Biological Molecules

Chemistry for the Biosciences

Chapter 7/9
Marcel Jaspars
m.jaspars@abdn.ac.uk
Organic Structures
The 3D structures of organic molecules are
crucial to determining their physical and
chemical properties
Carbon is 1s
2
2s
2
2p
2
, has 4 valence electrons
and forms 4 bonds in almost all its
compounds
Exceptions are CH
2
, CH
3
, CH
3
+
, CH
3
-
are
known but have limited lifetimes

If there are 4 single bonds they are arranged
tetrahedrally
Structures other elements
N forms 3 bonds in neutral compounds
O forms 2 bonds in neutral compounds
H forms 1 bond
These bonds are generally covalent:
sharing of electron pairs.
Hydrogens define the shape
Hydrogens are always on the surface of
an organic molecule:
C
C
C
C
C
H
H
H
H H
H H
H H
H
H
H
But in reality the shape is:
C
C
C
C
C
H
H
H
H H
H H
H H
H
H
H
Space-filling model
Ball and stick model
Line structure
A surface-
What the solvent sees
Stabilities of organic compounds
Bond strength for bonds in organic
compounds (kJ/mol):
C-H 413 O-H 463 N-H 391
C-C 348 C=C 614 CC 839
C-O 358 C-N 293 C=O 799
Bond lengths ()
C-C 1.54 C=C 1.34 CC 1.20


Bond polarities
Two atoms in a covalent bond may
have different electronegativities (_)
This results in the bond being polarised
with electrons concentrating at one end.
_=2.5
_=2.1
No polarisation
C C
H
H H
H
H H
Slight
polarisation
C O
H
H
H
H
_=2.5
_=3.5
_=2.1
e
-

e
-

C-O and O-H bonds are polarised
C-O-H is a functional group
o
+
o
-
o
+
Solubilities of organic compounds
C-C and C-H bonds have low polarity
The polarity of organic molecules is
often low
Soluble in nonpolar solvents, but not
water
Organic molecules with polar functional
groups (CH
3
OH, CH
3
NH
2
) are soluble in
water.

Acid/base properties of organic compounds
Many organic compounds contain acidic
or basic groups.
The most common acidic group is the
carboxylic acid group, -COOH
The most common basic group is the
amine group NH
2
C
OH
O
Carboxylic acid
N
H
H
Amine
Bonding in organic compounds
Carbon forms hybrid orbitals
sp
3
formed by combining one s orbital with 3
p orbitals
sp
2
formed by combining one s orbital with 2
p orbitals
sp formed by combining one s orbital with
one p orbital
o-bonds are formed by the overlap of two
orbitals
t-bonds are also possible by the combination
of two p orbitals
Carbon is sp
3
in methane CH
4
Did the Picts know Quantum Mechanics in 2500 BC?
Ethane
C C
H
H
H
H
H
H
109.5
o
1.54
Freely rotatable bond
Carbon is sp
2
in ethene H
2
C=CH
2
H s orbital
C sp
2
orbital
C p orbital
H
H
H
H
H
H
H
H
t orbital
H
H
H
H
122
o
116
o
1.34
Non-rotatable bond
Ethene is flat!
Carbon is sp in ethyne H-CC-H
C
C
H
H
H s orbital
C sp orbital
C p orbital
t
t
H C C H
180
o
1.20
Bonding in methanal H
2
C=O
C O
H
H
121
o
118
o
o
+
o
-
_=2.5 _=3.5
electrons
Bonding in benzene (C
6
H
6
)
sp
2
C
C
C
C
C
C
C H
H
H
H
H
H
120
o
1.39
1.39
p orbital
t
Aromatic t
orbital
C
C
C
C
C
C H
H
H
H
H
H
Sometimes drawn
like this to
indicate aromaticity

Electrons are
delocalised
What are Proteins?
What are Proteins?
Protection
Structure
Reactions
Signals
Enzymes
Herring antifreeze protein
Vanadium bromoperoxidase
(Corralina pilulifera)
Thermophilic DNA
polymerase
Shrimp cold alkaline phosphatase
Amino Acids
Almost all amino acids in living systems are o-
amino acids.
They are called o-amino acids because the
amino (NH
2
) group is joined to the 1st carbon
next to the COOH group.
If it was joined to the second carbon it would
be a |-amino acid.

