Transcript Precursor chemicals

SECTION 13.2 DRUGS
(BOOK 3B, CHAPTER 36)
1
SYLLABUS FOR CONSIDERATION
2
SYLLABUS FOR CONSIDERATION (12.6)
3
OVERVIEW
Drugs and medicine – an introduction
 Key stages of drug development
 Some common drugs
 Dangerous drugs
 Chiral drugs

4
OVERVIEW
Drugs and medicine – an introduction
 Key stages of drug development
 Some common drugs
 Dangerous drugs
 Chiral drugs

5
DRUGS AND MEDICINE
Drugs: chemical substances producing
physiological effects on human body
 Often act by altering a range of biological
processes
 Carefully researched, monitored by doctors or
pharmacists or else extremely hazardous
 Medicine: Drugs prescribed by doctors
 Poisons: if drugs taken abusively; excessive
intake – death (e.g. excessive paracetamol (a
painkiller,止痛藥撲熱息痛): coma or death)

6
DRUGS AND MEDICINE


Most drugs are natural products modified by chemical reactions or
are synthetic chemical substances.
Categorized according to their use:





Painkillers (止痛藥)
Antacids (抗酸劑)
Antibiotics (抗生素)
Cancer drugs (抗癌藥) etc.
Categorized according to their biological effects:






Narcotics (麻醉劑)
Analgesics (止痛劑)
Hallucinogens (迷幻劑)
Depressants (抑制劑)
Stimulants (興奮劑)
Tranquillizers (鎮靜劑)etc.
7
DRUGS AND MEDICINE (3B: 194 – 196)

In ancient times, drugs discovery related to finding of
natural products showing medicinal effects


Nowadays, drug development is a systematic process
including stages of






From extracts of animals, plants and even minerals
Lead compound discovery (先導化合物發現)
Molecular structural modeling (分子改良)
Dosage formulation (配方發展)
Safety tests and trials (安全測試及人體試驗)
Approval from government monitoring agency (批准銷售)
Two examples: aspirin (阿士匹靈) and cisplatin (順鉑)
8
OVERVIEW
Drugs and medicine – an introduction
 Key stages of drug development
 Some common drugs
 Dangerous drugs
 Chiral drugs

9
KEY STAGES OF DRUG DEVELOPMENT

Aspirin

Cis-platin
10
KEY STAGES OF DRUG DEVELOPMENT

Aspirin (Book 3B, p.191 – p.192)

Cis-platin
11
KEY STAGES OF ASPIRIN DEVELOPMENT:
LEAD COMPOUND DISCOVERY
Aspirin development originated from discovery
of medicinal use of the bark of the willow tree
(柳樹) 240 years ago
 In 1827, a Scottish physician used extracts to
treat acute rheumatism (風濕病)
 Active ingredient found to be salicin (水楊苷)
(isolated from willow bark and flowers of
meadowsweet (繡線菊屬植物) plant) CH OH

2
O glucose
Salicin
12
KEY STAGES OF ASPIRIN DEVELOPMENT:
MOLECULAR MODIFICATION)
1870, Prof von Nencki discovered : salicin was
converted to salicylic acid (水楊酸) in the body.
 Synthesis of salicylic acid and prescribed to cure
fevers
 BUT: salicylic acid causes serious burns and
irritation to oral cavity, oesophagus and stomach.
  patients taking salicylic acid: ulcers (潰瘍)

COOH
OH
Salicylic acid
(2-Hydroxybenzoic acid)
13
KEY STAGES OF ASPIRIN DEVELOPMENT:
MOLECULAR MODIFICATION
Reduce side effect, use sodium hydroxide to
neutralize carboxylic acid group
 i.e. use sodium salicylate instead
 This salt derivative works as an antipyretic (退
熱劑) and the irritation (發炎) is reduced.
+

- +
COO Na
OH
O
or
Sodium salicylate
(Sodium 2-hydroxybenzoate)
O Na
OH
14
KEY STAGES OF ASPIRIN DEVELOPMENT:
MOLECULAR FORMULATION
BUT sodium salicylate tastes awful and the patient
would vomit badly if a large dose is taken.
 1897: Felix Hofmann from Bayer synthesized a
new compound by acetylation of the phenol group
producing acetyl salicylic acid (or ASA).
 ASA: a mild irritant, a reasonable taste, good feverreducing and pain relieving properties

O
OH
O
CH3
O
2-Acetoxybenzoic acid
15
KEY STAGES OF DRUG DEVELOPMENT:
DOSAGE FORMULATION
ASA – large scale synthesis
 Initially as a powder in packers and later made
into tablets
 Today ASA formulations include additives like
buffers.

