Intercalating Drugs On
DNA
A presentation of Medicinal Chemistry
Instructor: Dr. M. Nawaz
Presentors:
M. Azam Ali (55331)
M. Shahzaib Ali Shah (55348)
Table of contents
Introduction
01 02
Proflavine Dactinomycin
03 04
Doxorubicin Bleomycins
Introduction
• Intercalating drugs are compounds that
contain plannar or heteroaromatic features
which slip between the base-pair layers of the
DNA double helix.
• Once they are inserted between the nucleic
acid base pairs, the aromatic/heteroaromatic
rings are held there by van der Waals
interactions with the base pairs above and
below.
Introduction
● Several intercalating drugs also contain ionized groups which can
interact with the charged phosphate groups of the DNA backbone,
thus strengthening the interaction.
● Once the structures have become intercalated, a variety of other
processes may take place which prevent replication and
transcription, leading, finally, to cell death. The following are
examples of drugs that are capable of intercalating DNA.
1. Proflavine
● A group of antibacterial compounds called the aminoacridines.
● which were used during World Wars I and II to treat deep surface
wounds.
● Proflavine is completely ionized at pH 7 and interacts directly with
bacterial DNA.
● The flat tricyclic ring intercalates between the DNA base pairs and
interacts with them by van der Waals forces, while the aminium
cations form ionic bonds with the negatively charged phosphate
groups on the sugar phosphate backbone.
1. Proflavine
● Once inserted, proflavine deforms the DNA double helix and
prevents the normal functions of replication and transcription.
2. Dactinomycin
● It is a naturally occurring antibiotic that was fi rst isolated from
Streptomyces parvullis in 1953, and was shown to be an effective
anticancer agent in children.
● It contains two cyclic pentapeptides, but the important feature is a
flat, tricyclic, heteroaromatic structure which slides into the double
helix via the minor groove.
● It appears to favour interactions with guanine–cytosine base pairs
and, in particular, between two adjacent guanine bases on alternate
strands of the helix.
2. Dactinomycin
● The molecule is further held in position by hydrogen bond
interactions between the nucleic acid bases of DNA and the cyclic
pentapeptides positioned on the outside of the helix.
3. Doxorubicin
● It is one of the most effective anticancer drugs ever discovered, and
belongs to a group of naturally occurring antibiotics called the
anthracyclines.
● It was first isolated from Streptomyces peucetius in 1967 and
contains a tetracyclic system where three of the rings are planar.
● The drug approaches DNA via the major groove of the double helix
and intercalates using the planar tricyclic system.
3. Doxorubicin
● The drug approaches DNA via the major groove of the double helix
and intercalates using the planar tricyclic system.
● The charged amino group attached to the sugar is also important, as
it forms an ionic bond with the negatively charged phosphate groups
of the DNA backbone.
● This is supported by the fact that structures lacking the aminosugar
have poor activity.
3. Doxorubicin
● Intercalation prevents the normal action of an enzyme called
topoisomerase II.
● When doxorubicin is intercalated into DNA it stabilizes this DNA–
enzyme complex and stalls the process.
● Agents such as doxorubicin are referred to as topoisomerase II
poisons rather than inhibitors, as they do not prevent the enzyme
functioning directly.
4. Bleomycins
● These are complex natural products that were isolated from
Streptomyces verticillus in 1962 and are some of the few anticancer
drugs not to cause bone marrow depression.
● Their structure includes a bithiazole ring system which intercalates
with DNA.
● Once the structure has become intercalated, the nitrogen atoms of the
primary amines, pyrimidine ring, and imidazole ring chelate a
ferrous ion which then interacts with oxygen and is oxidized to a
ferric ion.
4. Bleomycins
● These highly reactive species abstract hydrogen atoms from DNA,
which results in the DNA strands being cut—particularly between
purine and pyrimidine nucleotides.
● Bleomycin also appears to prevent the enzyme DNA ligase from
repairing the damage caused.
4. Bleomycins
Thank
You
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