Amino Acids
Amino Acids
Amino acids contain both an acidic and a basic
group within the same molecule
Intramolecular (within the same molecule)
acid/base reactions can occur to produce a
dipolar ion, known as a zwitterion
Amino acids can therefore act both as acids and
bases, and they are said to be amphoteric
The point (pH) at which the amino acid is exactly
balanced between the anionic and cationic forms,
and is primarily in the neutral or zwitterionic form
is known as the isoelectric point (pI).
Amino Acid Properties
All natural amino acids are L. This means that
all are S except glycine which is achiral and
cysteine which is R.
They vary in size, hydrophobicity, charge and
H-bonding potential.
The hydrophobic effect causes the
hydrophobic sidechains to be sequestered in
the interior of the protein. This is a major
driving force for protein folding.

Amino Acid Chirality
All amino acids in our body have S chirality except
cysteine which is R.
You often find the natural amino acids described as L
(L/D nomenclature is common in biochemistry texts)
Small Amino Acids
*Can form H-bonds or salt bridge
Medium/Large Hydrophobic
Amino Acids
*Can form H-bonds or salt bridge
*Can form H-bonds or salt bridge
Medium/Large Hydrophobic
Amino Acids
*Can form H-bonds or salt bridge
Medium/Large Hydrophobic
Amino Acids
Polar Amino Acids
*Can form H-bonds or salt bridge
Acidic Amino Acids
*Can form H-bonds or salt bridge
Basic Amino Acids
*Can form H-bonds or salt bridge
Amino Acid Properties

Umami
Savoury taste
MSG/Monosodium glutamate
Amide Bond Formation
The Peptide Bond
N
N
N
N
O H
O R
1
R
2
H
O
R
3
H
O
R
4
H
O
peptide bond
O
C N
H
R
R
High barrier to rotation
A Dipeptide - Aspartame
Source of
Phenylalanine
Bad if you have
phenylketonuria
Build up of Phe
causes mental
retardation if not
discovered early
enough.
Primary Structure
Primary structure is often written
Single letters: G-L-E-A-S-K
Three letters: Gly-Leu-Glu-Ala-Ser-Lys
Hydrogen Bonds
The O in C=O is negatively charged (o-)
The H in N-H is positively charged (o+)
They can form a bond known as a hydrogen bond
which stabilises peptide secondary structure

Salt Bridges
Charged
amino acids
can form
strong
interactions
that can
stabilise
peptide and
protein
structures.
Disulphide Bridges
Important in peptide and
protein structure
Prialt is a pain killer
derived from a cone snail
which has 3 disulphide
bridges
Protein Folding
Proteins have evolved so that one conformation
is significantly more stable than all others. This is
known as the folded or native state.
The folded state is governed by the amino acid
sequence alone.
Proteins only remain folded in a narrow range of
conditions of pH, salt concentration and
temperature.
A folding pathway has evolved that takes the
amino acid chain to the native conformation
reliably in a short time.

Anfinsen Showed That:
3D protein structure is dictated by amino
acid sequence alone.
MTPAVTTYKL
VINGKTLKGE
TTTKAVDAET
AEKAFKQYAN
DNGVDGVWTY
DDATKTFTVT E
Protein Structure
Covalent bonds such as disulphide bridges can enforce
certain conformations.
Bonds to metals can also be important to stabilise the
native state of a protein.
Polar atoms in proteins make H-bonds to water in the
unfolded state.
The H-bonding potential of these atoms must also be
satisfied in the folded state, even if there is no water
accessible (ie in the interior of the protein).
This is achieved through protein-protein H-bonds.
Hydrophobic residues congregate in the centre of the
protein, charged residues on the surface. The
accessible surface area of the protein is minimised to
achieve this.
Conformation of the Peptide Chain
The primary structure of proteins is the order of
the amino acids in the peptide sequence.
The secondary structure of proteins refers to the
types of ordered structures taken up by the
protein chain such as the a-helix and b-sheets.
The tertiary structure is the overall 3D shape of
the protein.
The folding pattern of a protein can be described
by the angles of rotation (dihedral or torsional
angles) around the bonds in the main chain.

Angles in Peptides
|
i
is defined as the
dihedral (or torsional
angle) C
i-1
-N
i
-C
ai
-C
i


i
is defined as the
dihedral (or torsional
angle) N
i
-C
ai
-C
i
-N
i+1

e
i
is the peptide bond
angle and is most often
180
o
, but can be 0
o
.
Sidechain
conformational angles
are called _
1
, _
2
, _
3
etc.

