Transcript Chemistry Project: Aspirin and Cis

CHEMISTRY PROJECT:
ASPIRIN AND CIS- PLATIN
Group member: Nathalie Lam (6AS) (16)
Gigi Lee (6AS) (19)
Katy Li (6AS) (25)
Alice Luk (6AS) (27)
Tiffany Mak (6AS) (28)
Rebecca Chan (6B) (1)
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
HISTORY AND DEVELOPMENT OF
ASPIRIN--- ORIGIN OF ASPIRIN
400 BC
 the bark and leaves of the willow tree were
prescribed

1832
 chemist experiments with salicin and creates
salicylic acid (SA) (Chemical name of aspirin)

1897
 the first stable form of a product introduced as
Aspirin is produced

1899
 Aspirin powder became the most popular drug

1915
 Aspirin is manufactured in tablet form

1920s
 Aspirin is used to treat symptoms of pain (Pain related
to foot waist and nerves)

1952
 Children's Chewable Aspirin is introduced.

Early 1970s
 Aspirin inhibits prostaglandins that are involved in
inflammation.

1988
 Aspirin was proposed for reducing the risk of heart
attack .It also approved the use of aspirin for the
prevention of mini-strokes in men, colon, esophageal
cancer and other diseases.

 1998
 Effectiveness
of Aspirin in the prevention of ministrokes in persons having cardiovascular risk
factors was confirmed.
 2001
 Evidences
showed that Aspirin is effective in the
prevention of cardiovascular events
 2003
 Bayer
broaden the professional labeling of aspirin
to include an indication for prevention of a first
heart attack in individuals at moderate or greater
risk of coronary heart disease.
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
HISTORY AND DEVELOPMENT OF ASPIRIN--5 KEY STAGES OF ASPIRIN DEVELOPMENT
1.
2.
3.
4.
5.
Lead compound discovery
Molecular modification
Molecular formulation
Dosage formulation
Safety tests and human trials
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
10
Salicin
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
 salicylic acid causes serious burns and irritation
to oral cavity, oesophagus and stomach.
 Consequently, patients taking salicylic acid:
COOH
ulcers (潰瘍)

OH
Salicylic acid
(2-Hydroxybenzoic acid)
11
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
O Na
or
+
OH
12
Sodium salicylate
(Sodium 2-hydroxybenzoate)
KEY STAGES OF ASPIRIN DEVELOPMENT:
MOLECULAR FORMULATION
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
fever-reducing and pain relieving properties

O
OH
O
CH3
O
13
2-Acetoxybenzoic acid
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.

14
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



15
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
Preparation of Aspirin
1. Weigh out salicylic acid.
2. Add 1 drop of H2SO4. Swirl the flask.
3. Heat the mixture at 50C, stir constantly.
4. Cool the mixture in iced water bath for 10 minutes. Stir occasionally.
5. Set up a vacuum filtration apparatus. Then decant the mixture onto
the filter paper.
6. Repeat the above steps until crystallization is completed.
7. Collect all crystals formed from the mixture and weight them.
8. Add ethanol and water to the crystals.
9. Warm the mixture at 60C for 15 minutes until all crystals are
dissolved.
10. Cool the mixture at iced water bath.
11. Crystallize the mixture and aspirin crystals can finally be obtained.
PREPARATION OF ASPIRIN
http://www.youtube.com/watch?v=3etL_QWkLM
M
 Chemical formula:

Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
USES OF ASPIRIN
1.






Current uses of aspirin include:
Over-the-counter pain relief, especially for
headaches
Reduction of swelling and inflammation in
arthritis and injuries
Anti-coagulant given to sufferers of heart
attack, mini-stroke and unstable angina
Can reduce severity of heart attack if taken at
first symptoms
Recovery after cardiovascular surgery (e.g.
bypass operation)
Treatment of rheumatoid arthritis,
osteoarthritis and other rheumatoid diseases
2. Special use of Aspirin

Fungal infections on soil: can be treated by using aspirin.
Dissolve an aspirin tablet in a liter of water and sprinkle
the mixture on the affected soil.



keep cut flowers to be fresh for a longer period of time:
before arranging cut flowers in a vase, put a soluble
aspirin tablet into the water. It helps to keep them fresh
for longer.
Solve dandruff problems: Powder two aspirin tablets and
mix it with your usual shampoo. Leave on the hair for two
or three minutes before washing.
remove nicotine stain: take a soluble aspirin and mix it
thoroughly with some freshly squeezed lemon juice. This
mixture will remove nicotine stains, grass stains, etc from
hands.
Clean areas with pimples: make a paste by adding
some water to powdered aspirin. Apply this paste on
the pimples and wash it off after a few minutes.
 remove sweat stains from T-shirts: dissolve two
aspirins in half a cup of warm water and apply to the
stained area of the fabric. Leave it for a couple of hours.



