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Thesis

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Julian Matthews

on 30 September 2013

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Transcript of Thesis

Investigating the Mechanism of Antitumor
Ruthenium-Beta-Diketonato Compounds Euma Matthews Conformation no. 937
Pi-pi interactions with DNA bases
Similar Results to Caruso et al. Study/understand the mechanism for antitumor activity
Additional docking simulations of similar ligands and/or curcumin derivatives into DNA
Obtain suitable crystals for X-ray Crystallography of Ruthenium curcumin derivatives Discovery Studio Metals in Medicine The Search for non toxic Antitumor Agents Cisplatin: very effective, highly toxic
Goal: non-toxic and effective antitumor agent
Ru metal complexes are less toxic than Pt
Curcumin binds to metals well
In 2007 ruthenium curcumin complex was synthesized
Promising anti-tumor activity, but was not very soluble Brainstorming Results Future Directions Protocol What is Aging?
Free Radical Theory of Aging
Antioxidants/Defense Mechanisms
Cancer
Anticancer Agents - metal complexes
The Search
My Work combining them
Theoretical Modeling
Results
Conclusion Aging
Theory Free Radical Theory of Aging Developed in 1954 by Denham Harman
Chemical Basis and explanation for aging
Overproduction of endogenous active free radicals, which react and damage integral biological components Modified to Mitochondrial Free Radical Theory of Aging in 1973 Free Radical
Chemistry short-lived chemical species that contain unpaired electrons
Reactive Oxygen Species (ROS)
Byproducts of mitochondrial electron transport ROS Reduction Mechanism of Damage Unstable radicals seeking stability randomly react with compounds
neighboring molecules become radicals procuring a vicious cycle
Affects proteins, lipids, nucleic acids, etc. Free Radical Scavenging Therapies Enzymatic
Radical Scavenging Small Molecules
Diet Curcumin extracted from curcuma longa found in South Asia.
many uses in traditional medicine
non-toxic, antitumor effects
symmetrical polyphenol comprising of two phenols and beta-diketone fragments
Use as a ligand, for creating metal complexes. My Work Investigate curcumin derivatives as ligands
Curcumin derivatives obtained from Dr. Subbaraju, NATSOL Labs, Visakhapatnam, India
I recrystallized two curcumin derivatives
Collected X-ray diffraction data to determine 3-D structure What Causes Cancer? Cancer is the uncontrollable growth of abnormal cells
This can be induced by many factors including free radical damage leading to tumor formation
Aging and cancer both have biological mechanisms that are altered due to these random changes. a) Vitamin C, b) Vitamin E,
c) Glutathione Curcumin Derivative
Crystal Structures 4-acyl-5-pyrazolone
Ligand Complexes Elena Monti tested antitumor activity of said Ru-ligand complexes at Univ. Insubria, Italy
RuNAPH was much more active than others.
RuNAPH had activity similar to the Ruthenium Curcumin Complex, especially with A549 cell line (Lung Cancer) RuCurDerivatives Dimethoxycurcumin Bisdemethoxycurcumin Ligands with similar properties & easier to work with
Metal complexes were synthesized in Camerino and two were successfully crystallized at Vassar
Ru(Me), Ru(Ph), Ru(CUR), Ru(F), Ru(NAPH) Ru-Arene-Chloro-betadiketonates Anticancer Activity Ru(Me) Ru(NAPH) (Nature 2007) Metals in biology are important
14 metals (mostly transition) required for biological function in humans
Na, K, Mg, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Mo, Cd
In addition seen in chemotherapy, x-rays, antidepressants, rheumatoid arthritis treatment. DNA Unbound vs Cisplatin Bound Cisplatin Why RuNAPH? RuNAPH potency may be due to its Ru-N7 Guanine interactions
Napthalene moiety in the 4-acyl-5-pyrazolone ligand may intercalate with DNA bases
Methods used to investigate:
Discovery studio for simulation studies 1. Dock RuNAPH into 1N37 (pdb)
2. Type and Minimize
3. Solvation, add counter ions
4. Standard Dynamics Cascade
5. Choose best conformation based on potential energy Constraints
Minimization with constraints
Solvation
Added counter ions Discovery Studio Obtained DNA from the Protein Data Bank www.Pdb.Org (code 1N37).
RuNAPH and DNA were both typed with Charmm and minimized separately
CDOCKER in DS 3.5 1N37 with Antibiotic RuNAPH Additional minimization
Standard dynamics cascade
Problems and tinkering Constraints Solvation Discovery Studio Pi-Pi Interactions We attempted to crystallize the Ruthenium complexed versions, but inadequate for x-ray diffraction but we are optimistic
Expected because the 2007 Ru-curcumin complex was very difficult to crystallize
So the next step is to try other ligands RuNAPH Docked Potential Energy Graph VC '07 Biochemistry Thesis, Aidan Benson
J. Med. Chem., 2012, 55 (3), pp 1072–1081 (Article)DOI: 10.1021/jm200912j Ru complexes using curcumin derivatives were synthesized in Pettinari lab, Univ. Camerino, Italy
Higher solubility *Curcumin derivatives obtained from Dr. Subbaraju, NATSOL Labs, Visakhapatnam, India Inhibition of 5 human cancer cell line growth (IC50 microMolar) Interest in substances from our diet that can be useful for free radical scavenging The next step is to make Ruthenium complexes using these ligands.
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