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Cisplatin Derivatives as Antiviral Agents
Figure 2.19. IdU.
47
Figure 2.20. Ribavirin.
Figure 2.21. Vidarabine.
Introduction to the Study of Macromolecules
48
2.3. CURRENTLY APPROVED PLATINUMCONTAINING DRUGS
Despite the fact that hundreds of cisplatin analogs have been made and
tested, only roughly 28 platinum compounds have been tested in clinical
trials as anticancer medicines. Only four of these are presently approved.
Cisplatin (Figure 2.22.), carboplatin (Figure 2.23.), oxaliplatin (Figure
2.24.), and nedaplatin have all been authorized (Figure 2.25.). Only the first
two are commercially accessible for use in cancer therapy.
Carboplatin (Figure 2.23.) is the most often used metal-containing
anticancer medication after cisplatin (Figure 2.22.). Although its cell-killing
power is similar to that of cisplatin, it has shown modest efficac in some
malignancies that are less susceptible to cisplatin, such as non-small cell
lung cancer. It also has a distinct pharmacokinetic profile.
The presence of the bidentate carboxylate moiety results in slower
reaction rates with the biological environment. As a result, it has reduced
nephrotoxicity and is favored for people with renal failure. It also demonstrates
a lower rate of serum protein binding, with just 10 to 20% permanently
bound to protein. This increases the bioavailability and concentrations of the
delivered medication by around a factor of five.
Figure 2.22. Cisplatin, Cis-DDP (Cis-diaminedichloroplatinum(II)).
Figure 2.23. Carboplatin (Diamine cyclobutane dicarboxylate platinum(II)
); cis-diamine-1,1-cy clobutanedicarboxylatoplatinum(II);cis-diamine(cyclobutane-1,1-dicarboxylato)-platinum(II).
Cisplatin Derivatives as Antiviral Agents
Figure 2.24. Nedaplatin (cis-diamineglycolatoplatinum (II)).
49
Figure 2.25. Oxaliplatin (Oxalatoplatinum(II)).
2.4. ACTIVE FORM OF CISPLATIN
Whereas the active forms of polymeric derivatives of cisplatin can vary,
it may well be helpful to understand how well the active component of
cisplatin itself is active both against cancers and viruses as a preliminary
step for comprehending how polymeric forms are effective against both
cancers and viruses.
Cisplatin is observed to undergo spontaneous hydrolysis in an
aqueous solution. As indicated in Eq. 2.1, the reaction creates species
such as monoaquo platinum and diaqua platinum complexes as a result of
nucleophilic substitution in water.
Eq. 2.1
Moreover, Other aqueous species can occur, including hydroxy
complexes, as shown in Figures 2.26. and 2.27. The hydroxyl species is pH
Introduction to the Study of Macromolecules
50
dependent. At pH 7.4, 85 percent of the monohydrated complex is in the less
reactive dihydroxy state. When the pH is reduced to 6.0, the most frequent
form (80 percent) is the monohydrate species.
As a result, the number of potential aquated forms formed from
cisplatin is large and highly dependent on pH, temperature, duration, and
the concentration of related reactants such as chloride ion and ammonia.
Diagram 2.1 has structures of several of these cisplatin aquated forms,
including those already mentioned.
The relatively high chloride concentration (about 100 mM) in blood
minimizes hydrolysis and the formation of aquated species. Once inside
of the cell, where the chloride ion concentration is much lower (~4 mM),
hydrolysis readily occurs giving a number of aquated species including the
diaqua complex. At 37 °C the half-life for the completion of the formation of
the diaqua complex is 1.7 hours with an activation energy of about 20 Kcal/
mol (80 KJ/mol). Although the active form within the cell is believed to
be the monohydrated structure (Figure 2.28.), the “preferred” extracellular
species contains two cis-oriented leaving groups that are normally chloride
ligands.
