Metals in Medicine & Biology - Coursework Example

Explain: 1a) i) Why the product of step 2, PtI2 (NH3)2, is 100% the cis isomer Because of a strong trans-directing influence of the iodo ligand relative to the ammonia ligand hence trans ligand is displaced. K[PtI3(NH3)] reacts with the second ammonia and can proceed to either lead to displacement of the iodo ligand which is trans to an ammonia ligand or lead to displacement of the iodo ligand which meaning shift from trans to another iodo ligand ii) The advantage of converting PtCl4 to PtI2 There is no contamination to the final product by Magnus' salt during the conversion reaction, b) Explain how step3 of this reaction proceeds and what drives it to completion. There is formation of insoluble silver halogenides and aquaderivative (with aqualigand) after adding excess (10%) of silver nitrate AgNO3 then heated. To yield final product the aquaderivative is reacted with an alkaline (KCl). The reaction is driven to completion by raising the temperature to about 80 degrees centigrade c) Predict the product of the reaction between [Pt(NH3)4]Cl2 and hot HCl. Explain your answer. The reaction between ([Pt(NH3)4]Cl2) and hot Hydrochloric acid can form tetrachloroplatinum. Can proceed to formation of diamminedichoroplatinum when the temperature of the reaction is raised because of ammine groups gain and loss. 2. Carboplatin is a2nd generation platinum anticancer drug active against the same range of cancers as cis--‐ platin. a)What advantage does carboplatin have over cis--‐platin? The side effects are not that significant like ototoxicity, neurotoxicity nephrotoxicity and emetogenesis is very minimal also it’s more stable as compared to cisplatin. b) Describe fully how the structures of Carboplatin results in this advantage. Through the stability increase of the drug's leaving groups the 1, 1- cyclobutanedicarboxylato ligand of Carboplatin complex in place of the chloride leaving groups in cis-platin seems to lower carboplatin's aquation rate as well as reactivity rate. Carboplatin has been designed to prevent hydrolysis. This is met through the chelating effect that leads high formation constant and slower exchange. The chemical changes seems to slow the rate of hydrolysis making drugs more selective for DNA intrastrand complexation. Its Less active than cis-platin but can use higher dose because it is Less ototoxic and nephrotoxic than cis-platin 3. Oxaliplatin is also a 2nd generation platinum anticancer drug. The stereochemistry of the amine ligand is important for activity. a) Assign the stereochemistry of the2 stereocentres in each of the1,2--‐diaminocyclohexane ligands (A--‐C) below. A-It’s a trans d- 1, 2 diaminocyclohexane B-It’s a cis-1, 2-diaminocyclohexane C-it’s a trans l- 1, 2-diaminocycloxehane (cannot exist in enantiomeric form) b) Which of these will form the active oxaliplatin drug? C because cytotoxicity against tumour cells is seen to be the highest. c) Explain why the stereochemistry of the amine ligand is important for activity. Its signifigantly importance for this amine ligand's stereochemistry in specifying tumor range, toxicity as well as mutagenicity of oxaliplatin. nonleaving group to support binding of the drug to cell carriers the relevant enantiomeric form is required and DNA repair is made difficult enough to induce apoptosis in this context 4. Physical half--‐life is an important consideration when selecting a radionuclide for imaging. a) Give the equations for the radioactive decay of 99Mo, 99mTc and 64Cu 99mTc undergoes an isomeric transition to yield 99Tc and a monoenergetic gamma emission: 99mTc → 99Tc + γ Cu decays to emit either negative or positive beta emission. The negative beta equation for the decay of 64Cu is: 2964Cu --> 3064Zn + -10e The -10e represents electron. or a negative beta particle The positive beta equation for decay of 64Cu is: 2964Cu --> 2864Ni + 10e The 10e represents positron or positive beta particle 99Mo → 99mTc + e− + νe The decay process produces 99mTc: can also be presented as 99Mo → 99mTc + β− + νe where e− (or β−) denotes beta particle emitted from the nucleus, and νe denotes the emitted antineutrino b) Determine the following: i) Time taken for a sample of 99mTc to decay to 40% of its initial value If T1/2 