GUIDED BY- Dr. S. L. DEORE.
Asst. Professor
Govt. College Of Pharmacy,
Amravati.
PRESENTED BY – Mr. SAGAR S. ALONE.
M.Phar...
 Introduction
 Review of Literature
 Aim & Objective
 Need & Scope
 Plan of Work
 Experimental work
 Result & Discu...
 QSAR is the mathematical relationship between the chemical
structure (Describe as Descriptors) and Biological activity.
...
 Biological properties
1) Bioconcentration
2) Biodegradation
3) Carcinogenicity
4) Drug metabolism and
clearance
5) Inhib...
 Carcinogens can be present in food ,water, air, in
chemicals and sunlight that people are exposed to.
 In 1996 there we...
 Soap-like foaming when shaken in aqueous solutions [4].
 Two kinds of saponins are recognized – The steroidal and The p...
 Quantifying the relationship between structure and
activity.
 Biological Activity data provides an understanding of the...
 Modern drug design & drug discovery.
 Prediction of biological activity.
 Study of different physicochemical propertie...
 Siddiqi Mohammad Imran,CDRI Lucknow have been reported which included following
aspects of molecular modeling containing...
 Gauthier Charles et al. (2009) have been investigated recent Progress in the Synthesis of
Naturally Occurring Triterpeno...
GovernmentCollege Of Pharmacy,Amravati. 11
From the literature [17] I have selected 17 saponin analogues for QSAR studies...
GovernmentCollege Of Pharmacy,Amravati. 122August 2013
 To review saponin analogues having anticancer
activity.
 To select training and test set of saponin analogues.
 To per...
 Medical oncology is an important frontier which has gained attention from various research
communities.
 The mortality ...
 1) Literature survey.
 2) Selection of saponin analogues for anticancer activity.
 3) Study of descriptors.
 4) Desig...
 Data set-
 17 saponins molecules isolated from the Pulsatilla koreana as anticancer agent are
taken from literature for...
 2D Physicochemical descriptors including Individual, Chi chain, Path count, Chiv,
Element count and Kappa categories and...
 Uni-column statistics of the training and test sets for QSAR models
GovernmentCollege Of Pharmacy,Amravati. 18
Cell line...
 Statistics of the Models for 4 different cancer cell lines
GovernmentCollege Of Pharmacy,Amravati. 19
Statistics A-549 S...
 Here generate four QSAR Equation which is a Mathematical relationship between
Physicochemical properties (Descriptors) &...
 Actual and predicted biological activities of Pulsatilla koreana saponin
analogues are given in Table
GovernmentCollege ...
9 PK09 135.28 104.038 114.32 93.2087 165.54 112.479 171.29 114.68
10 PK10 2.56 17.2984 2.31 14.9598 1.57 4.53761 8.36 8.13...
 Graphical representation & comparison of Actual vs. Predicted activity for
training and test set of 4 cancer cell lines
...
 SK-MEL-2
 HCT-15
GovernmentCollege Of Pharmacy,Amravati. 242August 2013
 Fitness plot of 4 model for 4 different cancer cell lines
Government College Of Pharmacy, Amravati. 25
A-549 SK-OV-3
SK-...
 Contribution plot of 4 model for 4 different cancer cell lines showing
which descriptors are responsible for anticancer ...
 I have evaluated a series of Pulsatilla koreana saponin analogues by doing 2D QSAR with the help of
different descriptor...
 To determine the better structural characteristics
and to study different descriptors (3D
Descriptors) responsible for a...
 [1] Chanin Nantasenamat et.al. (2009) A practical overview of quantitative structure-activity relationship, excli Journa...
 [13] Riguera, Ricardo, (1997). Isolating bioactive compounds from marine organisms Journal of Marine Biotechnology 5 (4)...