Secondary Structure
Protein structures must achieve:
Low energy conformations of individual residues.
Hydrogen bonding by polar groups, including
buried ones.
Formation of compact and well packed structures.

The o-Helix
The o-Helix
The pattern of hydrogen bonding is NH
i
to
C=O
i+4
:
The o helix has | = -57
o
and = -47
o
and
the peptide bond is trans.
There are 3.6 residues per turn (n)
The displacement (d) between successive
residues along the helix axis is 1.5
The distance along the helix axis per turn
(the pitch, p) is 5.5
p = n x d

N
N
N
N
O H
O R
8
R
7
H
O
R
6
H
O
R
5
N
N
N
N
O H
O R
4
R
3
H
O
R
2
H
O
R
1
H
H
The o-Helix
Antiparallel |-Sheet
The antiparallel | sheet has | = -139
o
and =
+135
o
and the peptide bond is trans.
There are 2.0 residues per turn (n)
The displacement (d) between successive
residues along the helix axis is 3.4
The distance along the helix axis per turn (the
pitch, p) is 6.8

N
N
N
N
O H
O R
8
R
7
H
O
R
6
H
O
R
5
N
N
N
N
O H
O R
4
R
3
H
O
R
2
H
O
R
1
H
H
N
N
N
N
O H
O R
8
R
7
H
O
R
6
H
O
R
5
N
N
N
N
O H
O R
4
R
3
H
O
R
2
H
O
R
1
H
H
Antiparallel |-Sheet
Parallel |-Sheet
The parallel | sheet has | = -119
o
and = +118
o
and the peptide
bond is trans.
There are 2.0 residues per turn (n)
The displacement (d) between successive residues along the helix
axis is 3.2
The distance along the helix axis per turn (the pitch, p) is 6.4
The strands which form a |-sheet may be far apart in the actual
protein structure.

N
N
N
N
O H
O R
8
R
7
H
O
R
6
H
O
R
5
N
N
N
N
O H
O R
4
R
3
H
O
R
2
H
O
R
1
H
H
N
N
N
N
O H
O R
8
R
7
H
O
R
6
H
O
R
5
N
N
N
N
O H
O R
4
R
3
H
O
R
2
H
O
R
1
H
H
Parallel |-Sheet
|-Sheet
Comparing o and |
o | (parallel) | (antiparallel)
| -57
o
-119
o
-139
o

-47
o
+118
o
+135
o

Residues per turn (n) 3.6 2.0 2.0
Displacement (d) 1.5 3.2 3.4
Pitch (p) 5.5 6.4 6.8
|-turn
Between to antiparallel |-sheets there is often
a |-turn
This is stabilised by H-bonds.
Secondary Structure Propensities
Some amino acids are found more often in
certain secondary structures.
The tendency for any amino acid to appear in a
secondary structure type is called its propensity.
Propensity values > 1 mean that a residue shows
a preference for that secondary structure type.
Values < 1 mean that a residues does not favour
that structural type.
These values can be used to predict structural
types expected.

Residue o-helix |-sheet |-turn
Gln 1.59 0.52 1.01
Ala 1.41 0.72 0.82
Leu 1.34 1.22 0.57
Met 1.30 1.14 0.52
Glu 1.27 0.98 0.84
Lys 1.23 0.69 1.07
Arg 1.21 0.84 0.90
His 1.05 0.80 0.81
Val 0.90 1.87 0.41
Ile 1.09 1.67 0.47
Tyr 0.74 1.45 0.76
Cys 0.66 1.40 0.54
Trp 1.02 1.35 0.65
Phe 1.16 1.33 0.59
Thr 0.76 1.17 0.90
Gly 0.43 0.58 1.77
Asn 0.76 0.48 1.34
Pro 0.34 0.31 1.32
Ser 0.57 0.96 1.22
Asp 0.99 0.39 1.24
MTPAVTTYKL
VINGKTLKGE
TTTKAVDAET
AEKAFKQYAN
DNGVDGVWTY
DDATKTFTVTE

o-helix
|-sheet
|-turn
Amyloid-|
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
|-sheet
|-turn
Amyloid Plaque Structure
Different Images
Ramachandran Plot
The main chain
conformation of a residue i
can be defined by two
angles, |
i
and

i
as e
i
is 180
o
in most cases.
A plot of |
i
versus
i
is called
a Ramachandran plot.
The Ramachandran plot
shows the conformational
space a protein is allowed to
inhabit.
Conformations that
correspond to low energy
states of individual residues
are also those that permit
the greatest number of H-
bonds to form.

