Rational design of Ru(II)-based anticancer complexes

By

Adebayo A. Adeniyi(201205578)

Ph.D Research Work

Supervisor: Prof P. A. Ajibade

Department of ChemistryUniversity of Fort Hare, South Africa

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OverviewIntroduction

Justification

Statement of the problems

Objective and aims

What we have done

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Introduction

Cancer Malignant neoplasm

Statistics

2nd leading cause of death in developed and 3rd in emergent nations [1]

Rate of death is 23% in developed And 64% in developing countries

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

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Literature reviewSurgery 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 drugsUse by 70% of all cancer patients [2, 3]

Use to treat cancers that have resisted other cancer therapy

90% of the patients usually died of testicular cancer before cis-platin [4]

Extremely effective against several cancers like testicular and ovarian cancers [5]

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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

What are the targets of cancer drugs?

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. 7

Justification

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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

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 functionalization of promising compounds address some of the limitations in cancer chemotherapy ?

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Statement of the problem

Can we combine both experimental and computation to elucidate the complicated chemistry of ruthenium organometallic Anticancer

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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

What we have done

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Method of docking of Ru complex to CatB

Better view with isodensity surface

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What have we observed in the prediction of the targets?

The binding site interaction of complexes 3 with TopII using Autodcock (Cyan), Gold (Magenta) and Glide (yellow) Docking redictions

The binding site interaction of Ru(II) complexes with Receptor using from Autodock (magenta), Molegro (cyan) and constrained (green) docking

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Predicting the potential target of Ru-based organometallic

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

The isotropic shielding of the atoms in a complex

Laplacian of the electron density of a complex

Effects of bidentate coordination on the molecular Properties rapta-C based complex

Adeniyi, A.A. and Ajibade, P.A. J. Mol. Model. 2013, 19(3), 1325-1338. 16

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From Virtual into Practical

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Structure of some synthesized ligands

Schematic representation of the 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)

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Structure of some synthesized complexes

Schematic representation of some of the synthesized complexes

A total of 40 Ru(II)-based Complexes were Synthesised precursors

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

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1. Predicting the IR by observation

The small pick vibration found at 867.06 assigned to TORS(HCCRu)

IR Vibration of complex [(Cym)Ru(bphpza)Cl]+

The small pick vibration found at 293.41 assigned to STRE(Ru-Cl)

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Using PED to assign the IR Vibration of complex [(Cym)Ru(bphpza)Cl]+

2. Prediction of IR by PED

[(Cym)Ru(bphpza)Cl]+3609.1 144.95 STRE(OH),

1798.55 171.22 STRE(OC), 1531.34 38.76 STRE(CC), STRE(NC)1528.97 45.11 STRE(CC), STRE(CC)1492.64 42.54 STRE(CC), 1417.34 43.78 BEND(NNC), 1414.33 39.75 STRE(NC), BEND(NNC)1378.56 58.02 STRE(OC), BEND(HOC)1364.62 41.94 TORS(HCCO), STRE(NC)1310.77 82.76 TORS(HCCO), STRE(NN)1205.49 118.13 STRE(NN), BEND(HCC)1193.04 100.24 BEND(HCC), BEND(HOC)1127.71 84.92 TORS(HCCC), STRE(OC)1127.45 52.8 STRE(OC), 1055.54 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)

[(Cym)Ru(bphpza)Cl]+1013.95 15.58 TORS(HCCRu)

890.22 4 TORS(HCCRu)867.06 18.69 TORS(HCCRu)702.5 3.72 TORS(HCCN),

OUT(NCRuN)649.45 15.57 BEND(OCO), OUT(CCRuC)646.76 72.85 BEND(OCO), OUT(CCRuC)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)

IR vibrations of [(Cym)Ru(bphpza)Cl]+ that are associated with Ru atom

The prominent IR vibrations of [(Cym)Ru(bphpza)Cl]+

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The NMR properties of complex [(Cym)Ru(bphpza)Cl]+

1H-NMRDirect Fitting Experiment CD3OD

CH3 0.1214 to 2.6711 0.640358 to 3.11357 0.8934 to 2.2399Ccy-H 2.8585 3.29535 3.3232CHOO 6.6128 6.93702 6.8836COOH 7.3528 7.65482 7.7363C4-H 6.4789, 6.5177 6.80713, 6.84477 6.7599 dCothers-H 3.9623 to 8.1705 4.36603 to 8.44798 3.8948--8.2431

15N-NMRN12 -178.776, -178.136 -199.121, -198.515*N18 -143.577, -139.581 -165.822, -162.041

13C-NMRCH3 18.7785 to 26.2859 9.73514 to 16.9648CcyH 35.3002 25.6455CHCOO 72.2393 61.2179Carene 73.5694 to 127.554 62.4988 to 114.486C4 109.993 to 110.92 97.5747 to 98.4673COOH 158.471 144.259Cothers 123.334 to 164.701 110.422 to 150.259

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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, 3760-3778.

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, 60-69.

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Conclusion ctd ...

Several quantum properties including the NEDA and QTAIM are computed

Interesting correlations within the computed properties and thereported 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), 1325-1338.26

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References ctd ...

AcknowledgementGod 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

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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)”

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According to this eternal truth, the secrete of discovery is interest