THANK YOU 31GovernmentCollege Of Pharmacy,Amravati.2August 2013
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Sagar alone qsar studies of saponin analogues for anticancer activity

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QSAR studies of saponin analogues for anticancer activity by Sagar S. Alone from Govt. college of Pharmacy, Amravati

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Sagar alone qsar studies of saponin analogues for anticancer activity

  1. 1. GUIDED BY- Dr. S. L. DEORE. Asst. Professor Govt. College Of Pharmacy, Amravati. PRESENTED BY – Mr. SAGAR S. ALONE. M.Pharm-2nd (Pharmacognosy & Phytochemistry)
  2. 2.  Introduction  Review of Literature  Aim & Objective  Need & Scope  Plan of Work  Experimental work  Result & Discussion  Conclusion  Future Scope  References 2Government College Of Pharmacy, Amravati.2August 2013
  3. 3.  QSAR is the mathematical relationship between the chemical structure (Describe as Descriptors) and Biological activity.  Physicochemical properties or descriptors are expressed by numbers.  One can form a mathematical relationship, or quantitative structure-activity relationship between the two.  The mathematical equation can then be used to predict the biological response of other chemical structures or analogues.  Biological Activity = ƒ (Physicochemical properties and /or structural properties) 3Government College Of Pharmacy, Amravati.2August 2013
  4. 4.  Biological properties 1) Bioconcentration 2) Biodegradation 3) Carcinogenicity 4) Drug metabolism and clearance 5) Inhibitor constant 6) Mutagenicity 7) Permeability 8) Blood brain barrier 9) Skin 10)Pharmacokinetics 11) Receptor binding  Chemical properties 1) Boiling point 2) Chromatographic retention time 3) Dielectric constant 4) Diffusion coefficient 5) Dissociation constant 6) Melting point 7) Reactivity 8) Solubility 9) Stability 10) Thermodynamic properties 11) Viscosity Government College Of Pharmacy, Amravati. 42August 2013
  5. 5.  Carcinogens can be present in food ,water, air, in chemicals and sunlight that people are exposed to.  In 1996 there were 10 million new cancer cases worldwide and six million deaths attributed to cancer.  In 2020 there are predicted to be 20 million new cases and 12 million deaths.  A globalization of unhealthy lifestyles, particularly cigarette smoking and the adoption of many features of the modern Western diet (high fat, low fibre content) will increase cancer incidence. 5Government College Of Pharmacy, Amravati.2August 2013
  6. 6.  Soap-like foaming when shaken in aqueous solutions [4].  Two kinds of saponins are recognized – The steroidal and The pentacyclic triterpenoid types [5].  More than half of terrestrial plants may contain saponins.  Diversified pharmacological effects (haemolytic, cytotoxic, antitumor, anti- inflammatory, molluscicidal [9].  Saponins have been shown to induce both cycle arrest and apoptosis within cancerous cells [10].  Isolation of saponins from plant extracts is often a long and fastidious process involving many purification steps and usually only small amounts of products are obtained in a pure and homogeneous form [11].  Therefore, chemical synthesis or semisynthesis of saponin analogue appear to be a rational way to gain access to adequate amounts of saponins in order to promote further pharmaceutical studies [12]. 6Government College Of Pharmacy, Amravati.2August 2013
  7. 7.  Quantifying the relationship between structure and activity.  Biological Activity data provides an understanding of the effect of structure on activity.  Potential to make predictions leading to the synthesis of novel analogues.  Help to understand interactions between functional groups in the molecules of greatest activity, with those of their target. 7Government College Of Pharmacy, Amravati.2August 2013
  8. 8.  Modern drug design & drug discovery.  Prediction of biological activity.  Study of different physicochemical properties affecting biological activity.  Prediction of Chemical toxicity.  To study Mechanism of action.  Prediction of molecular properties.  ADME properties prediction. 8Government College Of Pharmacy, Amravati.2August 2013
