DOXORUBICIN
The exact mechanism of action of doxorubicin is
complex and still somewhat unclear, though it is thought to interact with DNA
by intercalation. Doxorubicin is known to interact with DNA by intercalation
and inhibition of macromolecular biosynthesis. This inhibits the progression of
the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription.
Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA
chain for replication, preventing the DNA double helix from being resealed and
thereby stopping the process of replication.
The planar aromatic chromophore portion of the
molecule intercalates between two base pairs of the DNA, while the six-membered
daunosamine sugar sits in the minor groove and interacts with flanking base
pairs immediately adjacent to the intercalation site, as evidenced by several
crystal structures.
Intercalation occurs when ligands of an
appropriate size and chemical nature fit themselves in between base pairs of
DNA.
ETOPOSIDE
Etoposide phosphate (brand names: Eposin, Etopophos,
Vepesid, VP-16) is an anti-cancer agent. It inhibits the enzyme topoisomerase
II, which unwinds DNA, and by doing so causes DNA strands to break.
Etoposide forms a ternary complex with DNA and the
topoisomerase II enzyme, preventing re-ligation of the DNA strands. This causes
errors in DNA synthesis and promotes apoptosis of the cancer cell.
CAMPTOTHECIN
Camptothecin (CPT)cytotoxic quinoline alkaloid which
inhibits the DNA enzyme topoisomerase I. CPT binds to the topo I and DNA
complex (the covalent complex) resulting in a ternary complex, and thereby
stabilizing it. This prevents DNA re-ligation and therefore causes DNA damage
which results in apoptosis. CPT binds both to the enzyme and DNA with hydrogen
bonds.
Toxicity of CPT is primarily a result of conversion
of single-strand breaks into double-strand breaks during the S-phase when the
replication fork collides with the cleavage complexes formed by DNA and CPT
RIFAMPICIN
Rifampicin inhibits DNA-dependent RNA polymerase in
bacterial cells by binding its beta-subunit, thus preventing transcription to
RNA and subsequent translation to proteins. Its lipophilic nature makes it a
good candidate to treat the meningitis form of tuberculosis, which requires
distribution to the central nervous system and penetration through the
blood-brain barrier.
Rifampicin acts directly on messenger RNA synthesis.
It inhibits only prokaryotic DNA-primed RNA polymerase, especially those that
are Gram-stain-positive and Mycobacterium tuberculosis. Much of this
acid-fast positive bacteria's membrane is mycolic acid complexed with
peptidoglycan, which allows easy movement of the drug into the cell. Evidence
shows that in vitro DNA treated with concentrations 5000 times higher than
normal dosage remained unaffected; in vivo eukaryotic specimens' RNA and DNA
polymerases suffered few problems as well. Rifampicin interacts with the β
subunit of RNA polymerase when it is in an α2β trimer. This halts mRNA
transcription, therefore preventing translation of polypeptides. It should be
made clear, however, that it cannot stop the elongation of mRNA once binding to
the template-strand of DNA has been initiated. The Rifampicin-RNA polymerase
complex is extremely stable and yet experiments have shown that this is not due
to any form of covalent linkage. It is hypothesized that hydrogen bonds and π-π
bond interactions between naphthoquinone and the aromatic amino acids are the
major stabilizers, though this requires the oxidation of naphthohydroquinone which
is found most commonly in Rifampicin. It is this last hypothesis that explains
the explosion of multi-drug-resistant bacteria: mutations in therpoB gene that
replace phenylalanine, tryptophan, and tyrosine with non-aromatic amino acids
result in poor bonding between Rifampicin and the RNA polymerase.
Well due to blocking in RNA transcription, DNA
initiation is also not possible since the primer synthesis is also blocked by
the drug.
APHIDICOLIN
Aphidicolin is defined as a tetracyclic diterpene antibiotic
with antiviral and antimitotical properties. Aphidicolin is a reversible
inhibitor of eukaryotic nuclear DNA replication. It blocks the cell cycle at
early S phase. It is a specific inhibitor of DNA polymerase A, D in eukaryotic
cells and in some viruses and an apoptosis inducer in HeLa cells.
NOVOBIOCIN
The molecular basis of action of novobiocin,
and other related drugs clorobiocin and coumermycin A1 has been examined.
Aminocoumarins are very potent inhibitors of bacterial DNA gyrase and work by
targeting the GyrB subunit of the enzyme involved in energy transduction.
Novobiocin as well as the other aminocoumarin antibiotics act as competitive
inhibitors of the ATPase reaction catalysed by GyrB. The potency of novobiocin
is considerably higher than that of the fluoroquinolones that also target DNA
gyrase, but at a different site on the enzyme. The GyrA subunit is involved in
the DNA nicking and ligation activity.
CIPROFLOXACIN
Ciprofloxacin is a broad-spectrum antibiotic active
against both Gram-positive and Gram-negative bacteria. It functions by
inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, enzymes
necessary to separate bacterial DNA, thereby inhibiting cell division.
- Actinomycin -binding between adjacent G-C bases in DNA (intercalation
- chloramphenicol- inhibits peptidyltransferase of the 70S ribosome
- erythromycin - binds to the 50S particle and arrests synthesis of the 70S ribosome
- neomycin- binds to the 30S ribosomal subunits and inhibits binding of a tRNA
- puromycin- premature chain termination
- Rifamycin- inhibits RNA synthesis by binding to the β subunit of the RNA polymerase holoenzyme
- streptomycin as erythromycin
- tetracyclin -inhibits binding of tRNA to the 30S ribosomal subunit in eukaryotes
- α-amanitin - inhibits polymerase II
- chloramphenicol - inhibits peptidyltransferase of the mitochondrial ribosome
- cycloheximide -inhibits peptidyltransferase
- diptheria toxin - inhibits factor 2 and translocation
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