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Rational design of Ru(II)-based anticancer complexes

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Presentation on theme: "Rational design of Ru(II)-based anticancer complexes"— Presentation transcript:

1 Rational design of Ru(II)-based anticancer complexes
By Adebayo A. Adeniyi ( ) Ph.D Research Work Supervisor: Prof P. A. Ajibade Department of Chemistry University of Fort Hare, South Africa

2 Overview 1 2 Justification 3 Statement of the problems 4
Introduction 2 Justification 3 Statement of the problems 4 Objective and aims 5 What we have done

3 Introduction Malignant neoplasm Cancer Statistics
Rate of death is 23% in developed And 64% in developing countries 2nd leading cause of death in developed and 3rd in emergent nations [1]

4 Introduction ctd ... Cancer cells vary base on sites.
The best known anticancer drug is a metallic complex. The best of the drugs are associated with side effects. There is research increase on application of organometallic as potential anticancer. There are many challenges of organometallic design like: Lack of proper knowledge targets Side effects Complexity of their interactions Instability

5 Literature review The best is Cis-platin
Surgery is the best method for primary cancer but systemic chemotherapy helps [1] Therapeutic effect is exerted by decreasing proliferation and increasing apoptosis [1] Prediction of the best chemotherapy is difficult The best is Cis-platin Over 100 cancer drugs Use by 70% of all cancer patients [2, 3] 90% of the patients usually died of testicular cancer before cis-platin [4] Use to treat cancers that have resisted other cancer therapy Extremely effective against several cancers like testicular and ovarian cancers [5]

6 What are the targets of cancer drugs?
Cancer-selective or semi-selective targets Universally-vital targets Effective against enzymes likr rare kinase [4, 6, 7] Examples: Gleevec (imatinib) [7, 8, 9] targets Bcr-Abl and gefitinib [6] targets EGF-R Have highest application and are not limited to some cancer cells Are associated with more severe side effect than the selective anticancer drugs They are specific in their targets, but nonselective and can inhibit important molecular targets

7 Justification Many cancer cells cannot be cured despite over 100
existing drugs. The targets of many promising potential anticancer are not known. There is insufficient knowledge on the modes of action of ruthenium compounds are as anticancer. There is urgent need for alternative to cis-platin due to existing limitations. Most promising alternatives like NAMI-A and KP1019 could not pass the NCI test.

8 Why cancer research attention on Ru-based compounds?
Have stronger affinity for cancer tissues than normal tissues Bind readily to transferrin molecules to accumulate in cancer specific tissues [10] Mimic iron in binding to biological molecules such as serum transferrin and albumin [1, 3, 11] Have low toxicity and allow larger doses for more effective anticancer therapies Can bind to DNA reversibly to avoid many of the side-effects associated with cytotoxic drugs [4]. Similar ligand exchange kinetics to those of platinum(II) complexes Have different oxidation states that are accessible under physiological conditions

9 Statement of the problem
Can we computationally predict the possible targets of some selected Ru(II)-based anticancer agents ? Can computational predicted best inhibitors results in reduced toxicity, increased effectiveness, stability and selectivity ? Can we combine both experimental and computation to elucidate the complicated chemistry of ruthenium organometallic Anticancer Can functionalization of promising compounds address some of the limitations in cancer chemotherapy ?

10 Methodology The Docking are done using GLIDE, GOLD, AUTODOCK, and MOLGRO Quantum calculation are done using GAUSSIAN 03/09 and FIREFLY GAMES The QTAIM analysis done with AIMAll Ligands were synthesised The Ru(II) are synthesised Biological study are ongoing

11 What we have done

12 Method of docking of Ru complex to CatB
Better view with isodensity surface

13 What have we observed in the
prediction of the targets?

14 Predicting the potential target of Ru-based organometallic
The binding site interaction of Ru(II) complexes with Receptor using from Autodock (magenta), Molegro (cyan) and constrained (green) docking The binding site interaction of complexes 3 with TopII using Autodcock (Cyan), Gold (Magenta) and Glide (yellow) Docking redictions