  9. 9.  Siddiqi Mohammad Imran,CDRI Lucknow have been reported which included following aspects of molecular modeling containing, a technique for the investigation of molecular structures and Activities/properties using computational chemistry & biology and graphical visualization techniques in order to provide a plausible 3-D representation [16].  Bang Seong-Cheol, et al, (2005) have been reported antitumor Activity of Pulsatilla koreana Saponins and Their Structure–Activity Relationship he mentioned Seventeen saponins isolated from the root of Pulsatilla koreana were examined for their in vitro cytotoxic activity against the human solid cancer cell lines [17].  Yan L. L et al. (2009) have been reported invitro and in vivo anticancer activity of steroid saponins of Paris Polyphylla Var. Yunnanensis, to confirm the anticancer activity of steroid saponins isolated from the rhizome of Paris polyphylla var. yunnanensis and evaluate the structure-activity relationships of these steroid saponins in vitro and in vivo [18].  Malik Adeel et al. (2006) have been reported Databases and QSAR for Cancer Research in this review, he take a survey of bioinformatics databases and quantitative structure-activity relationship studies reported in published literature [19]. 9Government College Of Pharmacy, Amravati.2August 2013
  10. 10.  Gauthier Charles et al. (2009) have been investigated recent Progress in the Synthesis of Naturally Occurring Triterpenoid Saponins and describe recently reported semi- and total syntheses of naturally occurring triterpenoid saponins [20].  Matthew J. et al, (2009) have been reported Structural analogues of diosgenyl saponins synthesis and anticancer activity and he studied Saponins display various biological activities including anti-tumor activity [21].  Chanin Nantasenamat et al (2009) have been reported a practical overview of quantitative structure-activity relationship in this review article author describes history and development of QSAR model and study QSAR modeling pertains to the construction of predictive models of biological activities as a function of structural and molecular information of a compound library [1].  Dholwani K. K et al (2008) have been reported on plant derived natural product and their analogue with antitumor activity” and describes traditional medicine including Chinese herbal formulation can serve as a potential new drugs and initial research focus on the isolation of bioactive lead compounds [22].  Tsubuki Masayoshi et al. (2008) has been reported a new synthesis of potent antitumor saponin OSW-1 Via Witting rearrangement and he work on OSW-1 and its analogues [23]. 10Government College Of Pharmacy, Amravati.2August 2013
  11. 11. GovernmentCollege Of Pharmacy,Amravati. 11 From the literature [17] I have selected 17 saponin analogues for QSAR studies 2August 2013
  12. 12. GovernmentCollege Of Pharmacy,Amravati. 122August 2013
  13. 13.  To review saponin analogues having anticancer activity.  To select training and test set of saponin analogues.  To perform 2D QSAR of selected sets.  To relate different descriptor parameters to saponin chemical moieties.  To find out specific descriptors affecting anticancer activity.  To elaborate the role of structural changes in saponin analogues for Anticancer activity.  Finally to predict the structural changes which tends to increses anticancer activity. 13Government College Of Pharmacy, Amravati.2August 2013
  14. 14.  Medical oncology is an important frontier which has gained attention from various research communities.  The mortality rate of cancer patients is usually high (65%).  Primarily there are three treatment methods for cancer: [24]  Invasive methods - Surgical removal of cancer tissue.  Irradiation methods - Use of high energy radiation.  Chemotherapy - Administration of drugs.  To control cancer from mankind we should discover or make new compound by using QSAR before going work into actual wet laboratory.  QSAR techniques will continue to make a valuable contribution to the computer-assisted analysis of structure-bioactivity relationships.  Hence taking into consideration the part of present research which we are performing to do QSAR study of different saponin analogues having anticancer activity by using Modern computational technology (QSAR). 14Government College Of Pharmacy, Amravati.2August 2013
