 7: 1, 2, 6, 7, 10, 11 Supplemental Metabolism Problems Chapter 8: 1, 2, 3, 6, 7, 9

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