As noted, before, due to the high chloride ion concentration in blood
these leaving groups will remain in position resulting in the molecule
being electrically neutral until it enters the cell, as a result, the molecule is
electrically neutral until it reaches the cell.
Figure 2.26. Selected aquated forms of cisplatin.
Figure 2.27. Selected aquated forms of cisplatin.
Cisplatin Derivatives as Antiviral Agents
51
Figure 2.28. Selected aquated forms of cisplatin.
As previously stated, cis-DDP reaches cells through diffusion and
is transformed into an active form. The decreased intracellular chloride
concentration increases ligand exchange of chloride for water, resulting in
the formation of the active aquated complex. To enter the cell, the platinumcontaining complex must be neutral, and labile chloride groups must be
present to generate the active species within the cell.
As a monoaquo species, cis-antineoplastic DDP’s effe t appears to be
due to its interaction with DNA nucleotides. The monohydrated complex
combines with the nucleotides in the DNA to create intra and interstrand
crosslinks. Cis-DDP has been demonstrated to preferentially interact with
guanine among the four nucleic acid bases. Intrastrand crosslinks between
neighboring guanines are by far the most prevalent.
There are various conceivable DNA crosslinks. In an A-T rich area, one
preferred interstrand option occurs between the 6-NH groups of adenines
Introduction to the Study of Macromolecules
52
on opposing strands. This is due to the fact that these groups are around 3.5
apart, which is close to the 3 distance between the cis leaving groups on the
platinum.
Cross-linking between the amino groups guanine and cytosine in
opposing strands is the second preferred approach. This is preferred because
the platinum is at right angles to the bases, which are coplanar. This means
that the bases must either “bend down” or “turn edge” to reach the required
conformation to bind to the platinum complex.
This binding arrangement is thought to cause secondary structure
disruption and mild double helix disruption. This is enough to block DNA
replication and transcription, causing cell death, but too tiny to trigger a
reaction by damage detection proteins, resulting in excision of the damaged
section and strand repair.
Though cisplatin may generate many different forms of crosslinks,
intrastrand crosslinks are the most prevalent. The majority of these crosslinks
can be repaired, however, at least one form of interstrand crosslink may not
cause cellular repair enzymes to respond. Furthermore, while intrastrand
crosslinks are significant in characterizing cisplatin action, triggering
apoptosis appears to be a role in cisplatin’s anticancer process.
Whereas cis-DDP is thought to function within the cell, other platinumcontaining compounds, such as the so-called “platinum blues,” appear to
act on the cell membrane. As a result, the specific manner and location of
activity may diffe . Although cisplatin’s undeniable effec iveness, restrictions
exist, including severe toxic side effects. These toxic side effects include
gastrointestinal problems such as acute nausea, vomiting, and diarrhea;
rare cases of liver dysfunction; myelosuppression involving anemia,
leukopenia, and thrombocytopenia; nephrotoxicity; and, less frequently,
immunosuppression, hypo magnesia, hypocalcemia, and cardiotoxicity.
The most significant adverse effect is renal damage. Most of the cis-DDP
supplied is filtered out of the body within a few hours, exposing the kidneys
to bursts of high platinum concentrations. The renal difficultie are thought
to be caused by the quick pace at which the kidneys filter platinum from the
blood. Another issue is the permanent and cumulative hearing loss.
2.5. STRUCTURE-ACTIVITY RELATIONSHIPS
The issue of structure-activity correlations is difficult and poorly established
for anticancer action, and its potential to suppress viruses is unclear. Most
Cisplatin Derivatives as Antiviral Agents
53
approaches involving cisplatin polymeric derivatives are predicated in part
on the premise that the platinum-containing polymer will behave similarly
to cisplatin itself.
However, it is probable that at least some of these polymeric medicines
limit cancer development in other ways. Although this complicates overall
methods, it may be a benefit since they would work in a different way to
supplement cisplatin as a medicine.