16
KEY STAGES OF ASPIRIN DEVELOPMENT:
SAFETY TESTS AND HUMAN TRIALS

Two stages



Preclinical trials



Preclinical trial
Clinical trial
On tissue samples and live animals
Provide useful information on the drug’s absorption, distribution (transportation
inside the body), metabolism and elimination in the body.
Clinical trial




Involve human testing
Ethical and legal issues
To be conducted under stringent legal approval by a recognized ethical
committee
If pass all the trials: certificates
17
KEY STAGES OF ASPIRIN DEVELOPMENT:
MARKET APPROVAL
Aspirin: synthesized and marketed by Bayer
Company
 Initially as a powder than as a 500 mg tablet
 One of the first drugs in the world to be
available in a standardized dosage.

18
KEY STAGES OF DRUG DEVELOPMENT

Aspirin

Cis-platin (3B, p.193)
19
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
LEAD COMPOUND DISCOVERY
Discovered accidentally in 1961 by a biophysicist
(Prof Barnett Rosenberg)
 Studying effect of electromagnetic radiation on the
growth of E.coli.
 After the experiment, bacteria growth: inhibited by
electrolysis product of the Pt electrodes.
 Rosenberg: Growth of E. coli. Was inhibited by a
square planar complex, cisplatin (cisdichlorodiamineplatinum(II)) and light
 Further investigated by other chemists

20
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
LEAD COMPOUND DISCOVERY
Rosenberg: use of cis-platin in animal tests in
1968
 Cis-platin:

 capable
of stopping the rapid cell division in
bacteria at concentrations that are effective yet
without significant toxicity.
 Reduce the size of cancerous tumors in mice

Cisplatin: use in anti-cancer treatment
21
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
MOLECULAR MODIFICATION
Rosenberg: noticed that the trans isomer is
thermodynamically more stable, it is a much
less active complex for cancer treatment
 Other chemical derivatives (change its ligands):
potent anti-tumor variants of cis-platin

H3N
H3N
Pt
Cl
Cl
O
H3N
NH2
Pt
O
O
O
S
O
sulfato-1,2-diaminocyclohexaneplatinum(II)
Cisplatin
H3N
NH2
O
Pt
NH2
NH2
O
Pt
Cl
Cl
O
Carboplatin
cis-dichlorobis(cyclohexylamine)platinum(II)
22
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
MOLECULAR MODIFICATION

Common features in cis-platin and its derivatives:
Geometries (all square planar)
 All electrically neutral
 Two cis-monodentate ligands or a bidentate ligand
 Cyclic ligands can enhance the antitumor activities of the
complexes BUT the solubility of complex would be
decreased

H3N
H3N
Pt
Cl
Cl
O
H3N
NH2
Pt
O
O
O
S
O
sulfato-1,2-diaminocyclohexaneplatinum(II)
Cisplatin
H3N
NH2
O
Pt
NH2
NH2
O
Pt
Cl
Cl
O
23
Carboplatin
cis-dichlorobis(cyclohexylamine)platinum(II)
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
DOSAGE FORMULATION
Serious difficulties in formulation
 Side effects:

 Nausea
(嚴重噁心)
 Vomiting (嘔吐)
 Renal failure (腎衰竭)
24
KEY STAGE OF CIS-PLATIN DEVELOPMENT:
SAFETY TEST AND HUMAN TRIALS
In vivo studies (活體研究): almost discontinued
due to the toxicity
 Clinical trial:

 Cvitkovic
and coworkers: aggressive diuresis (強力
利尿) in minimizing renal damage
 Gralla et al.: using antiemetic drugs (鎮吐劑)
resolving nausea and vomiting problems
25
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
MARKET APPROVAL
Administered in a chloride containing solution
 Side effects: several drugs taken together

 Mannitol
(甘露醇): increase urine flow (deal with
renal failure)
 Injecting anti-emetics (止吐針): minimize nausea
and vomiting

