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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: anne.kotchevar@csueastbay.edu
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 = 360 pts


Final Paper = 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 8
Th 12/3 Exam 3 (Chapters 6-8), Final Paper Due

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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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