This document discusses cisplatin, an anticancer drug. It summarizes computational studies examining the effects of substituting different ligands on cisplatin's central platinum atom. Bond lengths, angles, and electrostatic charges were calculated. Iodine substitution caused the greatest increase in bond length due to iodine's large size. Bromine substitution most affected bond angles. More electronegative ligands led to more positive charges on the platinum atom. In general, larger and less electronegative ligands had greater effects on geometry and charge distribution compared to the original cisplatin molecule.

1. Cisplatin
ABSTRACT:
Since the discovery of anti cancer activity of Cisplatin, it has enjoyed a huge proclamation and clinical hit.
In this report using Spartan `10 V1.1.0 Molecular mechanics and Hartee-Fock calculations have been performed
using different substituent on the central Platinum atom, substituent like F, Cl, Br, I, NH2, OH are used for studying
energy and geometrics. The parameters like bond length, bond angle, electrostatic charge, dipole moment, Energy
have been compared. The deviation in the bond length from the original molecule is observed greatest with iodine;
this might be due to the larger size. Further bond angle calculations have been performed; the most affected is the
bromine substituted; this might be due to the higher electronegativity. The electrostatic charge studies showed that
with the increase in charge of the substituent atom, the electro positive charge on the central metal atom kept
increasing. Dipole moment calculations showed that, when –OH group –NH3group is substituted it displayed
relatively lower dipole moment which interpreted the molecule is much more stable, than when iodine is substituted
which has relatively a much larger dipole moment.
INTRODUCTION:
Cancer is one of the most common
diseases in the world; it has also
become the most important cause
of deaths in recent years1
. The use
of metals in curing diseases can be
traced back almost 5000 years.
Transitional metal complexes are
nowadays used as alkylating
agents in the treatment of cancer.
The development of the
coordinating chemistry has
revolutionized and facilitated
chemists using metals
centers for synthesizing
coordinating complex
molecules as drugs, metal centers
being positively charged are able
to bind to the negatively charged
biomolecules2
.
Cisplatin is one those
complex molecule which has a
platinum center, it was only in
mid 1960`s when anticancer
activity of Cisplatin was
discovered. Cisplatin is believed
to exert its anticancer effect by
interacting with DNA, inducing
programmed cell death. Cisplatin
and its analogues interacts with
the purine base pairs in the DNA;
forming DNA-Pt (NH3)2-DNA,
which inhibits DNA replication
and ultimate cell death3
.
Cisplatin is a metallic
coordinating complex, molecular
formula is (NH3)2PtCl2. It has a
molecular weight of 300gm/mol.
It has square planar geometry. It is
white or deep yellow to yellow-
orange crystalline powder at room
temperature4
.
Fig 1: Structure of Cisplatin

2. Cisplatin
Cisplatin can be prepared by using
Potassium
tetracholoroplatinate(II), the first
NH3 ligand can be added at any
position the second one is added
to cis or trans to the bound amine
ligand5
. Further investigation with
this drug is complicated mode of
action of the drug.6
Cisplatin has –NH3 groups
attached to the central Platinum
metal atom, the bond distance
from Pt-Cl measure 2.5A, where
as the bond distance between Pt-
NH3 is 2.1A. The electro
negativity of Cl and N is 3.0, so
the charge is symmetrically
distributed, due to which the
molecule is slight soluble in water.
Table 1: Physicochemical properties
of Cisplatin
Property Data
Molecular Formula H6Cl2N2Pt
Molecular weight 300.1g/mol
Physical State Crystalline powder
Molecular Shape Square planar
Solubility Slightly soluble in
water, soluble in
dimethylprimanide
and N,N-
dimethylfor
mamide
Density 3.74gm/m3
Stability Transforms to
trans over time
2. MECHANISM OF ACTION:
Cancer can be considered a failure
of cell to undergo apoptosis. In
norma cells, sensors to cell
abnormalities lead to withdrawal
of survival signals, there by
leading to cell death7
. In Cisplatin,
it induces cell death of cancer cell
by interacting with the DNA
synthesis. The platinum atom
binds to the DNA base pairs; cross
linking of the complex occurs
when chloride ligand is displaced.
By this way several cross linking
occurs there by interfering with
the cell division, which in turn
activates apoptosis8-9
.
3. EXPERIMENTAL SECTION:
3.1 Computational Methods:
The present study on the
Cisplatin molecule is completely
theoretical. Using Spartan `10
V1.1.0 the theoretical studies have
been carried out on a high
performance computer. The
calculations that are carried out
include Molecular mechanics and
Hartree-Fock. The Equilibrium
Geometry studied with Hartree-
Fock is studied under 6-31G*. The
other calculations include simpler
findings like Bond Angle, Bond