Since 1970s, treat various cancers
 Ovarian
 Testicular
 Lung
26
OVERVIEW
Drugs and medicine – an introduction
 Key stages of drug development
 Some common drugs
 Dangerous drugs
 Chiral drugs

27
OVER-THE-COUNTER DRUGS AND PRESCRIPTION
DRUGS (3B, P.197)
 Over-the-counter drugs
 Aspirin
 Acetaminophen
 Vitamin

C
Prescription drugs
 Albuterol
 Amlodipine
 Loratadine
 Amoxicillin
 Omeprazole
28
OVER-THE-COUNTER DRUGS

Aspirin
O
OH
O
CH3
O
2-Acetoxybenzoic acid
29
OVER-THE-COUNTER DRUGS

Analysis of aspirin
(See handout)
30
OVER-THE-COUNTER DRUGS

Acetaminophen (paracetamol, pacetaminophenol)
 An
analgesic that relieves pains such as headaches
 Less corrosive to stomach and is an alternative to
aspirin
 Present in Panadol, Saridon, Tylenol and Fortolin
31
OVER-THE-COUNTER DRUGS

Vitamin C (Ascorbic acid)
32
COMMON NAMES OF PRESCRIPTION DRUGS (3B,
P.198)
33
COMMON NAMES OF DRUGS: USE COMMON
NAMES FOR EASIER REFERENCE (3B, P.198)

Albuterol (舒喘靈)
 Asthma
medicine (哮喘藥)
HOCH2
HO
CHCH2 NHC(CH3)3
OH
34
COMMON NAMES OF DRUGS: USE COMMON
NAMES FOR EASIER REFERENCE (3B, P.198)

Amlodipine (氨氯地平)
 Reduces
blood pressure
 Peripheral arterial vascodilator (輔助性動脈血管擴
張藥)
Cl
O
H3 C
O
O
O
H3 C
CH3
N
H
O
NH2
35
COMMON NAMES OF DRUGS: USE COMMON
NAMES FOR EASIER REFERENCE (3B, P.198)

Prilosec (Omeprazole,奧美拉唑)
 Treatment
of heartburn, stomach ulcers
O
H
N
H3 C O
S
N
N
H3 C
CH3
O
CH3
36
COMMON NAMES OF DRUGS: USE COMMON
NAMES FOR EASIER REFERENCE (3B, P.198)

Loratadine (氯雷他定)
 Antihistamine
(抗組織胺)
Cl
CH2 CH3
O
N
O
N
37
COMMON NAMES OF DRUGS: USE COMMON
NAMES FOR EASIER REFERENCE (3B, P.198)

Amoxicillin (阿莫西林、羥氨苄青霉素)
 Antibiotic
(抗生素)
O
HO
H
C CONH
NH2
H
COOH
CH3
N
S
CH3
H H
38
OVERVIEW
Drugs and medicine – an introduction
 Key stages of drug development
 Some common drugs
 Dangerous drugs
 Chiral drugs

39
DANGEROUS DRUGS

Narcotic drugs
 Morphine

and heroin
Stimulant drugs
 Ketamine,
methamphetamine and
phenylethylamine
40
DANGEROUS DRUGS

Narcotic drugs
 Morphine

and heroin
Stimulant drugs
 Ketamine,
methamphetamine and
phenylethylamine
41
DANGEROUS DRUGS:
NARCOTIC DRUGS (麻醉藥物)
Chemical substances relieving pain by numbing
the senses, inducing sleep
 Highly addictive
 Many countries ban their imports; manufacture;
or possession
 Commonly abused narcotic drugs:

 Morphine
(嗎啡)
 Heroin (海洛英)
42
DANGEROUS DRUGS: NARCOTIC DRUGS
(3B, P.199)

Opium (鴉片) and morphine (嗎啡)
 From
opium puppy (罌粟)
 A mixture of alkaloids,有機生物鹼(organic bases)
 Most abundant alkaloid: morphine (10% opium)
HO
O
H
HO
NCH3
43
DANGEROUS DRUGS: NARCOTIC DRUGS
Morphine and its analogues: most effective
painkillers BUT strong addiction
 Codeine (可待因): less addictive while less
pain-killing
 Replacing the hydroxyl group by methoxy group