  15. 15.  1) Literature survey.  2) Selection of saponin analogues for anticancer activity.  3) Study of descriptors.  4) Design and making structure of saponin analogues.  5) QSAR studies.  6) Result and Discussion. 15Government College Of Pharmacy, Amravati.2August 2013
  16. 16.  Data set-  17 saponins molecules isolated from the Pulsatilla koreana as anticancer agent are taken from literature for QSAR analysis.[17] Pulsatilla koreana belongs to the family Ranunculaceae and is an endemic species in Korea containing 17 saponins in which eight lupane-type (1, 3, 5, 7, 9, 11, 13, 15) and nine oleanane-type (2, 4, 6, 8, 10, 12, 14, 16, 17), isolated from P. koreana roots. Molecule sketching- sketched by using 2D draw application of VLife MDS (Molecular Design Suite).  2D to 3D- by using VLife MDS (Molecular Design Suite) TM 3.5 software supplied by VLife Sciences Technologies Pvt. Ltd., Pune, India.  Batch optimization & energy minimization - Batch optimization by taking 100000 cycle  Statistical method- Multiple linear regression (MLR)  QSAR models were generated by a training set of 11 molecules for each model and a test set of 6 molecules  Training set of molecules (3,4,6,7,11,12,13,14,15,16,17)  Test set of molecules (1,2,5,8,9,10) GovernmentCollege Of Pharmacy,Amravati. 162August 2013
  17. 17.  2D Physicochemical descriptors including Individual, Chi chain, Path count, Chiv, Element count and Kappa categories and Alignment independent including topological structure descriptors were calculated for QSAR analysis using Vlife MDS software.  Multiple linear regression method is used to generate QSAR equation.  For validating the quality of the models, Selection of molecules in the training set and test is a key and important feature of any QSAR model.  Therefore, the care was taken in such a way that biological activities of all compounds in test lie within the maximum and minimum value range of biological activities of training set of compounds.  The Uni-Column Statistics of test and training sets further reflected the correct selection of test and training sets. A Uni-Column statistics for training set and test set were generated to check correctness of selection criteria for trainings and test set molecules.  MLR is a statistical method for creating linear relationship between a dependent variable Y (ED50) and independent variable X (2D descriptors). GovernmentCollege Of Pharmacy,Amravati. 172August 2013
  18. 18.  Uni-column statistics of the training and test sets for QSAR models GovernmentCollege Of Pharmacy,Amravati. 18 Cell line Training/Test set Average Max Min Std. Dev Sum A-549 Training set 94.1109 300.000 4.2400 114.9137 1035.2200 Test set 131.5417 300.000 2.5600 138.64.97 789.2500 SK-OV-3 Training set 88.6536 300.0000 3.9500 112.7344 975.1900 Test set 127.3850 300.0000 2.3100 139.3976 764.3100 SK-MEL-2 Training set 94.0000 300.0000 3.0400 116.5289 1034.0000 Test set 136.1183 300.0000 1.5700 139.8473 816.7100 HCT-15 Training set 96.4845 300.0000 5.5000 114.9111 1061.3300 Test set 138.8817 300.0000 8.3600 138.1815 833.2900  Multiple linear Regression equation takes the form  Y = b1 x1 + b2 x2 + b3 x3 + c  Where- Y is dependent variable, ‘b’s are regression coefficients for corresponding ‘x’s (independent variable), ‘c’ is a regression constant or intercept [6, 7]. 2August 2013
  19. 19.  Statistics of the Models for 4 different cancer cell lines GovernmentCollege Of Pharmacy,Amravati. 19 Statistics A-549 SK-OV-3 SK-MEL-2 HCT-15 N 11 11 11 11 Degree of freedom 8 8 8 8 r2 0.9281 0.9554 0.9160 0.9203 q2 0.8691 0.9187 0.8285 0.8357 F test 51.6079 85.7357 43.6084 46.1887 r2 se 34.4579 26.6109 37.7639 36.2697 q2 se 46.4909 35.9315 53.9485 52.0702 pred_r2 0.9538 0.9686 0.8950 0.8899 pred_r2se 31.0692 25.8051 47.7110 48.3659 Here: N - Number of molecules, K - Number of descriptors in a model, DOF - Degree of freedom (higher is better), r2 - Coefficient of determination (> 0.7), q2 - Cross-validated r (>0.5), pred_r2 - r for external test set (>0.5), F-test - F-test for statistical significance of the model (higher is better, for same set of descriptors and compounds), r2_Se, q2_se, pred_r2_se = error for r2, q2, pred_r2 respectively. 2August 2013