As a result, they may act in a variety of ways, allowing cancer
development to be inhibited by a variety of pathways. Nonetheless, it may be
useful to review some structure-activity connections identified for cisplatin
as an anticancer drug.
Despite the fact that numerous promising products have been developed,
underlying structure-activity connections remain unknown for a variety
of reasons, not the least of which is that various platinum-containing
compounds may suppress cancer development in different ways. As a result,
the following discussion should be seen as a single quick attempt to describe
broad structure-activity correlations.
First, there should be two anionic leaving groups available, such as
chloride, bromide, or oxalate. Except for the exceptionally labile malonato
ligand, bidenate chelating groups such as dicarboxylate dianions are
frequently preferred to monodentate ligands due to their greater ability to
remain intact in the circulation.
Complexes with more labile groups, such as the nitrate ion, hydrolyze
too quickly for in vivo application, while ligands, such as the cyanide
ion, bind the platinum too firml , reducing its activity. Furthermore, such
complexes should have cis geometry and be neutral, with moderately
innocuous amine or nitrogen donor groups. The molecule’s neutrality is
thought to help the platinum-containing medication to pass more easily
across the cell membrane. The amines should really be primary or secondary
amines, allowing for hydrogen bonding. Because of the comparatively high
Pt–N bond strength, amines and similar ligands are tightly bound, whereas
leaving groups such as chlorides and carboxylate anions are weakly bonded
and easily replaced by other nucleophiles. With these aqua structures that
are replaceable, a multitude of aqua complexes is produced.
Whenever the pH exceeds 6.0, chloride displacement by the hydroxyl
anion is preferred, resulting in complexes containing the hydroxo group, a
generally weak leaving group.
Introduction to the Study of Macromolecules
54
2.6. ARGUMENTS FOR CISPLATIN-DERIVATIVE DRUGS
Since Rosenberg discovered that cisplatin is an excellent anti-cancer agent,
major synthesis and assessment projects have sought to develop cisplatin
derivatives with stronger and more widespread anticancer efficacy but lower
toxicity. Recent research has concentrated on the development of platinumcontaining homing compounds that function directly at the desired tumor
location.
Oncologists all around the world have used the cytotoxic activity of
a wide range of medication systems to treat cancer for decades. Despite
undeniable success in cancer chemotherapy, particularly in conjunction with
surgery and other treatment modalities, multiple significantpharmacological
shortcomings of anticancer medications have been widely acknowledged in
the medical community.
Most medications lack cell specificit , making it impossible to distinguish
between normal and malignant cells. As a result, they frequently produce
severe and dose-limiting systemic toxicity. They instantly reveal themselves
as targets for scavenger proteins or as substrates for glomerular filtration and
first-pass liver metabolism as extraneous agents.
As a result, serum residence periods are frequently short, the majority
of given dosages are prematurely eliminated (and hence squandered), and
bioavailability (concentration in the target tissue) is typically poor. Many
medications have polar, charged, or salt-like properties. As a result, they
are poor substrates for membrane penetration, intracellular trafficking and
cell entrance via the passive diffusion process that is shared by neutral and
nonpolar substances.
Furthermore, medicines with low water solubility are slowly and
incompletely dispersed in the central circulation, making them accessible
targets for the reticuloendothelial system. Finally, and most significantl ,
acquired drug resistance, which progressively develops in target cells
after initially effective chemotherapy, is a reasonably common event that
necessitates early treatment discontinuation. As a result of these flaws, the
therapeutic window is restricted and overall chemotherapeutic efficac is
severely reduced.
Another method to overcome these shortcomings is to turn the active
substance into a prodrug which will experience little hindrance from
scavenger processes. This prodrug would be able to penetrate intercellular
Cisplatin Derivatives as Antiviral Agents
55
membranes and approach the target location, which in cancer treatment
implies breaking into the malignant cell’s lysosomal compartment. One such
kind of prodrug is characterized by the inclusion of a platinum-containing
compound in polymers.