CH3O
O
H
HO
NCH3
44
DANGEROUS DRUGS: NARCOTIC DRUGS

Heroin (3B, p.199)
 Two
hydroxyl groups replaced by two acetoxy groups
 More powerful narcotic BUT more addictive
CH3
O
O
O
O
CH3
H
NCH3
O
45
DANEROUS DRUGS: HEROIN

Precursor chemicals:
 Acetic
anhydride (CH3 C – O – CCH3)
||
||
O
O
 Acetyl bromide (CH3COBr)
 Acetyl chloride (CH3COCl)
 Acetone ((CH3COCH3)
 Ethyl ether (CH3CH2OCH2CH3)
46
METHADONE (美沙酮)
http://en.wikipedia.org/wiki/Methadone
accessed on 28/12/2007
47
COMPARING STRUCTURES OF HEROIN AND
METHADONE
Heroin
48
CANNABIS (大麻)

Contains Cannabinoids: Some examples
http://en.wikipedia.org/wiki/Cannabinoids accessed on 28/12/2007
49
CANNABIS
50
DANGEROUS DRUGS: NARCOTIC DRUGS
(3B, P.200)

Adverse effects (不良反應) of narcotics
 Dependence
(上癮)
 Respiratory depression (呼吸困難)
 Drowsiness (昏昏欲睡)
 Death in high dosages
 Severe withdrawal symptoms繼癮徵狀(cramps痙孿,
sweating冒汗, running nose流鼻水and tearing)

Illegal in trafficking and possession in many
countries
51
DANGEROUS DRUGS
 Narcotic
drugs
 Morphine
 Stimulant
and heroin
drugs
 Ketamine,
methamphetamine and
phenylethylamine
52
DANGEROUS DRUGS:
STIMULANT DRUGS (興奮劑藥物)
Chemicals causing an increase of alertness
and physical awareness (提升警覺性及人體生
理的應變能力) in the body
 Often addictive
 Increase pulse rate and respiratory rate
 Addicts of stimulants indulge (沉醉) in the
temporary feeling of a boost of energy (短暫精
力充沛感覺) brought on by the drug
 To counter the effect of depressants鎮靜劑(e.g.
sleeping pills安眠藥)

53
DANGEROUS DRUGS: STIMULANT
DRUGS

Ketamine (氯胺酮) (3B, p.201)
A
stimulant patented (專利) in 1963
 A general anesthetic (麻醉劑) if properly
prescribed
 Dream-like feelings: hallucinations(幻覺), deliria
(精神紊亂)
H3C
 Also named “Ketalar” K仔
NH
Cl
54
DANGEROUS DRUGS: STIMULANT
DRUGS

Ketamine (氯胺酮)
H3C
NH
Cl
Ketamine
M
55
DANGEROUS DRUGS: STIMULANT
DRUGS

Ecstasy (MDMA, 狂喜 ‘Fing Tau’ Pills)
http://www.3dchem.com/molecules.asp?ID=60 accessed on 28/12/2007
56
DANGEROUS DRUS: ECSTASY

Precursor chemicals:
 Safrole
(黃樟素)
 Isosafrole
 Piperonal
http://www.chemblink.com/products/9459-7.htm accessed on 28/12/2007
http://potency.lbl.gov/chempages/ISOSAF
ROLE.html accessed on 28/12/2007
http://www.inchem.org/documents/jecfa/je
cmono/v44aje32.htm accessed on
28/12/2007
 3,4-Methylenedioxy-phenyl-2-propanone
http://www.isomerdesign.com/Cdsa/schedu
leUN.php?schedule=3&section=ALL&structur
e=C accessed on 28/12/2007
57
DANGEROUS DRUGS: LSD 迷幻藥

Lysergic acid diethylamide (LSD)
http://en.wikipedia.org/wiki/LSD accessed on 28/12/2007
58
DANGEROUS DRUGS: LSD

Precursor chemicals:
Ergotamine
http://www.isomerdesign.com/Cdsa/scheduleUN.php?schedule=3&section=ALL&struct
ure=C accessed on 28/12/2007
Ergometrine
Lysergic acid
59
DANGEROUS DRUGS: STIMULANT
DRUGS

Methamphetamine (甲基安非他明)
member of amphetamine 安非他明 family
 Causes a release of dopamine 多巴胺 and
noradrenaline 去甲腎上腺素 from the CNS
 Feelings of arousal 情緒亢奮, euphoria 欣快,
strength 精力充沛, self-assertion 偏執,
enhanced motivation 增強幹勁 and focus 專注
力, diminished need for sleeping or eating
 Last for many hours as amphetamine is not
readily broken down by body
A
60
DANGEROUS DRUGS: STIMULANT
DRUGS

