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Chapter 12: Health and Medicine

Homework assignment

From the end of chapter 12, questions 2,4,7,11,17,21,27,30,40.

How strong is an interaction between a target and a drug?

So far we have seen essentially non-reversible reactions, such as:

H+ + OH- è H2O

Some reactions are reversible, however, especially those that involve non-covalent interactions in biological systems:

A + B ↔ AB

What is the forward reaction?

What is the reverse reaction?

How is Keq determined?

What does Keq represent?

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How do receptor blockers work?•  Molecules that are designed to bind a

specific receptor should resemble the hormone that naturally binds that receptor.

•  The set of characteristics that determine the binding of drug to receptor is called the pharmacophores.

•  Affinity is one of the most important measurements of a drug binding to a target.

•  How is affinity measured? What would happen if a drug bound a receptor with a greater affinity than the natural substrate?

How are natural products used as drugs?Since the 4th century BC it was known that boiling the bark of the white willow tree (Salix alba) in water produces an awful-tasting tea with powerful medicinal properties. The concoction acts as an:• antipyretic (fever-reducing)• analgesic (pain-reducing)• anti-inflammatory (reducing redness, heat, pain, and swelling due to injury or irritation)

C

O

O

OH

C

O CH3

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Drug discovery: conversion of salicylic acid to aspirinreaction of a carboxylic acid with an alcohol yields an ester

C

O

O

OH

C

O CH3

+ H2O

C

O

O

OH

H

+C CH3

O

HO

Draw the expected reaction products of the following alcohols and acids:

1. CH3CH2OH + C CH3

O

HO

2. + CH3OHC OH

O

H3CH2C

How does aspirin work?

Hormones, our chemical messengers, are produced by the body’s endocrine glands.

Hormones encompass a wide range of functions and a similarly wide range of chemical composition and structure.

Enzymes are proteins and/or nucleic acids that act as biochemical catalysts, influencing (mostly accelerating) the rates of chemical reactions.

Aspirin works by inhibiting the cyclooxygenase enzymes COX1 and COX2. These enzymes participate in the prostaglandin synthesis pathway. Prostaglandins are responsible for fever, swelling, increased sensitivity of pain receptors, inhibition of blood vessel dilation, and the production of stomach acid and mucus.

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Two COX-2 Inhibitors

These COX2 inhibitors were thought to be potentially more effective than the non-selective COX inhibitors. This follows because COX1 produces prostaglandins that are responsible for maintaining kidney function and stomach lining maintenance, whereas COX2 produces prostaglandins that are responsible for inflammation, pain, and fever.In 2004, Vioxx was pulled off the market due to concerns about heart attacks and strokes.Total sales of Vioxx and Celebrex by 2003 were $5.4 billion, although their efficacy has not been shown conclusively.

Carbon-containing molecules (1): bonding and drawings•  Carbon obeys the octet rule, that is, it will normally share 8 electrons with other

atoms. This means that carbon can (and usually does) make 4 covalent bonds to other non-metal atoms.

•  Nitrogen typically makes 3 covalent bonds.•  Oxygen typically makes 2 covalent bonds.•  Hydrogen can only make 1 covalent bond.•  These bonds (except with hydrogen) can be any combination of single, double, and

triple bonds.•  Line drawings often replace structural formulas for brevity.•  Example: butane.

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Carbon-containing molecules (2): structural isomers

Because carbon atoms can make 4 covalent bonds, different arrangements of atoms is possible in molecules containing 4 carbons or more. Two molecules with the same numbers and types of atoms, but with different arrangements of these atoms, are called structural isomers.

What are 3 structural isomers of C5H12?

Functional groups (1)

In organic chemistry, functional groups are groups of atoms that are connected to carbon-containing molecules. Each functional group has a set of characteristic properties.Examples: alcohol, aldehyde, carboxylic acid, amine, amide. Also see Table 12.3 in the textbook.