  20. 20.  Here generate four QSAR Equation which is a Mathematical relationship between Physicochemical properties (Descriptors) & Biological activity  For (A-549): ED50= + 55.3309( 6.5096) T_2_C_7 + 23.9224( 8.9012) 6ChainCount - 616.7280  For (SK-OV-3): ED50= + 53.2371( 0.5713) T_2_C_7 + 553.1007( 130.2520) chi6chain -612.2515  For (SK-MEL-2): ED50 = + 53.9707( 7.2274) T_2_C_7 + 7.3979( 2.5587) T_O_O_5 - 493.8088  For (HCT15): ED50 = + 53.2728( 6.9414) T_2_C_7 + 7.3583( 2.4574) T_O_O_5 - 484.2732 GovernmentCollege Of Pharmacy,Amravati. 202August 2013
  21. 21.  Actual and predicted biological activities of Pulsatilla koreana saponin analogues are given in Table GovernmentCollege Of Pharmacy,Amravati. 21 Sr. No. Saponins ED50 (µM) A-549 SK-OV-3 SK-MEL-2 HCT15 Expt. Pred. Expt. Pred. Expt. Pred. Expt. Pred. 1 PK01 >300.0 341.798 >300.0 333.826 >300.0 340.972 >300.0 340.723 2 PK02 >300.0 310.389 >300.0 313.994 >300.0 294.399 >300.0 294.808 3 PK03 >300.0 317.875 >300.0 308.737 >300.0 311.381 >300.0 311.289 4 PK04 >300.0 286.467 >300.0 288.905 >300.0 372.206 >300.0 272.733 5 PK05 38.14 80.1154 36.27 73.2989 37.44 119.877 40.06 122.038 6 PK06 11.25 17.2984 13.27 20.1392 3.04 11.9355 11.86 15.4923 7 PK07 145.62 104.038 120.38 93.2087 167.82 127.275 174.34 129.396 8 PK08 13.27 17.2984 11.41 14.9598 12.16 19.3334 13.58 22.8506 2August 2013
  22. 22. 9 PK09 135.28 104.038 114.32 93.2087 165.54 112.479 171.29 114.68 10 PK10 2.56 17.2984 2.31 14.9598 1.57 4.53761 8.36 8.13401 11 PK11 43.64 80.1154 38.90 68.1195 39.67 90.2853 49.04 92.6047 12 PK12 13.49 -6.624 13.71 -10.1294 14.12 -17.6561 14.17 -13.9409 13 PK13 155.32 104.038 124.12 93.2087 145.68 127.275 138.73 129.396 14 PK14 4.24 17.2984 3.95 14.9598 3.47 19.3334 5.50 22.8506 15 PK15 41.35 80.1154 38.91 68.1195 40.02 75.4896 40.86 77.8882 16 PK16 9.58 -6.624 11.39 -10.1294 10.37 -32.4518 12.74 -28.6574 17 PK17 10.73 41.2208 10.66 40.049 9.81 48.925 14.09 52.2837 GovernmentCollege Of Pharmacy,Amravati. 22  From the following data we can conclude that first 4 analogues has no anticancer activity because all 4 has sugar ester group attached to C-28.  But all analogues from 5 to 17 has free carboxylic acid group at C-28 position and showing anticancer activity. 2August 2013
  23. 23.  Graphical representation & comparison of Actual vs. Predicted activity for training and test set of 4 cancer cell lines GovernmentCollege Of Pharmacy,Amravati. 23 A-549 SK-OV-3 2August 2013
  24. 24.  SK-MEL-2  HCT-15 GovernmentCollege Of Pharmacy,Amravati. 242August 2013
  25. 25.  Fitness plot of 4 model for 4 different cancer cell lines Government College Of Pharmacy, Amravati. 25 A-549 SK-OV-3 SK-MEL-2 HCT-15 2August 2013
  26. 26.  Contribution plot of 4 model for 4 different cancer cell lines showing which descriptors are responsible for anticancer activity Government College Of Pharmacy, Amravati. 26 A-549 SK-OV-3 SK-MEL-2 HCT 15 2August 2013
  27. 27.  I have evaluated a series of Pulsatilla koreana saponin analogues by doing 2D QSAR with the help of different descriptors in order to determine the better structural characteristics and to study different descriptors responsible for anticancer activity.  From the QSAR studies it was found that the Alignment Independent category is most responsible for all 4 types of cancer cell lines which includes  T_2_C_7: This is the count of No. of double bounded atoms (i.e. - Any double bonded atoms, T-2) separated from carbon atom by 7 bonds in a molecule.  T_O_O_5: This is the count of No. of oxygen atoms (Single double or triple bounded) separated from other other oxygen by 5 bond distance in a molecule.  6chain count: These descriptors signify total numbers of six membered rings in a compound.  Chi6chain: These descriptors signify a retention index for six membered rings.  It was found that all descriptors have positive correlation with the anticancer activity.  Hence increase in all descriptor values will help to increase the anticancer activity of Pulsatilla koreana saponins analogues for anticancer activity.  Hence, the model proposed in this work is useful and can be employed to design new saponin derivative of Pulsatilla koreana as most active anticancer agent. GovernmentCollege Of Pharmacy,Amravati. 272August 2013