99MTc = 6.02 hrs is the time taken to decay to 50 % of 50% decay This means that for it to decay to 40 %: 60 % decay it will take (6.02 hrs/50)*60 = 7.224 hours ii) The mass of 64Cu remaining in a 0.8g sample of 64Cu after 27.5 hrs T1/2 64Cu = 12.7 hrs, this takes 12.7 hrs to decay to 0.8g/2 =0.4g It would have decayed by (0.4g/12.7)*27.5= 0.8661g if 64Cu decays by 0.4g after 12.7 hrs, In 27.5 hrs The whole mass might have decayed before the end of 27.5 hrs. 0.8g-0.8661g is the mass that remained, practically zero. c) Would 89Zr or 68Ga be most appropriate for use in a bioconjugate imaging agent with the following biomolecules, explain your answer: i) Monoclonal antibodies 89Zr would be appropriate a bioconjugate imaging agent with monoclonal antibodies. Reason being positron emition emitted is relatively long lasting a. 89Zr is good for immuno-PET because it half life of 78.4 hours, is enough for intact monoclonal antibodies to reach optimal tumor-to-nontumor ratios. ii) Peptides with relatively short biological half--‐lives Data T1/2 99MTc = 6.02 hrs, 64Cu = 12.7 hrs, 89Zr = 78.4 hrs, 68Ga = 68 mins According to the above 68Ga is taken to be suitable for a bioconjugate imaging agent for peptides which has relatively short biological half lives This is due to its half life of 68 minutes is short. 5. Bioconjugates are very popular for the targeted localization of radionuclides. a) What are the 4 main components of a bioconjugate imaging agent and what factors should be considered when selecting each component for a task -Chelating Ligand, The targeting bimolecule, the radiotracer group and Linker -The targeting biomolecule: It must have specificity for a particular biomarker of disease Mostly, cell-surface receptors are used as biomarkers -The radiotracer group: Choice is mainly based on half-life for example in labelling IgG antibody 68Ga can’t be used because by the time the antibody optimal distribution is reached in the body the nuclide will have gone through many half-life decays longer lived radionuclide such as 64Cu and 86Y are preferred -Chelating Ligand: Must bind the metal very tightly – high in vivo stability – kinetically inert The formation of metal complex should be relatively fast as well as must have functionality to enable linking to the biomolecule – bifunctional chelate (BFC) -Linker – should be stable under physiological Conditions. It should also not effect binding ability and specificity of biomolecule. Thioether, peptide and thiourea are the most common linker groups used b) Draw2 bioconjugates used in PET or SPECT imaging and identify each of the4 major components in each 68Ga DOTATOC (a somasatin bioconjugate agent) it binds to somasatin receptor, SSTR and later accumulates in areas that is diseased 64Cu(II) diacetyl-bis(N4-methylthiosemicarbazone) is a PET imaging agent that accumulates in low-oxygen tissues. Cu–PTSM 64Cu(II) pyruvaldehyde bis(N4-methylthiosemicarbazonato) is used in PET imaging to study blood flow in the brain, heart and also tumours. 6.a) In PET imaging although the nuclei emit positrons it is gamma rays that are detected, explain this. PET Imaging agents contain radionuclides which decay via positron (β+) emission. The Positron move a short distance (positron range) into surrounding tissue before it annihilates by combining with an electron. On annihilation, positron and electron are converted into energy to give to 511keV γ-rays which are emitted simultaneously at 1800 to each other later γ-rays are detected by surrounding detectors which calculate position of annihilation. Radionuclide must be γ-emitting .This is because they have Suitable physical half-life that is long enough to monitor the physiological functions which is studied; this is not seen to be too long which helps to minimize the patients radiation exposure. Mostly γ-radiation are ~100 – 200 eV which produces good images but that of positrons can be too low that may result to no image if it is too high there will be poor contrast. Photon penetrates body tissue with minimal attenuation because they have sufficient energy. They also have sufficiently low energy which can be registered efficiently in detector and this enables use of lead collimator systems efficiently. The decay product has minimal -lived