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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5542_Библиотеки_им_академика_М_И_Перельмана.pdf
Cisplatin Derivatives as Antiviral Agents
57
the resultant polymer was collected as a precipitate. Polymer formation can
take anywhere from a few minutes to many days, depending on the reactivity
of the Lewis base.
Polymers can be produced in gram amounts or in greater quantities as
needed, using basic equipment and commercially accessible reactants. As a
result, the polymers are well suited for commercialization.
2.9. ANTIVIRAL ACTIVITY
Certain malignancies are thought to have a viral connection. As such,
studying the viral response to certain platinum polymers is instructive.
Tetramisole is an antihelmintic that works by inhibiting cyclic nucleotide
phosphodiesterases. It is actually a mixture of optical isomers, the most
active of which is levamisole. Levamisole was the first synthetic molecule
to be discovered to have immunomodulatory effects. It seems to return
macrophage and T-lymphocyte functioning to normal.
Cisplatin polymer analogues created by reacting tetrachloroplatinate
with tetramisole were investigated in ICR Swiss male mice for their potential
to suppress EMC-D viruses that cause the emergence of juvenile diabetes
symptoms.
In brief, the mice were given doses of 1, 5, and 10 mg/kg. In comparison
to untreated mice, doses of 1 and 5 mg/kg reduced the severity and incidence
of virus-induced diabetes. In another set of testing, dosages of 1 and 10
mg/kg were given 1 day before the viral injection, however, there was an
increase in the severity and incidence of virus-induced diabetes. Other tests
revealed that the polymer had distinct activity profiles than the tetramisole
(Figure 2.29.).
Methotrexate is a folic acid antagonist that inhibits purine synthesis
indirectly. It is especially effective in rapidly reproducing cell types such as
cancer. It inhibits the production of primary and secondary antibodies, the
homograft reaction, the graft-versus-host response, and the development of
hypersensitivity. Methotrexate is used to cure some malignancies. Longterm usage is extremely harmful, especially to the liver. The usage of folinic
acid reverses the harmful impact of methotrexate. This “discovery” resulted
in the invention of the “rescue procedure,” in which the most quickly
proliferating cells are destroyed while the remaining cells remain unaffected
The polymers were created by combining equal molar water solutions of
potassium tetrachloroplatinate II and methotrexate, and the resultant polymer
Introduction to the Study of Macromolecules
58
(Figure 2.30.) was collected as a precipitate. A methotrexate polymer (Figure
2.30.) was evaluated in research comparable to that of tetramisole. Female
mice were treated in the original trial. Only male IRC Swiss mice acquire
diabetes-like symptoms. Female mice must first be treated with testosterone
before they can acquire diabetes-like symptoms.
The mice were placed into three groups, each of which got polymer
injections (0.5 cc IP of a polymer solution containing 6.4 mg/kg). A week
later, testosterone was administered to Groups I and II. On day 8, group 1
received a second 0.5 cc intraperitoneal (i.p.) inoculation of the polymer
solution. On day 9, all groups got 1 104 pfu (plaque forming units) of
EMC-D virus. On day 17, all mice were subjected to a one-hour glucose
tolerance test.
Figure 2.29. Tetramisole.
Figure 2.30. Methotrexate Polymer.
The glucose levels in groups I and III were comparable and much lower
than the levels in diabetic mice in group II. This is consistent with the polymer
successfully inhibiting the virus’s diabetogenic effect . Furthermore, other
findings from this study suggested that this breed of female mice was
vulnerable to developing diabetes-like symptoms even without testosterone
therapy.
A similar investigation, but with male mice, was conducted. Again,
the polymer (Figure 2.30.) had a stronger favorable effect on diabetes
Cisplatin Derivatives as Antiviral Agents
59
management than either of the reactants. For the polymer-treated animals,
glucose levels were comparable to noninfected mice.
Again, the integration of both platinum and methotrexate into a polymer
proved an effective agent, rather than either medication alone. These two
investigations are connected to the development of a vaccination that can be
used to prevent the onset of -cell damage caused by RNA viruses.
The third trial concentrated on therapy after viral infection. The polymer
was 100 percent efficien in viral control when administered 1 day after the
mice were infected (Figure 2.30.). In conclusion, the methotrexate polymer
(Figure 2.30.) is a potent antiviral agent against at least the EMC RNA virus.
Researchers recently investigated the antiviral activity of methotrexate,
tetrachloroplatinate, a physical combination of methotrexate and
tetrachloroplatinate, and a methotrexate-platinum polymer. A similar
investigation was conducted using tilorone and a tilorone derivative, as well
as cisplatin polymeric compounds.