Methamphetamine
 After-effects
(後遺症)
 Lows
of intense mental depression (嚴重抑鬱)
 Fatigue (疲勞)
due to the depletion of dopamine
 An
illegal drug
 Common names: “speed” 「快速丸」, “chalk”
「粉筆」
 Also known as ‘ice’ 「冰」 as
methamphetamine hydrochloride in form of
clear chunky晶瑩剔透crystals
61
DANGEROUS DRUGS: STIMULANT
DRUGS

Methamphetamine (3B, p.202)
H
N
CH3
CH3
Methamphetamine
62
DANGEROUS DRUGS: AMPHETAMINE-TYPE
STIMULANT

Precursor chemicals:
http://www.isomerdesign.com/Cdsa/scheduleUN.php?schedule=3&section=ALL&struct
ure=C accessed on 28/12/2007
Ephedrine Pseudoepherdrine 1-phenyl-2propanone
Phenylacetic acid
Norephedrine
63
DANGEROUS DRUGS: STIMULANT
DRUGS

Phenylethylamine (苯基乙胺) (3B, p.202)
 Resembles
amphetamines
 Increase blood glucose level and blood pressure to
enhance alertness and a sense of well being and
contentment (幸福滿足的感覺)
 Prescribed to treat narcolepsy (嗜睡症)
 Found in chocolates
 High dosage: a physiological effect similar to
ketamine
64
DANGEROUS DRUGS: STIMULANT
DRUGS

Phenylethylamine (苯基乙胺)
NH2
65
DANGEROUS DRUGS: STIMULANT
DRUGS
Ketamine and methamphetamine: illegal
stimulants in HK
 Adverse effect (3B, p.203)

 Prolonged
abuse will cause
 Insomnia
(失眠)
 Depression (抑鬱)
 Loss of appetite (食慾不振)
Eventually
 Heart and kidney failure (心臟及腎臟衰竭)
66
OTHER DANGEROUS DRUGS: MANDRAX
(METHAQUALONE 忽得, 海米那 )

sedative hypnotic drug
http://www.indopedia.org/Methaqualone.html
accessed on 28/12/2007
http://www.indopedia.org/Methaqualone.html accessed on 28/12/2007
67
OTHER DANGEROUS DRUGS: MANDRAX
(METHAQUALONE)

Precursor chemicals
 Anthranilic
http://www.isomerdesign.com/Cdsa/scheduleUN.php?schedule=3&section=ALL&struct
ure=C accessed on 28/12/2007
acid
 N-acetylanthranilicacid
68
OTHER DANGEROUS CHEMICALS: ANGEL
DUST (PHENCYCLIDINE, PCP &
TENOCYCLIDINE, TCP)
Originally used as anaesthetic (麻醉)
 Exhibits a hallucinogenic (迷幻) effect

http://en.wikipedia.org/wiki/Phency
clidine accessed on 28/12/2007
http://en.wikipedia.org/wiki/Te
nocyclidine accessed on
28/12/2007
69
OTHER DANGEROUS CHEMICALS: ANGEL
DUST (PCP & TCP)
http://www.isomerdesign.com/Cdsa/scheduleUN.php?schedule=3&section=ALL&struct
ure=C accessed on 28/12/2007

Precursor chemical: Piperidine
70
OTHER DANGEROUS DRUGS:
COCAINE可卡因

A stimulant drug
http://en.wikipedia.org/wiki/Cocaine accesed on 27/12/2007
71
OTHER DANGEROUS DRUGS: COCAINE

Precursor chemicals:
http://www.isomerdesign.com/Cdsa/scheduleUN.php?schedule=3&section=ALL&struct
ure=C accessed on 28/12/2007
 Potassium
permanganate
 Methyl ethyl ketone
 Toluene
 Sulphuric
acid
 Hydrochloric acid
72
OTHER DANGEROUS DRUGS: GHB (GAMMA
HYDROXYBUTYRATE, 迷姦水 )