activity in this case short. b) Given that positron range is influenced by positron energy why is it important that nuclei do not emit positrons with very high energies? Low energy levels will be registered more efficiently in the detector that may result to lead collimator systems to be used meaning the energy will be absorbable in lead hence the positron energy should be low enough. If it’s too high there will be poor contrast c) Explain how a gamma camera works When γ-ray hits NaI, the electron is knocked out of I anion, this Electron then roams for a moment but it recombines with iodine atom. During this process a photon of light is released which is amplified and computers collate data to create image. Collimator is a lead sheet that has tiny holes which allow gamma rays through. d) In SPECT imaging why is it important that the gamma rays emitted are neither too low nor too high in energy? Mostly γ-radiation are ~100 – 200 eV which produces good images but it should not be too low that may result to no image if it’s too high there will be poor contrast. 7. 99mTc is the most commonly used radionuclide in SPECT imaging. This is in part due to its availability and cost. a) Explain how a99mTc generator works Commercial Mo-99/Tc-99m generators mostly use column chromatography, Mo-99 is adsorbed onto alumina then the column is eluted with normal saline,Mo-99 is then immobilized, but the solubleTc-99m is eluted, later from the end of the column the saline solution having the Tc-99m is obtained. b) Clinics/hospitals return generators to the nuclear reactor after approximately 3 half--‐lives of the mother radionuclide for charging. If a charged99mTc generator has not been used could it be stored for a period of weeks/months? Why? No, because 99mTc is produced by a generator charged with 99Mo and it has a half life of 66hrs meaning that Generators can only be kept for about 3 half-lives of the parent which is 1 week for instant. 8.Special‘kits’ are used to prepare imaging agents in hospitals quickly and with little/no chemical expertise– a solution containing the radionuclide from the generator is added to the kit (a pre--‐made solution) and the imaging agent is formed after stirring and in some cases heating. a) What are the common components in a kit used for preparing 99mTc imaging agents and what is the purpose of each? A reaction vial -contains ingredients of 2.8 mg minimum stannous tin as stannous chloride dehydrate, -12.0 mg of sodium pyrophosphate - 4.9 mg maximum total tin (stannous chloride dehydrate); -Hydrochloric acid (adjusts pH is to between 5.3 and 5.7 before to lyophilization) -Isotonic saline solution for preparation of a blood pool imaging agent (useful in Sodium Pertechnetate Tc 99m intravenous injection after about 30 minutes) -.Rhenium is used as a carrier (Larson and Nelp 1996; Patton et al 1996) b) Cardiolite is a 99mTc heart imaging agent. The kit for preparing this complex contains BIMI complexed to Cu+. Why is the necessary? Copper emission is able to be detected on the detector and can be reduced easily as well as trapped in cells from where it decays. 9 Questions 9 Magnevist [Gd (DTPA)]2- is a commonly used contrasting agent in MRI. a) What are the features of Gd3+ that make it such a successful contrasting agent? I) It reduces the T1 relaxation time (the time the disturbed chemical system takes to return to equilibrium). This is due to its paramagnetic properties with a 1S electronic ground state. Relaxation effect time reduction is effected by water binding intermittently to the paramagnetic structure. Incorporation of Gd into polymer-incorporated protein cage nanoparticles can provide high r1 relativity It constitute paramagnetic compounds, the mostly used paramagnetic ion is gadolinium and it attaches with various ligands such as DTPA that acts as chelating agents.Changes in the T1 and T2 relaxation times of protons is affected due to the presence of unpaired electrons in the paramagnetic ion. There is utilization of a paramagnetic ion with the highest spin quantum number. The Gd ion of Ianthanide metal group has high spin quantum number hence this makes it suitable contrast agent ii) Which of the contrasting agents shown below would be most suitable for use with a patient in an impaired renal system and why? Dotarem [Gd(DTPA)]- -There is better contrast values in vivo due to higher relaxivity values. Magnevist- The reaction between the Gd and DTPA forms a stable chelate complex. 