o helix
| sheet (parallel)
| sheet (antiparallel)
Protein Structure In the Lab
Protein Structure - Ubiquitin
Ubiquitin (Nobel 2004)
Carbohydrates
Carbohydrates are fuel for chemical reactions
in our body.
We are all taught:

Photosynthesis
Respiration
Carbohydrates
There are three classes of carbohydrate.
Monosaccharides
Disaccharides
Polysaccharides

Monosaccharides
These are the simplest carbohydrates and cannot
be broken down into any smaller carbohydrates
One of these is glucose this can exist in two
forms, an open-chain form and a cyclic form
Most monosaccharides are cyclic

Hemi-acetal
Hemi-acetal central C connected to OH and OR.
Fructose
A ketose
Glucose
An aldose
Aldose and Ketose
If C=O is attached to terminal carbon in chain
then it is an aldose
If C=O is attached to second carbon atom then
it is a ketose
Anomers
The hemi-acetal position can adopt two different stereochemistries
these are called anomers
If the stereochemistry at C1/C5 is opposite then it is o, if it is the
same then it is |
Different anomers are possible giving 6 membered ring (pyranose)
and 5 membered rings (furanose)
Sugar stereochemistry is described as D or L, most sugars being D
oanomer
|anomer
Disaccharides
Formed by the linkage of two
monosaccharides with the elimination of
water.
One of these is maltose which consists of two
glucose units joined together.

Maltose and Scotland
Glycosidic Bond
Sucrose is made from glucose (pyranose form) and fructose
(furanose form)
Glycosidic bond is from 1 position on glucose to position 2 on
fructose
Glucose is o-anomer and fructose is |-anomer
Both sugars are D
Sucrose is -D-glucopyranosyl-(12)--D-fructofuranoside


Glucose
Fructose
Lactose
Made up of galactose (pyranose) and glucose
(pyranose)
Linked from 1 position on galactose to 4 position on
glucose
Both are D
Galactose is | anomer and glucose is o/| anomer o
shown here
-D-galactopyranosyl-(14)-o-D-glucopyranoside
Glucose Galactose
Polysaccharides
Polysaccharides are carbohydrates which can
have thousands of monosaccharides linked
together.
Cellulose, starch and glycogen are examples of
polysaccharides.
Cellulose is the most abundant organic
compound on earth and is cotton in its purest
natural form.
Cellulose is also part of the woody part of trees
and the supporting material in plants and leaves.
Glycogen is the bodys way of storing energy
glucose units from starch or sugary foods are
assembled to make glycogen.

Polysaccharides
Two very important polysaccharides are cellulose and
starch.
Both are made up of D-glucose units which are 1-4 linked.
Cellulose is | linked
Starch is o linked.
Starch actually has 2 forms
Amylose which is linear
Amylopectin which has some 1-6' links in addition to the 1-4'
links; i.e. it is branched
Cellulose cant be metabolised by humans because humans
do not possess enzymes capable of dealing with |-linkages.
Starch can be metabolised because it has o-links.
Glycogen is branched like amylopectin.
In glycogen branches occur every 10-15 units
In amylopectin branches occur every 25 unite

Different Linkages
Glycogen
Lipids
Lipids are naturally occurring organic
molecules isolated from cells and tissues.
They contain large hydrocarbon portions
They are generally insoluble in water (grease-
like)
They are usually the esters of long-chain
carboxylic acids

Beeswax
n = 20, m = 27
Oils and Fats
These are all tri-esters of glycerol and long-chain
carboxylic acids
Oils are liquids and fats are solid
Fatty Acids
Saturated no
double bonds
Monounsaturated
1 double bond
Polyunsaturated
more than 1
double bond

e6
e3
e3
e6
e3 and e6 PUFAs
For good health we have to
have the right balance
between e3 and e6
polyunsaturated fatty acids
(PUFAs)
We can get this from oily
fish, fish oil supplements or
some types of vegetable oils
Some have even been
clinically approved to
improve heart health.
Non-fish PUFAs
Martek Biosciences produce
PUFAs from non-fish sources
Source organism is marine
micro alga Cryptecodinium
cohnii
Rich source of
docosahexaenoic acid (DHA)
and arachidonic acid (ARA)
Both DHA and ARA are
present in breast milk and
vital to infant brain
development