15 The approaches to elucidating the complicated
chemistry of Ru-based organometallic

16 Effects of bidentate coordination on the molecular
Properties rapta-C based complex Laplacian of the electron density of a complex The isotropic shielding of the atoms in a complex Adeniyi, A.A. and Ajibade, P.A. J. Mol. Model. 2013, 19(3),

17 From Virtual into Practical

18 Structure of some synthesized ligands
Bis(pyrazol-1-ly)methane (bpzm) Bis(pyrazol-1-ly)acetic (bpza) Bis(3,5-dimethylpyrazol-1-ly)methane (bdmpzm) Bis(3,5-dimethylpyrazol-1-ly)acetic (bdmpza) bis(3-phenylpyrazol-1-ly)acetic (bphpza) bis(pyrazol-1-ly)pyridine (bpzpy) Bis(3,5-dimethylpyrazol-1-ly)pyridine (bdmpzpy) bis(pyrazol-1-ly)pyridinic (bpzpya) Schematic representation of the Synthesized ligands

19 Structure of some synthesized complexes
Schematic representation of some of the synthesized complexes A total of 40 Ru(II)-based Complexes were Synthesised precursors

20 Theoretical elucidating of the IR spectra of complex [(Cym)Ru(bphpza)Cl]+

21 IR Vibration of complex [(Cym)Ru(bphpza)Cl]+
1. Predicting the IR by observation The small pick vibration found at assigned to STRE(Ru-Cl) The small pick vibration found at assigned to TORS(HCCRu)

22 Using PED to assign the IR Vibration of complex [(Cym)Ru(bphpza)Cl]+
2. Prediction of IR by PED The prominent IR vibrations of [(Cym)Ru(bphpza)Cl]+ [(Cym)Ru(bphpza)Cl]+ 3609.1 144.95 STRE(OH), 171.22 STRE(OC), 38.76 STRE(CC), STRE(NC) 45.11 STRE(CC), STRE(CC) 42.54 STRE(CC), 43.78 BEND(NNC), 39.75 STRE(NC), BEND(NNC) 58.02 STRE(OC), BEND(HOC) 41.94 TORS(HCCO), STRE(NC) 82.76 TORS(HCCO), STRE(NN) 118.13 STRE(NN), BEND(HCC) 100.24 BEND(HCC), BEND(HOC) 84.92 TORS(HCCC), STRE(OC) 52.8 57.83 BEND(HCC), BEND(HCC) 761.15 38.85 TORS(HCCN), TORS(HCCC) 753.46 38.96 TORS(HCCC), TORS(CCCC) 749.49 62.31 TORS(HCCC) 722.32 93 TORS(HOCC), 646.76 72.85 BEND(OCO), OUT(CCRuC) IR vibrations of [(Cym)Ru(bphpza)Cl]+ that are associated with Ru atom [(Cym)Ru(bphpza)Cl]+ 15.58 TORS(HCCRu) 890.22 4 867.06 18.69 702.5 3.72 TORS(HCCN), OUT(NCRuN) 649.45 15.57 BEND(OCO), OUT(CCRuC) 646.76 72.85 293.41 11.9 STRE(RuCl), 213.7 4.81 TORS(HCCC), OUT(CRuCC) 111.38 6.03 OUT(CCRuC), 109.34 5.47 TORS(CCCRu), OUT(ClCNRu)

23 The NMR properties of complex [(Cym)Ru(bphpza)Cl]+
1H-NMR Direct Fitting Experiment CD3OD CH3 to to to Ccy-H 2.8585 3.3232 CHOO 6.6128 6.8836 COOH 7.3528 7.7363 C4-H 6.4789, , d Cothers-H to to 15N-NMR N12 , , *N18 , , 13C-NMR to to CcyH CHCOO Carene to to C4 to to Cothers to to

24 Conclusion We have been able use computational method to confirm successful Synthesis of Ru complexes We have been able to predict possible targets of the Ru complexes using docking Despite several limitations in the docking of metal-based complexes, our results are highly correlated with the available experimental The methods of docking predicted CatB, HP-NCP and Kinases as parts of the best targets in agreement with experiment The observed poor interaction of rapta complexes with DNA further confirms the experimental reports Adeniyi, A.A. and Ajibade, P.A. Molecules 2013, 18,