2.7. ARGUMENTS FOR POLYMERIC DRUGS
Polymers can function as transporters, medications, or a mix of the two. This
subject is covered in greater depth in research. Polymers with numerous
positive components, such as homing devices and the “bullet,” can be
created as carriers. The polymer can also be changed to obtain solubility
in water, appropriate control release kinetics, a balance of hydrophilic and
hydrophobic character, as well as nontoxic and nonimmunogenic properties.
Its size serves to protect the medicine from serum protein attack, resulting
in longer serum circulation half-lives. An often-mentioned molecular weight
range is 25,000 to 80,000, which will delay early renal excretion while
limiting harmful consequences as evidenced by high molecular weight
polymers occasionally.
The carrier-attached medication, whether polar or charged, will be
delivered into the intracellular space through a pinocytotic cell entry
mechanism, overcoming probable influx inhibition or efflu acceleration
caused by certain well-defined drug resistance mechanisms. The inclusion
of potentially cationic moieties, such as tert-amino groups, speeds up the
process. Cationic regions in polymers are known to improve pinocytosis
while also boosting affinit for the neoplastic cell, which is negatively
charged in many malignancies. Finally, the enhanced permeability and
retention (EPR) effect associated with macromolecules, as opposed to tiny
chemicals, allows polymers to be distributed preferentially to tumoros tissue.
As a result, conjugate buildup in the tumor is preferential to that in
healthy tissue. As a result, systemic toxicity is decreased as well as increased
bioavailability the drug-containing polymer can also function as a drug.
The incorporation of the cisplatin-like molecule into a polymer is
expected to accomplish the following:
1. It will restrict the physiologically active drug’s movement.
Polymers, due to their bulk, are more difficul to penetrate through
bodily membranes. Cisplatin is rapidly eliminated from the body,
exposing the kidney and other organs to high levels of platinum.
Introduction to the Study of Macromolecules
56
Polymers having chain lengths of 100 units or more often have difficul
moving across biological membranes. Restricted mobility may reduce renal and
other organ damage by preventing a buildup in the kidneys and other organs.
Moreover, platinum from polymers might be released gradually, decreasing
organ exposure to high concentrations of platinum-containing complexes.
2. This may boost activity by increasing the possibility of numerous
bonding contacts at a given location (e.g., chemical bonding,
hydrogen bonding, hydrophobic interactions).
3. It should improve bioactive moiety delivery while decreasing
toxicity. Cisplatin hydrolyses in aqueous solutions with a reaction
half-life of nine hours at ambient temperature or 2.4 hours at 37
°C. Cisplatin hydrolyzes in the body, producing a wide range of
platinum-containing compounds, none of which are as active as
cisplatin and most of which are hazardous to the body.
The formation of these hydrolysis products increases the quantity of
platinum complex required to achieve the desired tumors decrease. As a
result, the number of platinum complexes that must be digested by the body
rises. The polymeric structure should also protect the platinum moiety from
undesired hydrolysis, so by increasing the concentration of platinum in the
favorable form preserved in the body as a result, smaller effective dosages of
the medicine can be utilized. The more hydrophobic polymer chain should
also shield the platinum moiety from direct water attack.
4. It should be able to avoid the cell’s protection mechanism. As
a result of the invasion of other chemo medicines, the cell’s
defense reaction is active. According to recent research, the entry
of chemotherapy medications into cells induces the accumulation
of “housekeeping” proteins, which are fairly universal in their
capacity to pick and eliminate foreign chemicals existing in the
cell. This might be one of the main reasons why chemo treatments
cause drug resistance, even to medications that have never been
used before. The polymeric structure of the platinum carriers may
deter housekeeping proteins from removing them, allowing the
polymers to operate as anticancer medications in situations where
smaller platinum-containing pharmaceuticals fail.
2.8. POLYMER SYNTHESIS
The polymers were made by combining equal molar water solutions of
potassium tetrachloroplatinate II and the diamine-containing reactant, and