Anandamide
Anandamide is a fatty acid amide. In the brain
it interacts with the cannabinoid receptor and
plays a role in making and breaking short term
neural connections.
Cannabis
Cannabis sativa
O
H
H
HO
A-9 tetrahydrocannabinol
May have a role in the
treatment of MS and glaucoma

Our ancestors ate cabbage!
Boil in water
Find pot shards
From AD 1000
analyse
O
Nonacosan-15-one
Present in cabbage leaf wax
J Archeol Sci 1997, 24, 1
Glycerophospholipids
Elements of the cell
membrane
Contains phosphodiester
Contains amino alcohol
Lipid Bilayer Formation
Membranes
Not just lipid
bilayers
Real Membranes
Steroids
A steroid is an organic molecule whose
structure is based on the tetracyclic (4 ring)
system.
The rings are designated A, B, C and D.
The carbons are numbered starting in ring A.


Steroids
Steroids are found throughout plants and
animals and have an interesting range of
biological activity.
All steroids share the same basic shape but
have a variety of constituent groups attached
and may have double bonds in various places.
Steroids have the 4 rings fused together, but
the two rings A and B can be joined in a cis or
a trans arrangement, as shown here.
Steroids
An A,B-trans steroid
An A,B-cis steroid
A, B trans-fused steroids are considerably more common
than cis-fused steroids. The cis fused steroids are found in bile.

Cholesterol
Important Steroids
Cortisone: anti-inflammatory drug
used in the treatment of arthritis
and many other conditions.
Testosterone: male sex hormone;
controls secondary male sexual
characteristics

Estradiol: female sex hormone; controls
secondary female sexual characteristics and
regulates uterine cycle.
Norethinodrone: ovulation suppressant;
active ingredient of one type of
contraceptive pill.
Other Important Steroids
Digitoxigenin:
a foxglove
constituent
used as a
heart
stimulant
Nandrolone: an anabolic or
tissue-building steroid
(19-nortestosterone).
Testosterone
What a difference a double bond
makes!
CH
3
CH
3
OH
O
H
H H
Testosterone the male hormone
CH
3
CH
3
OH
O
H
H H
Dihydrotestosterone cause of male pattern baldness
Nucleic Acids
DNA (deoxyribonucleic acid) and RNA (ribonucleic
acid) are composed of nucleotides.
Nucleotides have 3 parts
Nitrogenous base
Sugar
Phosphate
In nucleosides the
phosphate is missing
Pyrimidine Bases
Purine Bases
Ribose and Deoxyribose
DNA Nucleotides
RNA Nucleotides for Energy Storage
Nucleic Acid Formation
DNA and RNA are made by joining nucleotides
in a chain.
A human chromosome (DNA) is about 130
million nucleotides
RNA strands are shorter 75 1000s of
nucleotides
They are formed by making phosphodiesters
between two nucleotides.
Nucleic Acid Formation
Phosphodiester bond
Longer Chains
DNA Base Pairing
DNA Base Pairing
Why Not Other Base Pairs?
Pyrimidines too small
to enable complementary
strands to form double helix
Cannot form enough H-bonds
for stable interaction
Purines too bulky
to enable complementary
strands to form double helix
Cannot form enough H-bonds
for stable interaction
Watson and Crick
DNA Double Helix
Major and Minor Groove
Structure of tRNA
Carries amino
acids
Allows
ribosomes to
synthesise
peptide chains
Accepts
amino acid
Anticodon
Interacts with mRNA
DNA Sequencing
Human Genome Project
Metals in Biology - Structure
Zinc finger motif found in many DNA binding proteins
X-Cys-X
2-4
-Cys-X
3
-Phe-X
5
-Leu-X
2
-His-X
3-5
-His
Conserved residues bind to Zinc (II) and hold protein in
characteristic shape
Fits into major groove of DNA upon binding affects
expression of DNA encoded in genes

Metals in Biology Function
Dicopper Oxidases
Natural Products
Also known as secondary metabolites
A substance that has no known role in the
internal economy of the producing organism,
normally below 3000 MW
Many have defined ecological roles