3. Cisplatin
Length data and charges on the
atoms are calculated.
Further Calculations are
done by changing the ligands on
the central atom; atoms which are
more electronegative and also less
electronegative than the parent
molecule have been studied, along
with other ligands.
4. RESULTS AND
DISCUSSION:
Different forms of Cisplatin are
formed by substituting the –Cl
with different electron donating
groups and electron withdrawing
groups. The affect on the bond
length and bond angle have been
observed.
Fig. 2. Cisplatin and other substituted
forms of cisplatin
4.1 Molecular Mechanics
The Cisplatin molecule which
contains two chlorines, the
chlorines are substituted with
different halogens, hydroxyl group
and NH3 group and the bond
distance, bond angle and the
charge on the molecule is found
out. For calculating the mentioned
parameters Spartan `10 V1.1.0
have been used.
4.1.1 Bond Lengths
Bond length or bond distance is
the average distance between
nuclei of two bonded atoms in a
molecule.
Table 2: Bond length parameter
of Cisplatin and its substituent
In the above table the
values of bond angle for the
different substituted groups on the
platinum center of Cisplatin,
which is studied with hartree-Fock
set.
Substituent Bond Angle in Ao
Pt-
Substituted
N-H Pt-N O-H
-F 1.90 1.00 1.85 -
-Br 2.48 1.00 2.13 -
-I 2.70 1.01 2.10 -
-OH 2.10 1.01 1.98 0.958
-NH3 2.10 1.01 2.10
-Cl 2.63 1.08 2.12 -

4. Cisplatin
4.1.2 Bond Angle and
Electrostatic Charge
From the results obtained in the
table 2, it can be interpreted that
the change in the bond length due
to various substituent. The most
deviation from the original value
of bond length is observed with
iodine, this is due to the large size
of the iodine molecule
Table3:Hartree-Fockoptimizedbondanglesforcisplatin
BondAngles
N2H5H6
35.26
35.26
35.26
35.26
35.26
35.26
H4N2H5
109.47
109.47
107.95
109.47
109.47
109.47
N1H2H3
35.26
35.26
35.26
35.26
35.26
35.26
N1H1H3
35.26
35.26
35.26
35.26
35.26
35.26
N1PtN2
75.36
45
43.23
90
90
90
suPtN
90
90
85.57
90
90
90
su,Pt,su
90
90
95.36
90
90
90
Substitu
F
Cl
Br
I
OH
NH3
The results obtained from
the table 3 indicate that, the
various changes that occurs in the
bond angle due to substitution of
various group on the central metal
atom. The most deviated result
obtained is the substitution of
fluorine, due to its high
electronegativity the bond angle is
constrained. Another deviation
observed in the substitution of
Bromine, due to the large size of
bromine the bond angle changes.
From the table 4, the
results obtained showed
electrostatic charge which varies
according to the change in the
substituent group; with the
decrease in electronegativity on
the substituent group the positive
charge on the central atom
increase. Fluorine is the most
electronegative group; fluorine
substitution has lowest positive
charge on the central atom when
compared to the least negative
group Iodine; which shows
highest positive charge on the
central metal atom.
Fluorine is the most
electronegative atom; it pulls the
electron density from the adjacent
metal atom there by leaving least
positive charge on the central
metal atom when compared to the
lesser electronegative atom than
fluorine

5. Cisplatin
Table4.Hartree-FockStabalizedElectrostaticchargeoncisplatinanditssubstituents
N2
-2.46
-3.48
-3.88
-24.41
N1
-2.46
-3.48
-3.88
-24.41
Charge
Pt
49.66
52.44
53.39
312.26
Sub
-5.56
-13.14
-15.13
-148.2
Sub
-5.56
-13.14
-15.13
-148.2
Subs
F
Cl
Br
I
5. CONCLUSION:
From the Hartree-Fock and
molecular mechanics calculations
its is observed that there is a much
larger deviation in the iodine
substituted Cisplatin, this is
probably due to the larger size and
lower electronegativity of iodine
when compared to chlorine in the
original molecule. In the
calculation related to bond angle,
the bond angle increases with the
increase in the size of the
substituent group; in this very
particular case; the increase in
bond angle is subjected to increase
with electron donating group.
The study related to the
electrostatic charge; the charge on
the central atom increases with the
decrease in the electronegativity
and size of the substituent group,
fluorine which is the most
electronegative atom substituted
made the central atom positive by
drawing electron towards itself;
there by developing a positive
charge on the central atom
5.1 Note
The study done through this paper
is theoretical work. The affect of
the Cisplatin drug or its
substituent on the human body or
stimulated system is not known.
6. ACKNOWLEDGEMENTS:
I would like to thank Dr. Allan D.
Headley and for giving me this
opportunity to work on this
software and for their assistance.
7. REFERENCES:

6. Cisplatin
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Carmen Manuela Plesa (Mitar), Daniel Ghibu,
Gabriela Garban, Zeno Garban, Daniel I.
Hădărugă (2012).Hematological properties of
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[2] Irena Kostova,(2006), Platinium
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[3] Rebecca A.Alderden, Matthew D.Hall, and
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[5] Alderen RA, Hall MD, Hambley TW (2006),
Discovery and development of Cisplatin,
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[6] DF Long and AJ Repta (1981), Cisplatin:
Chemistry, distribution and
biotransformation 1981, Biopharmaceutics
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[7] Wilson and Gisvold, Organic medicinal
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[9] Pruefer FG, Lizarraga F, Maldonado V,
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54
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COMPUTATIONAL STUDIES ON THE
ANTI- NEOPLASTIC AGENT

7. Cisplatin
“CISPLATIN” AND ITS SUBSTITUENT
USING SPARTAN `10
- Syed Zia ul Quasim, Dr. Allan D Headley
- Department of chemistry, Texas A&M University -
Commerce, Texas 2013 USA.