For these research assays, each cell line was specifica ly chosen to be
compatible with the virus’s development. DSC-1 cells are kidney epithelial
cells from African green monkeys, mouse L929 cells are fibroblast cells,
Vero cells are kidney epithelial cells from African green monkeys, and
human 143 cells are fibroblast bone osteosarcoma cells
The viruses were chosen to illustrate a wide spectrum of viruses. The
reovirus ST3 virus is an RNA virus that is now being studied due to its
potential to suppress particular cancer cells while leaving normal cells
alone. In general, medications that can block one RNA virus will be effective
against other RNA viruses.
The other viruses are all DNA viruses, and their action against distinct
DNA viruses must be researched separately. Vaccinia causes smallpox;
herpes simplex causes at least 45 million infections every year in the United
States, or one out of every five adolescents and adults; and varicella-zoster
causes chickenpox and shingles.
The cell lines utilized for viral replication experiments are cancer cell
lines in order to provide a measure of the test agents’ capacity to limit cell
proliferation. Each cell line is carefully selected to be compatible with the
virus’s proliferation. All of the cell lines have been transformed. Table 2.1
shows the GI50 values for these chemicals in g/ml for the various cell lines.
Viral replication experiments are conducted at doses where cell mortality is
less than 5%.
Introduction to the Study of Macromolecules
60
For comparison, Cisplatin has a GI50 of 50 g/ml in L929 cells.
Therefore, with the exception of tetrachloroplatinate, all of the examined
compounds have GI50 values lower than cisplatin and, with the exception
of tetrachloroplatinate, equal ability to suppress cell growth.
Table 2.1.Toxicity of methotrexate-related compounds to cancer cell lines
Compound GI50(microgram/mL)
L929 Cells 143 Cells Vero Cells BS-C-1 Cell
K
PtCl
2
4
375 275 225 225
Methotrexate 15 10 12 10
Polymer 10 10 10 12
Methotrexate Mix 12 8 10 10
Table 2.2. Inhibition concentrations (µg/ml) for the tested compounds
→Tested compound K2PtCl
Methotrexate Polymer mixture
4
Reovirus ST3
GI50
GI100
*
GI150
*
GI100
-
-
-
-
Vacinia WR
GI50
GI100
*
GI150
*
GI100
-
-
-
8
4
-
HSV-I
GI50
GI100
*
GI150
*
GI100
-
-
-
-
2
8
2
8
3
6
3
3
2
4
2
2
VZV
GI50
GI100
*
GI150
*
GI100
-
-
-
-
3
8
3
8
4
4
2
4
4
6
2
3
Tables 2.1 and 2.2 present early findings on the potential of several
polymeric medicines to suppress DNA and RNA related viruses. The
Cisplatin Derivatives as Antiviral Agents
61
findings are provided in the form of four experiments, each with duplicate
samples. Table 2.2 summarizes the capacity of each chemical to suppress
viral growth using a plaque reduction test. Tetrachlorate is virtually inert
against the viruses examined. Methotrexate, tetrachloroplatinate, and the
polymer all have good activity against HSV-1 and VZV, both DNA viruses
whose genome replication occurs in the nucleus, with some activity against
vaccinia virus, a DNA virus with cytoplasmic DNA replication, and no
activity against reovirus, a dsRNA virus with cytoplasmic replication.
At lower doses than methotrexate, the polymer and physical combination
demonstrate excellent action. Table 2.3 also includes the GI50 and GI100
values for the different compounds, as well as columns depending on the
quantity of methotrexate itself, because much of the action appears to be due
to the presence of methotrexate and little, if any, from tetrachloroplatinate.
It is noticed that the polymer often has the lowest inhibition
concentrations, which is consistent with the polymer’s stronger capacity to
block the tested viruses. Polymer activity may occur from methotrexatecontrolled release, the polymer itself functioning as a medication, or some
mix of the two extremes.
In conclusion, methotrexate, the combination, and the polymer are all
active against HSV-1 and VZV viruses, however, tetrachloroplatinate had
little or no action against any of the viruses tested. The polymer and the
combination showed the best inhibition, that is, inhibition at the lowest
concentration, consistent with a cooperative impact of the methotrexate and
platinum moieties.
It is probable that when tetrachloroplatinate and methotrexate were
combined together in solution, they created a polymer, which is consistent
with comparable findings for the combination and polyme .