10) Superoxide dismutases enzymes catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. They are important antioxidant, they play defense role in almost all cells exposed to oxygen. Has been implicated to be a new therapies for the treatment of inflammatory bowel disease (SeguiJ et al 2004), It may also reduce free radicals that damage the skin-- e.g. It can reduce fibrosis due to radiation for breast cancer 11. Explain how chemical reactions in DNA can lead to changes in DNA sequence following mitosis. (7 marks) Changes in DNA sequence is as a result of mutation which is a change in the base sequence of the DNA. Enzymes can’t recognize mutation once the base change is present in both DNA strands; this implies that a mutation cannot be repaired. Oxidation is a process by which a chemical group with a free radical, unpaired electron(s), stable neutral atom gains an electron from DNA that result to a cascade of events hence mutation in DNA sequence. 12) Not all mutations can lead to cancer and can depend on the location for the mutation. Explain why this is the case and give specific examples of mutations that could increase the chances of cancer. The most of mutations which are not neutral in their effect are deleterious to a cell’s survival. For example, mutant cells will seem to be lost in a population of cells comprising a tissue with replicating cells,. But incase where there is infrequent mutations that favors a survival of cells will tend to clonally expand at the expense of neighboring cells in the tissue. Such mutant cells can give rise to cancer which is disadvantageous to the whole organism. The most likely cause of aging is DNA damage in infrequently dividing cells. Tumour suppressor gene causes cancer when it is turned off due to disrupted sequence i.e mutation in nucleotide sequence. Adenomatous polyposis is a cancer caused by deactivated tumour suppressor genes among many others. 13 Aflatoxin BI The mutational effect ofAFB1-N7 correlates with structural models this means that aflatoxin moiety of the aflatoxin guanine covalently intercalates on the 5' face of the guanine residue. These suggest a molecular mechanism that could explain an important step in the carcinogenicity of aflatoxin B1 has an electrophilic carbon 2 that reacts with water to form hydrophilic Alatoxin that forms covalent adducts with DNA. Cyclophosphamide It’s an alkylating agent that adds an alkyl group (CnH2n+1) to DNA. The alkyl group is attached to the guanine base of DNA, at position 7 nitrogen atom of the imidazole ring. Diaziquone It is an alkylating agent,hence is an aziridinylbenzoquinone. This results in disruption of DNA function, cell cycle arrest and apoptosis. The drug shows broad antitumor activity against numerous transplantable murine tumors including curative activity against several intracerebrally implanted tumors. 14. The compound 4-nitrobiphenyl is a known carcinogen. Show how the molecule is metabolized to a reactive intermediate and how it would react with G-07 and lead to single strand DNA breaks. 4-Nitrobiphenyl is metabolized to 4-aminodiphenyl. The reaction pathway is as below: 4-Nitrobiphenyl 4-aminodiphenyl (carcinogenic) 4‑aminobiphenyl is carcinogenic when it is metabolized via N‑hydroxylation (a process mediated by cytochrome P450 liver enzymes). Metabolites like N‑hydroxylamine including N-hydroxyacetamide this metabolites can be transformed to reactive compounds that can bind to DNA. 4-aminobiphenyl nitronium ion is a potential carcinogenic. The nitrenium ion interacts with G-07 charged groups to form 4-ABP–DNA complex. The 4-ABP–DNA complexes are formed through pathway that activates the 4-Aminobiphenyl to induce the formation of the nitrenium ion. Reference Seguí J, Gironella M, Sans M, Granell S, Gil F, Gimeno M, Coronel P, Piqué JM, Panés J (September 2004). "Superoxide dismutase ameliorates TNBS-induced colitis by reducing oxidative stress, adhesion molecule expression, and leukocyte recruitment into the inflamed intestine". J. Leukoc. Biol. 76 (3): 537–44. doi:10.1189/jlb.0304196. PMID 15197232. Read More