Terpenes
Essential oils of many plants responsible for
fragrances and smells.
May or may not contain oxygens joined to or
in the hydrocarbon backbone.
Terpenes
Limonene
lemons
OH
Pinene
pine trees
OH
Terpineol
O
Menthol
mint
OH
Carvone
caraway
O
Thymol
thyme
O
Cineole
eucalyptus
Camphor
Medicinal Plants
Medicinal plants play a dominant role in the
primary healthcare of 80% of the worlds
population
In the remaining 20% of the worlds
population 50% of drugs in clinical use are of
natural origin.
There are written records going back 5000
years detailing the use of plants as medicines

Emperor Shen-nung
(the divine farmer)
2737 BC

Cowslips, Primula veris
Deadly nightshade, Atropa
belladonna
Henbane, Hyoscyamus
niger
Mint, Mentha pulegium
Pomegranate tree, Punica
granatum
Purple fox gloves, Digitalis
purpurea
Rosemary, Rosmarinus
officinalis
Saffron, Crocus sativus
Saxifrage, Saxifraga
cuneifolia
Thyme, Thymus vulgaris
Valerian, Valeriana
officinalis
Wormwood, Artemisia
absinthium
Medicinal Plants
Of the 119 plant derived drugs in common use, 74% were
discovered as a result of plants used in traditional
medicine.
These drugs are derived from only 90 species of plant.
Of the 250 000 known species of plant, little is known
about their potential to give us new drugs.
Of these plants, 60% are tropical and 40% are temperate.
The current global value of drugs derived from plants has
been estimated at 23 billion annually.
Papaver somniferum
Opium harvest
Morphine, codeine and heroin
Morphine
R
1
= R
2
= H
narcotic analgesic
Codeine
R
1
= Me, R
2
= H
narcotic analgesic
Heroin
R
1
= R
2
= (C=O)Me

O
R
2
O
H
R
1
O
NMe
Uses of morphine.
Uses of Heroin
In 1897, Felix Hoffmann
acetylated morphine to
make a non-addictive
alternative. He called it
the heroic drug, heroin
for the feelings it
created in the user.
Lifesaving Pharmaceuticals
NP as Medicines
61% of 877 small molecule NCEs introduced between
1981-2002 originated from NP:
6% NP
27% NP derivatives
5% synthetic with NP pharmacophores
23% NP mimics
78% of antibacterials originated from NP
74% of anticancer agents originated from NP
J Nat Prod 2003, 66, 1022
Willow bark gave the idea for a painkiller
CH
2
OH
O O CH
2
OH
OH
OH
HO
COOH
O CH
3
O
salicin
acetylsalicylic acid
(aspirin

)
lead structure
Aspirin
In 1899, Felix
Hoffmann, a chemist
with Bayer, acetylated
salicylic acid to give
aspirin.
O OH
O
O
Ephedra sp.
First recorded as ma-huang
by the Chinese emperor
Shen-Nung in 2700 BC
Used to improve circulation
and as cough suppressant
Drunk as tea in Africa (Khat,
Catha edulis) as euphoriant
and appetite suppressant
OH
NHMe
OH
NHMe
Ephedrine Pseudoephedrine
Bronchodilator Decongestant
Penicillium chrysogenum
Related to Penicillium
notatum first discovered by
Fleming and developed by
Florey and Chain before
WW II
This strain was found
growing on a mouldy
canteloupe melon at a
market in Peoria, Illinois

Penicillins
These antibiotics
revolutionised the
treatments of bacterial
infections
The penicillins are still
used for respiratory
infections, but resistant
strains are a real
problem
N
S
COOH
O
H
N
O
H
2
N
COOH
N
S
COOH
O
H H
H
N
Penicillin N - natural
Penicillin G - semi synthetic
Taxus brevifolia
The bark of the Pacific yew
was used by the Chumash
to ward of infections
Wani & Wall discovered it
contained the anti-cancer
agent taxol in the late 1960s
It was not approved until
the mid 1990s
Mainly used for breast and
ovarian cancers
Taxol
O
O
OAc
OH
AcO
BzO
OH
O NH Ph
O O
OH
Ph
Acts as mitotic spindle toxin
The rosy periwinkle (Catharanthus roseus) is
singlehandedly responsible for the 80% success
rate with childhood leukaemia.
Catharanthus roseus (Vinca rosea)
Used in Madagascar as treatment for diabetes
Once the extracts were injected into rats,
immune suppression resulted, similar to that
observed in anti-cancer drugs
The vinca alkaloids are tubulin binders arrest
the metaphase of mitosis

