![Cisplatin
[1] Cornel Baltă, $icoleta G. Hădărugă1,
Carmen Manuela Plesa (Mitar), Daniel Ghibu,
Gabriela Garban, Zeno Garban, Daniel I.
Hădărugă (2012).Hematological properties of
cisplatin and its Ficaria verna Huds. extracts /
β-cyclodextrin complexes in rats, Journal of
Agroalimentary Processes and Technologies
2012, 18 (4), 356-359
[2] Irena Kostova,(2006), Platinium
complexes as anti cancer agents, Recent
patents on anti cancer drug discovery, 2006,
1, 1-22
[3] Rebecca A.Alderden, Matthew D.Hall, and
Trevor W.Hambley (2006), The discovery and
development of Cisplatin, Journal of Chemical
Education, 2006, Vol 83, No 5.
[4] P. J. Gee a & W. F. van Gunsteren,(2011)
Report on Carcinogens, National Toxicology
program 2011, Vol 12.
[5] Alderen RA, Hall MD, Hambley TW (2006),
Discovery and development of Cisplatin,
Journal of Chem Ed. Vol 83 (5) 728-724
[6] DF Long and AJ Repta (1981), Cisplatin:
Chemistry, distribution and
biotransformation 1981, Biopharmaceutics
and Drug dipostion, VOl 2, 1-16
[7] Wilson and Gisvold, Organic medicinal
and pharmaceutical chemistry, 12th
edition,
Philadelphia. PA 2004.
[8] Stephen Trzaska (2005); Cisplatin; C&EN
News Vol 83, 25
[9] Pruefer FG, Lizarraga F, Maldonado V,
Melendez-Zajgla J ( 2008). "Participation of
Omi Htra2 serine-protease activity in the
apoptosis induced by cisplatin on SW480
colon cancer cells". J Chemother 20 (3): 348–
54
_____________________________________
__________
COMPUTATIONAL STUDIES ON THE
ANTI- NEOPLASTIC AGENT](https://image.slidesharecdn.com/794eba83-57ab-40c3-893b-868b6d574600-160510184605/85/Syed-Zia-Spartan-Modelling-6-320.jpg)
Syed Zia-Spartan Modelling
- 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 [1] Cornel Baltă, $icoleta G. Hădărugă1, Carmen Manuela Plesa (Mitar), Daniel Ghibu, Gabriela Garban, Zeno Garban, Daniel I. Hădărugă (2012).Hematological properties of cisplatin and its Ficaria verna Huds. extracts / β-cyclodextrin complexes in rats, Journal of Agroalimentary Processes and Technologies 2012, 18 (4), 356-359 [2] Irena Kostova,(2006), Platinium complexes as anti cancer agents, Recent patents on anti cancer drug discovery, 2006, 1, 1-22 [3] Rebecca A.Alderden, Matthew D.Hall, and Trevor W.Hambley (2006), The discovery and development of Cisplatin, Journal of Chemical Education, 2006, Vol 83, No 5. [4] P. J. Gee a & W. F. van Gunsteren,(2011) Report on Carcinogens, National Toxicology program 2011, Vol 12. [5] Alderen RA, Hall MD, Hambley TW (2006), Discovery and development of Cisplatin, Journal of Chem Ed. Vol 83 (5) 728-724 [6] DF Long and AJ Repta (1981), Cisplatin: Chemistry, distribution and biotransformation 1981, Biopharmaceutics and Drug dipostion, VOl 2, 1-16 [7] Wilson and Gisvold, Organic medicinal and pharmaceutical chemistry, 12th edition, Philadelphia. PA 2004. [8] Stephen Trzaska (2005); Cisplatin; C&EN News Vol 83, 25 [9] Pruefer FG, Lizarraga F, Maldonado V, Melendez-Zajgla J ( 2008). "Participation of Omi Htra2 serine-protease activity in the apoptosis induced by cisplatin on SW480 colon cancer cells". J Chemother 20 (3): 348– 54 _____________________________________ __________ 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.