  28. 28.  To determine the better structural characteristics and to study different descriptors (3D Descriptors) responsible for anticancer activity (3D QSAR Study).  To identify all other cancer cell lines to which Pulsatilla koreana saponin analogues exhibits its affinity/Inhibition potential.  To design new saponin derivative of Pulsatilla koreana as most active anticancer agent. GovernmentCollege Of Pharmacy,Amravati. 282August 2013
  29. 29.  [1] Chanin Nantasenamat et.al. (2009) A practical overview of quantitative structure-activity relationship, excli Journal, pp.74-88.  [2] Tatsuhiko Yoshino, (2010) QSAR in Catalysis in Silico Catalyst Design, pp.1-15.  [3] Alison Malcolm R, (2001) Cancer. Encyclopedia of life sciences, Nature Publishing Group, pp.1-8.  [4] Hostettmann, K et.al. (1995). Saponins. Cambridge: Cambridge University Press. Pp.32970-71.  [5] Osbourn, A. (1996) Saponins and plant defence – a soap story. Trends Plant Sci. vol 1, pp 4-9.  [6] Vincken, J. P.et.al. (2007) Saponins, classification. And occurrence in the plant kingdom. Phytochemistry, 68, pp.275 297.  [7] Agrawal, P. K et.al. (1985) Carbon-13 NMR spectroscopy of steroidal sapogenins and steroidal saponins. Phytochemistry, pp.2479-2496.  [8] Agrawal, P. K. et.al. (1992) NMR spectroscopy of oleanane triterpenoids. Prog. Nucl. Mag, pp.1-90.  [9] Agrawal, P. K et.al. (1996) Nuclear magnetic resonance spectroscopic approaches for the determination of interglycosidic linkage and sequence in oligosaccharides. Phytochem. Anal.7, pp.113-130.  [10] Sahu N. P et.al. (2001) Advances in structural determination of saponins and terpenoid glycosides. Curr. Org. Chem 5, pp.315- 334.  [11] Qin, G. W et.al. (1998) Some progress on chemical studies of triterpenoid saponins from Chinese medicinal plants. Curr. Org. Chem 2, pp.613-625.  [12] Liu, J.et.al. (2002) Traditional Chinese medicine (TCM): Are polyphenols and saponins the key ingredients triggering biological activities? Curr Med. Chem 9, pp.1483-1485. 29Government College Of Pharmacy, Amravati.2August 2013
  30. 30.  [13] Riguera, Ricardo, (1997). Isolating bioactive compounds from marine organisms Journal of Marine Biotechnology 5 (4) pp.187–193.  [14] Liener, Irvin E (1980). Toxic constituents from plant foodstuffs. New York City: Academic Press. p.161.  [15] Francis, George et.al. (2002). The biological action of saponins in animal Systems: a review. British Journal of Nutrition 88 (6): pp.587–605.  [16] Mohammad Imran Siddiqi, (2007) QSAR: Principles and Selected Case Studies, CDRI, Lucknow.  [17] Seong-Cheol Bang, et al (2005) Antitumor Activity of Pulsatilla koreana Saponins and Their Structure–Activity Relationship Chem. Pharm. Bull, pp.1451—1454.  [18] L.L. Yan, et al (2009) In vitro and in vivo anticancer activity of steroid saponins of Paris Polyphylla var. Yunnanensis Exp Oncol pp.27–32.  [19] Malik Adeel, Singh Hemajit, et al. (2006) Databases and QSAR for cancer research cancer informatics, Cancer Inform 2: pp.99–111.  [20] Charles Gauthier et.al. (2009) Recent Progress in the Synthesis of Naturally Occurring Triterpenoid Saponins, Mini-Reviews in Organic Chemistry vol-6, pp.321-344.  [21] Kaskiw M. J et al, (2009) Structural analogues of diosgenyl saponins: Synthesis and anticancer activity, Bioorg. Med. Chem pp.7670–7679.  [22] Dholwani K.K., et al, (2008) A review on plant derived natural product and their analogue with antitumor activity, Indian J pharmacol Apr, issue 2, pp.49-58.  [23] Masayoshi Tsubuki et. al. (2008) A new synthesis of potent antitumor saponin OSW-1Via Wittig rearrangement Tetrahedron, pp.229–232.  [24] Paila, Hari Srinivas Kalyan, (2008) M.S. Molecular Modeling Studies of Curcumin Analogs as Anti-Angiogenic Agents pp.97. 30Government College Of Pharmacy, Amravati.2August 2013
  31. 31. THANK YOU 31GovernmentCollege Of Pharmacy,Amravati.2August 2013

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