Originally used as a sleep-aid
HO
O
OH
73
OTHER DANGEROUS DRUGS:
BENZODIAZEPINE (BZD,苯二氮)
Sedative, hypnotic drug
(使鎮靜的安眠藥)
 As tranquillizers (鎮定劑)
 Surreptitiously slipped into
the drink of the intended victim

http://en.wikipedia.org/wiki/Benzodiazepine accessed on 28/12/2007
74
BENZODIAZEPINES
http://en.wikipedia.org/ accessed on 28/12/2007
75
POSTER FROM CUSTOMERS & EXCISE
DEPARTMENT
76
POSTER FROM CUSTOMERS & EXCISE
DEPARTMENT
(HTTP://WWW.ISOMERDESIGN.COM/CDSA/SCHEDULEUN.PHP?SCHEDULE=3&SECTION=ALL&STRUCTURE=C ACCESSED ON 28/12/2007)
77
VIAGRA (SILDENAFIL CITRATE)
78
FOR TREATMENT OF OBESITY: SIBUTRAMINE
(西布曲明)
trade name Meridia in the USA, Reductil in
Europe and other countries)
 Structurally related to amphetamines

H3C
NH
H
N
Cl
CH3
CH3
Amphetamine
Sibutramine http://en.wikipedia.org/wiki/Sibutramine accessed on
28/12/2007
Ketamine
Methamphetamine79
FOR TREATMENT OF OBESITY:
DEXFENFLURAMINE (右旋芬氟拉明)
http://en.wikipedia.org/wiki/Dexfenfluramin
e accessed on 28/12/2007
80
OVERVIEW
 Drugs
and medicine – an introduction
 Key stages of drug development
 Some common drugs
 Dangerous drugs
 Chiral drugs
81
SYLLABUS FOR CONSIDERATION
11.4: Under relevant activities (3rd column)
 Search and present information ion ‘chiral
drugs’

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CHIRAL DRUGS
What is chirality?
 3 types of stereoisomers
 Importance of chirality in drug development
 Chiral drugs in daily life

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CHIRAL DRUGS
 What
is chirality?
 3 types of stereoisomers
 Importance of chirality in drug development
 Chiral drugs in daily life
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WHAT IS CHIRALITY?
 “Chirality”
is the property possessed by a
molecule with such spatial arrangement of
atoms that it cannot superimpose on its
mirror image.
 The object and mirror image pair of
molecules has the same constituents and
structural formula.
 Their relationship with each other is similar
to
 our left and right hands.
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WHAT IS CHIRALITY?

The carbon atom of a simple chiral centre
has four different groups arranged
tetrahedrally.
 Isomers
of such nature are called
enantiomers.
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CHIRAL DRUGS (手性藥物)
 What
is chirality?
 3 types of stereoisomers
 Importance of chirality in drug development
 Chiral drugs in daily life
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3 TYPES OF STEREOISOMERS (立體異構體)

Enantiomers

Diastereomers

Geometrical isomers.
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ENANTIOMERS (對映異構體)




Enantiomers are two stereoisomers containing
asymmetric carbon atoms related as nonsuperimposable object and mirror images.
If an enantiomer rotates polarized light to the right or in
a clockwise direction, it is said to be the (+) or the
dextrorotatory isomer.
If the plane polarized light is rotated to the left or in a
counter-clockwise direction, the isomer is called as the
(−) or the levorotatory isomer.
Enantiomers are identical in chemical and physical
properties except for the direction of rotation of plane
polarized light.
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DIASTEREOMERS (非對映異構體)



Diastereomers are stereoisomers that are not
related as object and mirror images.
They contain at least two asymmetric carbon atoms.
Unlike enantiomers, the physical and chemical
properties of diastereomers can differ and it is not
unusual for them to have different melting and
boiling points, refractive indices, solubility, etc.
麻黃素
假麻黃素
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GEOMETRICAL ISOMERS (幾何異構體)
Geometrical isomers are molecules with a
carbon-carbon double bond and they are not
optically active.
 When the groups attached to each end of
the double bond are on the same side, the
stereoisomer is named as cis-isomer; when
the groups are on the opposite sides, the
trans-isomer designation is used.

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CHIRAL DRUGS
 What
is chirality?
 3 types of stereoisomers
 Importance of chirality in drug development
 Chiral drugs in daily life
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WHY IS CHIRALITY IMPORTANT IN DRUG
DEVELOPMENT?
Biological systems like that of human beings
have been known to exhibit chirality.
 This is reflected by the existence of chirality
of drug receptor areas and the requirement
of chiral specificity on drugs.
 In order to understand the biological effect
of drugs, we have to distinguish the three
main phases of their action.