25 Conclusion ctd ... Many of our new models are predicted to have better interaction than RAPTA complexes The carboxylic units in the new models are found to enhance the receptor binding Binding of the complexes show that some of the complexes preferentially target specific macromolecule than the other Metals gives preference to positioning the coordinated ligands in rightful position for optimal receptor interactions Our introducing the calculated quantum atomic charge improved the Docking predictions of these anticancer metallocompounds. Adeniyi, A.A. and Ajibade, P.A. J. Mol. Graph. & Model. 2012, 38,

26 Conclusion ctd ... Several quantum properties including the NEDA and QTAIM are computed Interesting correlations within the computed properties and the reported anticancer activities of some of the complexes are obtained The stability of bidentate RAPTA complexes is associated with their high hydrogen bonding stability and existence of stronger non-covalent M-L bonds The inter-atomic interactions and stability are governed by the CT with a significant contributions from POL and ES terms They can also act as a good NLO materials Adeniyi, A.A. and Ajibade, P.A. J. Mol. Model. 2013, 19(3),

27 References 1. Egger, A.E., Hartinger, C.G.; Renfrew, A.K.; Dyson, P.J. J Biol Inorg Chem. 2010, 15, 919–927. 2. Dyson, P.J.; Sava, G. Dalton Trans. 2006, 1929–1933. 3. Allardyce, C.S.; Dorcier, A.; Scolaro, C. Dyson, P.J. Appl. Organometal. Chem. 2005, 19, 1–10 . 4 . Sava, G.; Bergamoa, A.; Dyson, P.J. Dalton Trans. 2011, 40, 5. Groessl, M.; Tsybin, Y.O.; Hartinger, C.G.; Keppler, B.K.; Dyson, P.J. J Biol Inorg Chem. 2009, 15, 677–688. 6. Blagosklonny, M.V. Cell Cycle 2005, 4, 7. Blagosklonny, M.V. Cell Cycle 2004, 3, 8. Newman, D.J.; Cragg, G.M.; Snader, K.M. J. Nat. Prod. 2003, 66, 9. Newman, D.J.; Cragg, G.M. J. Nat. Prod. 2007, 70, 10. Ang, W.H.; Daldini, E.; Scolaro, C.; Scopelliti, R.; Juillerat-Jeannerat, L.; Dyson, P.J. Inorg. Chem. 2006, 45, 9006−9013. 11. Chatterjee, S.; Kundu, S.; Bhattacharyya, A.; Hartinger, C.G.; Dyson, P.J. J. Biol. Inorg. Chem. 2008, 13, 1149–1155.

28 References ctd ... 12. Adeniyi, A.A.; Ajibade, P.A. Spec. Acta Part A: Mol. and Biomol. Spec. 2013, 115 , 426–436. 13. Adeniyi, A.A.; Ajibade, P.A. Molecules 2013, 18, 14. Adeniyi, A.A.; Ajibade, P.A. Spec. Acta Part A: Mol. and Biomol. Spec. 2013, 105, 456–465. 15. Adeniyi, A.A.; Ajibade, P.A. J. Mol. Model. 2013, 19(3), 16. Adeniyi, A.A.; Ajibade, P.A. J. Mol. Graph. & Model. 2012, 38, 17. Adeniyi, A.A.; Ajibade, P.A. Molecules, 2013, 18(9), 18. Adeniyi, A.A.; Ajibade, P.A. J. Biomol. Struc. & Dynamics, 2013, 1-15. 19. Adeniyi, A.A.; Ajibade, P.A. J. Chem., 2013, 1-25.

29 Acknowledgement God the creator and the giver of life
Prof. P. A. Ajibade my kind and supporting supervisor Department of Chemistry as my host Department GMRDC for funding CHPC for computational facilities Member of our lab for moral support and understanding

30 Thanks for Listening God Bless You All (Amen)
It may interest you to note that “The works of the Lord are great, sought out of all them that have pleasure therein (Ps 111:2)” According to this eternal truth, the secrete of discovery is interest

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