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1. Name the functional group in each compound

a. CH3CH2CH2COH

b. CH3CH2CH(CH3)CH2OH

c. CH3CH(NH2)CH2CH3

d. CH3COOCH2CH3

Functional groups (2)

e. CH2OHCH3COOH

f. NH2CH2CH2OCH3

g. NH2CH2CONHCOCH2CONHCH2COOH

Functional groups and the activity of aspirin

What are the 3 functional groups in aspirin?

1. Benzene ring

2.

3.

In general , functional groups increase the polarity of the molecule. This has strong implications for the solubility of the molecule in cell membranes and inside the cell.The cell membrane is non-polar, whereas the inside of the cell is mostly water, which is polar.

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Pharmacophores are the portions of a molecule(s) that interact with the cellular target

A comparison of morphine and Demerol shows the pharmacophores of both molecules.

OxyContin (oxycodone)

Left- and right-handed molecules (1)

Chiral isomers have the same chemical formula, but they differ in the arrangement of atoms around at least one atom, which is called the chiral center.

Often, the chiral center is a carbon atom. For a carbon to be a chiral center, it has to have 4 different atoms (or groups of atoms) around it.

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Left- and right-handed molecules (2)

Biological systems often discriminate among chiral molecules, preferring one enantiomer over another. Amino acids and sugars have chiral centers, and living systems usually can use only one enantiomer, not both.Levomethorphan is an opiate. dextromethorphan is a non-addictive cough suppressant.

Left- and right-handed molecules (3)

Which is the chiral carbon in these molecules?

OH

O

4. Ibuprofen

Cl C

H

H

C

Cl

Cl

C

O

C

O

H

Cl

H 1. 2.C

Cl

C

Cl

H

Cl

Br

H

3. C

Cl

C

Cl

O

Cl

Br

H C

H

H

H

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Steroids (1)

The most abundant (and much maligned) steroid is cholesterol. It is made of 4 non-planar rings and a C3 hydroxyl group.

Steroids (2)Cholesterol functions as a precursor to steroid hormones.

Glucocorticoids affect many biological functions including inflammatory responses, mentalstress management, and carbohydrate, protein, and lipid metabolism. Example: cortisol.

Aldosterones and mineracorticoids regulate salt balance, includingexcretion of salts bythe kidneys.

Androgens and estrogens regulate sexual development and function.Examples: testosterone,β-estradiol (estrogen),progesterone.

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Steroids (3)

• Many diseases are associated with steroid malfunction. Cholesterol-related heart disease isan obvious example.

• Vitamin D is a cholesterol derivative. The various forms of vitamin D, especially D2 and D3, regulate calcium absorption from food. Vitamins D2 and D3 are formed by exposure to sun light (although sun light does not contain vitamin D), which triggers a non-enzymatic conversion of a cholesterol derivative into vitamin D precursors. These precursors then become hydroxylated, thereby activated, in the kidneys and liver.

• In the absence of adequate amounts of active vitamin D, calcium cannot be absorbed efficiently from the diet, and this results in a disease called rickets. Rickets is characterized by bone malformation, bone softness, and tooth brittleness.

• Excessive vitamin D can cause high serum calcium levels, which can lead to kidney stones,kidney failure, and calcification of soft tissue. It has been suggested that the increase in skin pigmentation in populations leaving near the equator is a protective mechanism against excessive absorption of vitamin D.

Anabolic SteroidsThese steroids are synthetic steroidal hormones used to stimulate muscle and bone growth.Side effects include mood swings, increase risk for strokes, heart attacks, liver-related issues, acne, development of breasts and testicular shrinkage in males, development of masculine body features in females, and lower sex drive.

These molecules are illegal for non-medical use, and banned by most sports organizations, although some athletes continue to take them.

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Herbal supplements, drugs of abuse

Herbal and dietary supplements are loosely regulated by the FDA. Current policy is that herbal supplements are safe unless the government shows otherwise.

OxyContin (oxycodone)

THC (delta-9-tetrahydrocannabinol)

MDMA: 3,4-methylenedioxy-n-methylamphetamine