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WHY IS CHIRALITY IMPORTANT IN DRUG
DEVELOPMENT?
The first phase is the initial receptor differentiation
phase, where different drugs have different affinity
and tissue specificity due to receptor (受體)
differentiation and distribution for the parent
compound formed.
 The second phase is the absorption, distribution,
metabolism and excretion phase, where the type
of bioavailability (生物利用率) is determined.
 The third phase is the interaction of the drug with
the molecular site of action, leading to the
observed therapeutic effect (療效).

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WHY IS CHIRALITY IMPORTANT IN DRUG
DEVELOPMENT?




The three phases of action are based on the receptor
theory, similar to the lock-and-key hypothesis
proposed by the famous scientist Emil Fischer.
Receptor molecules in the body are proteins that
exhibit high affinities for the binding of molecules with
certain structures.
This is completely analogous to enzyme-substrate
binding.
Mismatching of drug molecules with the targeted
receptors may cause undesirable side effects such as
requirement of higher dosage and increased toxicity.
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WHY IS CHIRALITY IMPORTANT IN DRUG
DEVELOPMENT?




All pharmacological activity may reside in one
enantiomer.
The therapeutic inactive isomer is regarded as an
impurity that possesses a different or undesirable
pharmacological entity.
This situation may become even more acute if the active
enantiomer exhibits a low therapeutic value or there is
clinically significant toxicity.
A well-known example of therapeutic-specific pair is the
R- and S-enantiomers of thalidomide (the R and S
designation, after Cahn, Ingold and Prelog, is a way of
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naming enantiomers by their structures).
WHY IS CHIRALITY IMPORTANT IN DRUG
DEVELOPMENT?
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WHY IS CHIRALITY IMPORTANT IN DRUG
DEVELOPMENT?




The R-enantiomer is an effective sedative (鎮靜劑),
which is a medication with calming and soothing
effect that relieves anxiety(減輕焦慮) and promotes
sleep(催眠).
However, the S-enantiomer may cause teratogen (畸
胎) formation.
A teratogenic foetus is one with deficient, redundant,
misplaced or grossly misshapen parts.(肢體或器官殘
缺不全或生長位置不當的胎兒)
S-Thalidomide was shown to be responsible for over
2,000 cases of serious birth defects in children born
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of women who took it during pregnancy.
CHIRAL DRUGS
 What
is chirality?
 3 types of stereoisomers
 Importance of chirality in drug development
 Chiral drugs in daily life
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WHAT DRUGS IN OUR DAILY LIFE ARE
CHIRAL?
Chirality is an essential dimension in
pharmacology.
 Worldwide sales of chiral drugs in singleenantiomer forms continue to grow.

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WHAT DRUGS IN OUR DAILY LIFE ARE
CHIRAL?
 The
commonly used single-enantiomer
drugs are grouped as follows:
 Cardiovascular
disease (冠心病):
Atorvastatin calcium (阿伐他汀鈣)
 Simvastatin (辛伐他汀)
 Pravastatin sodium (普伐他汀鈉)and
 Valsartan (纈沙坦)

 Central
nervous system(中樞神經系統疾病):
Paroxetine hydrochloride (鹽酸帕羅西汀)and
 Sertraline hydrochloride (鹽酸舍曲林)

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WHAT DRUGS IN OUR DAILY LIFE ARE
CHIRAL?
 The commonly used single-enantiomer drugs
are grouped as follows:
 Respiratory
(呼吸系統疾病)
 Fluticasone
propionate (氟體卡松丙酸酯) and
 Salmeterol (沙美特羅)
 Hematology
 Clopidogrel
(血液毛病)
bisulfate (氯吡格雷酸氫鹽)
 Gastrointestinal
 Esomeprazole
 Antibiotic
(腸胃疾病)
magnesium (左旋奧美拉唑鎂)
(抗生素)
 Amoxicillin
and (羥氨芐青霉素)
 Potassium clavulanate (克拉維酸鉀)
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OVERVIEW
Drugs and medicine – an introduction
 Key stages of drug development
 Some common drugs
 Dangerous drugs
 Chiral drugs

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