Vincristine/Vinblastine
NH
N
N
N
COOMe
OH
OCOMe
OH
H
MeO
R
COOMe
H
R = Me (Vinblastine)
R = CHO (Vincristine)
Podophyllum peltatum
Rhizomes of this tree (the
mayapple) were used by
native Americans to cure
warts
The active constituent,
podophyllotoxin, was
modified to give the anti-
cancer drugs etoposide and
teniposide
Podophyllotoxin
O
O
O
MeO
OMe
OMe
OH
H
H
O
O
O
O
MeO
OMe
OMe
O
H
H
O
O
O
O
OH
HO
R
R = Me (Etoposide)
R = (Teniposide)
S
Podophyllotoxin
Rauvolfia serpentina
The roots of this plant were
used to treat mentally ill
patients in India
Reserpine isolated in 1952
Used as tranquiliser now
superseded by librium/valium
It was once the only
treatment for schizophrenia
Also lowers blood pressure
first anti-hypertensive
Reserpine
NH
N
H
H
H
OMe
O
MeO
O
OMe
OMe
OMe
MeO
O
Reserpine
Modulators of Immune Function
N
O
O
H
3
C
O
O
O
H
O
H
3
C
OH
H
3
CO
H
3
C
CH
3
OH
H
H
3
CO
CH
3
O
CH
3
CH
3
OCH
3
H H
OH
CH
3
O
H
3
C
OH
H
3
CO
HO
O
N
O
O
O
OCH
3
H
3
C
OH
OCH
3
H
3
C
O
CH
2
H
3
C
Rapamycin FK-506 (Tacrolimus)
Large naturally derived molecules, discovered accidentally
Cyclosporin
Immunosuppressant
Made transplant surgery possible
Interferes with protein-protein interactions
N
N
N
N
N
H
N
N
H
N
N
H
N
N
H
O
O
O
O
O
O O
O
O
O
O
HO
H
From Neocosmospora vasinfecta, Tolypocladium inflatum
Isolated from soil sample from Hardanger Vidda (Norway)
Planet Ocean
How inappropriate to
call this planet Earth
when it is quite clearly
Ocean
Arthur C. Clarke
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The Dream
? ?
Biological Diversity = Chemical Diversity
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H
N
N
H H
Br N
O
N
OH
Br O
Br
N
N
O
HO
Br
O
OH
OH
COOH
O
O
OH
O
O
O
OH
O
OH
O
OH
HO
OH
OH
OH
O
OH
HO
OH
N
HO
H
H
H
HO
N
N
N
OH
N+
H
H
H
OH
H3C
O
OH
O
O
HO
O
O
HO
H
H H
H
OH
HO
O
HO
O
H
H
OH
OH
H
HO
O
O
NH
N
S
HN
S
N
NH
O
O
O
N
N
O
O
O
O
H
O
H
O HO
OH
OH
O
HN
N
N
O
O
O
N
HN
O
N
O
N
H
H
N
O
HN
O
HN
N
H
N
N
O
O
O
O
HN
O
H
N
NH
N
N
H
O
O
O
OH
O
N
OMe
Br Br
H
N
O
O
Br
Br
HO
R
H
N
N
O
OH MeO
Br
Br
O R
Br
Produce chemicals that act
as alternative immune system
Derive selectional advantages
Chemicals have specific targets
DRUGS?
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COLLECTION
Prialt (Neurex/Elan)
Conus geographus
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Ecteinascidin-743
Yondelis/Trabectidin (Pharmamar)
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Ecteinascidia turbinata.
N
N
O
O
HO
OMe
Me
Me
OAc
Me
H
OH H
H
H
O
S
O
NH
HO
MeO
Halaven/Halichondrin B (Eisai)
Halichondria okadai
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The Deepest Place on Earth
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Extreme Environments
Novel Organisms Novel Natural Products
Cultures
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Deep Oceans
95 % > 1000 m deep
50 % > 3000 m deep
Average depth = 3790 m
Skropeta D., Nat. Prod. Rep., 2008, 25, 1131-1166
Mariana Trench
-10911 m at
Challenger deep
Access via
JAMSTEC XBR
(Prof Koki
Horikoshi)
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Kaiko lost in 2003
The Deep
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Mariana Trench Compounds
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*
T. brucei
IC
50
MRC5
C 0.28 mM >50
E 1.57 mM >50
Dermacoccus abyssi