The same research was done using tilorone and a tilorone derivative
(Figure 2.31.). A molecular compound comprising tilorone and RNA is
known to have an antiviral action comparable to polynucleotide interferon
(IFN) inducers such as poly(I)-poly(C), larifan, and ridostin. It’s probable
that the present reactions are connected to this.
Tilorone, 2,7-bis[2-9diethylamino) ethoxy]-9H-fluorene-9-one is the
first synthesized small molecule structure that has been identified as an
orally active interferon inducer. A number of comparable structures were
synthesised due to their potential relevance. These derivatives are assigned
differentnumerals after the term tilorone. One of these derivatives is tilorone.
Introduction to the Study of Macromolecules
62
Figures 2.32. and 2.33. show the structures of platinum polymers.
Each is a cis-derivative that follows the trans-effect. Table 2.3. shows the
toxicity of tilorone polymers to several cell lines in ng/ml. Both chemicals
had equivalent toxicity to the cancer cell lines studied, but not to the partly
transformed Balb 3T3 cells.
To compare, cisplatin has a GI50 of 50,000 ng/ml, which is more than
250 times that of any platinum-tilorone polymer. Table 2.4.summarizes
preliminary research on the efficac of Pt-tilorone polymeric medicines to
inhibit DNA and RNA related viruses.
Table 2.3. Toxicity of tillorone compounds to various cell lines
Compound GI50(nanogram/mL)
L929 Cells 143 Cells Vero Cells BS-C-1
Cells
Pt-Tilorone
11.567
Pt-Tilorone 180 125 175 200 500
225 200 175 200 10,000
Balb 3T3
Cells
Figure 2.31. Tilorone.
At small doses, both of the tillorone polymers inhibited all of the viruses
tested. In comparison, the organotin polymers of norfloxacin and ampicillin
inhibited these identical viruses effectively at somewhat greater doses,
Cisplatin Derivatives as Antiviral Agents
Figure 2.32. Product of potassium tetrachloroplatinate II and tilorone.
63
Figure 2.33. Product of potassium tetrachloroplatinate II and tilorone 11,567.
Table 2.4. Plaque-reduction assay results for the platinum-tilorone polymers
Compound GI
Concentration(ng/ml)
99+
Reovirus ST3 Vaccinia WP HSV-I BS-C-1 C
Pt-Tilorone
200 150 150 150
11.567
Pt-Tilorone 125 100 125 100
Figure 2.34. Polymer derived from tetrachloroplatinate.
Introduction to the Study of Macromolecules
64
within in the range of less than 1 to 2 mg/ml, whereas tilorone compounds
demonstrated excellent efficac at 0.2 mg/ml, as previously stated. To
summarize, tilorone polymers block both RNA and DNA viruses and should
be investigated further as an antiviral drug in the fight against viruses and
potential bioterrorism employing viruses.
Furthermore, they demonstrate excellent reduction of virus replication
in both transformed and normal cell lines, a state that more closely resembles
human antiviral treatment.
A number of platinum polyamines have been evaluated in tumor cells for
antiviral effica . For example, a polymer derived from tetrachloroplatinate
and 2,6-diamino3-nitroso-pyridine (Figure 2.34.) with a cell differentialratio
of 3.4 was evaluated on L929 cells infected with Encephalomyocarditis at a
dosage of 2.2 g/ml (EMC)MM virus strain A viral decrease of around 25%
was seen. This is regarded as a moderate antiviral reaction.
Agents generally, that inhibit one RNA virus will often inhibit other
RNA viruses, whereas each DNA virus must be studied independently.
Platinum polyamines were tested for their antiviral activity against RNA
viruses. The behavior toward RNA viruses varied, with some displaying
minimal action but the majority indicating suppression of viral reproduction
at polymer concentrations lower than that required for tumor inhibition (1
g/ml).
The effect of platinum polyamines on SV40 viral transformation of 3T3
cells was also investigated. In conclusion, these polymers had no influence
on the process of transformation.
2.10. VANADOCENE-CONTAINING POLYMERS
Mostly all vanadium-containing organometallics are generated primarily
from dicyclopentanylenevanadium (IV) dichloride and vanadocene
dichloride. Vanadocene dichloride and its derivatives belong to a class
of chemicals known as deformed sandwich compounds. Vanadocene
dichloride, unlike ferrocene, has distorted tetrahedral geometry, with the
cyclopentadienes facing the vanadium atom. It has structural similarities to
a variety of other metallocene dichlorides, including those with Ti, Zr, Hf,
Mo, and Nb as the metal. These compounds have comparable geometries as
well as chemical reactions and biological activity.