Prevent fungus forming around the roots of new plants.
Treat yellowish hair: dissolve eight to ten aspirin
tablets in a glass of water and rub the solution into
your hair. Wash it away after leaving it on for about
ten minutes and shampoo it in the usual way.
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
SIDE EFFECTS OF ASPIRIN
most common side effects :
heartburn, nausea, upset stomach
 severe side effects :
severe allergic reactions, confusion,
diarrhea, dizziness, drowsiness, hearing loss

Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
HISTORY AND DEVELOPMENT OF
CIS-PLATIN--- ORIGIN OF CIS-PLATIN
The chemical name of Cis-platin:
cis-diamminedichloroplatinum
 Discovered by M. Peyrone in 1845


Known as Peyrone's salt
Structure was deduced by Alfred Werner in 1893
 In 1965, Barnett Rosenberg, of Michigan State
University discovered that electrolysis of platinum
electrodes generated a soluble platinum complex

HISTORY AND DEVELOPMENT OF CIS-PLATIN
--- ORIGIN OF CIS-PLATIN
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
LEAD COMPOUND DISCOVERY
a
biophysicist (Prof Barnett Rosenberg)
conducted series of experiments on the
growth of E.coli.
 Growth of E. coli. Was inhibited by a
square planar complex, cisplatin (cisdichlorodiamineplatinum(II)) and light
 Further investigated by other chemists
29
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
 Cis-platin: use in anti-cancer treatment

30
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
H3N
H3N
Pt
Cl
NH2
Cl
NH2
Cisplatin
O
H3N
H3N
O
Pt
O
O
S
O
sulfato-1,2-diaminocyclohexaneplatinum(II)
NH2
NH2
O
Pt
O
Pt
Cl
Cl
O
Carboplatin
cis-dichlorobis(c yclohexylamine)platinum(II)
31
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
MOLECULAR MODIFICATION

Common features in cis-platin and its derivatives:
 Geometries (all square planar)
 All electrically neutral
 Cyclic ligands can enhance the antitumor
activities of the complexes BUT the solubility
of complex would be decreased
32
KEY STAGES OF CIS-PLATIN DEVELOPMENT:
DOSAGE FORMULATION

Serious difficulties in formulation
33
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:
 As aggressive diuresis (強力利尿) in
minimizing renal damage
 As antiemetic drugs (鎮吐劑) resolving nausea
and vomiting problems

34
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
PREPARATION OF CIS-PLATIN
1.
2.
3.
4.
potassium tetrachloroplatinate(II), K2[PtCl4],
NH3 are added to any of the four equivalent
positions,
Cl− has a larger trans effect than NH3, the
second amine preferentially substitutes trans to
a chloride ligand
The trans effect of the halides follows the order
I->Br->Cl-,
[PtI4]2− to ensure high yield and purity of the
cis isomer
Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
USES OF CIS-PLATIN: SPECIFICITY

Only cis-platin (cis-DDT) has anti-cancer activity
but not its geometric isomer- trans-platin
USES OF CIS-PLATIN
coordinates to DNA of cancer cells
 inhibits replication of DNA and leads to cell death
 widely used as anticancer drug for
testicular cancer and ovarian cancer.

USES OF CIS-PLATIN
Cis-platin is given to patients by injection
 retains its neutral form in the blood due to high [Cl-].
 passes through the cell membrane of the cancer cell in
its neutral form.
 Hydration of cis-platin in cytoplasm due to low [Cl- ].

Part 1
1.
History and development of Aspirin
(a) Origin of Aspirin
(b) 5 key stages of Aspirin development
2.
Preparation of Aspirin
3.
Uses of Aspirin
4.
Side effects of Aspirin
Part 2
1.
History and development of Cis-platin
(a) Origin of Cis-platin
(b) 5 key stages of Cis-platin development
2.
Preparation of Cis-platin
3.
Uses of Cis-platin
4.
Side effects of Cis-platin
SIDE EFFECT OF CIS-PLATIN
Nephrotoxicity (kidney damage) > reduce renal
function
 Neurotoxicity (nerve damage)
 toxic side effects to bone marrow

nausea and vomiting
 hearing loss, hair loss