The primary application of these metallocenes is as catalysts in
the manufacture of a variety of stereoregular vinyl polymers such as
Cisplatin Derivatives as Antiviral Agents
65
polyethylene and polypropylene. These are also being studied for their
biological properties.
Because the biological activity is a primary driving force in the
synthesis of polymeric derivatives, we will quickly cover some of this work,
concentrating on vanadocene dichloride as the molecule more commonly
researched.
2.11. ANTICANCER ACTIVITY
The deformed tetrahedral metallocene dihalides are a type of hydrophobic
organometallic anticancer drug that inhibits several cancer cell types. They
inhibit leukemias P388, L1210, colon 38, Lewis lung carcinomas, B16
melanoma, and solid and fluid Ehrilich ascites tumors. Titanocene dichloride,
which is now in phase II clinical studies, is active against xenografted
malignancies of the rectum, stomach, colon, breast, neck, and stomach.
Titanocene and vanadocene dichloride both impede DNA and RNA
replication in nucleic acid-rich tumor cells. As a result, it is thought that the
formation of DNA-metallocene adducts in vivo plays a role in their capacity
to suppress cell proliferation. Furthermore, metallocene-protein interactions
have been discovered to be crucial, and metal-tranferrin compounds have
been incorporated into their mechanism of action.
Proteins involved in cellular replication, in addition to blood plasma
proteins, have been linked to the activity of many metallocenes. Vanadocene
dichloride inhibits the activities of both protein kinase C and bacterial
topoisomerase. Mokdsi and Harding () recently investigated the suppression
of human topoisomerase II using a variety of metallocenes.
Their findingssuggest that the mechanism of action includes a complicated
route involving many species that modulates the transport and delivery of
active chemicals to cancer cells. There is also a subsequent interaction with
nucleic acids and/or proteins. While toposiomerase II inhibition is a plausible
site of action, additional sites are not ruled out. Several recent reviews in
this field have been published. Unlike cisplatin, vanadocene complexes
did not stimulate DEL recombination in yeast or any of the DNA damage
related promoters in HepG2 cells. Vanadocene compounds activate the c-fos
promoter while having no effect on the minimum promoter including p53
response elements or the GADD45 promoter.
The findings supported the idea that the apoptotic signal associated with
the presence of vanadocene chemicals is not generated by primary DNA
Introduction to the Study of Macromolecules
66
damage and does not need p53 activation. As a result, it appears to regulate
cell development differentlythan cisplatin and may be used in addition to it.
It should be noted that many metallocene derivatives lack the previously
mentioned biological activities, hence their existence does not automatically
confer biological activity on molecules that contain this moiety.
2.12. SPERMICIDAL ACTIVITY
The Wayne Hughes Institute has pioneered studies on the use of metallocene
complexes as spermicidal medicines, with an emphasis on vanadocene
derivatives. Several vanadium salts were discovered to operate as cellular
redox potential modulators and to have pleiotropic effects in a variety of
biological systems by accelerating the formation of active oxygen molecules.
These reactive oxygen species influence sperm motility by per oxidizing
membrane lipids and proteins. Peroxidative damage to the sperm plasma
membranes is also thought to have a role in the development of male
infertility. Because of the large amount of unsaturated fatty acids in sperm
and the relative scarcity of cytoplasmic enzymes that scavenge reactive
oxygen molecules that trigger lipid peroxidation, sperm are vulnerable to
oxidative stress.
Researchers investigated metallocenes including Ti, Zr, Mo, and Hf
and discovered that they lacked spermicidal action. In comparison, a large
variety of vanadocene molecules have spermicidal action.
In cancer cells, vanadocene dichloride impairs mitotic spindle formation.
Although the control cancer cells had organized mitotic spindles organized as
a bipolar microtubule array with the DNA organized on a metaphase plate, the
vanadocene dichloride treated cancer cells had aberrant monopolar mitotic
structures with microtubules on only one side of the chromosomes arranged
in a circular pattern. This demonstrates that vanadocene dichloride can
inhibit cell division by interfering with bipolar spindle formation, resulting
in a halt in the G2/M phase of cell cycle reproduction. A consequence of the
research into vanadocenes as antiproliferative chemicals has shown a new
pathway for their anticancer action.
2.13. FIBERS
In a separate investigation, it was discovered that when vanadocene
polymers are separated, they form fibers. Nonfibrous flat plate-like objects
were intermingled in with the fibers. Fibers have been discovered for a