Ribonucleotide reductase – potential target in cancer treatment

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Table of contents

1. Introduction
1.1. History of medicinal inorganic chemistry
1.1.1. Metals in medicine
1.1.2. Cisplatin – the first anticancer drug
1.1.3. Reducing side-eects – Cisplatin analogues
1.2. Ruthenium complexes in cancer treatment
1.2.1. Simple ammine and amine ruthenium complexes
1.2.2. Ruthenium dimethyl sulfoxide complexes
1.2.3. NAMI-A, KP1019 and their analogues – ruthenium antimetastatic agents
1.2.4. Ruthenium-arene complexes
1.2.5. Ruthenium polypyridyl complexes
1.2.6. Ruthenium complexes bearing biologically active molecules – theranostic application
1.3. Biological activity of semicarbazones and thiosemicarbazones
1.3.1. Anticancer activity
1.3.2. Ribonucleotide reductase – potential target in cancer treatment
1.4. Hydantoins – anticonvulsant drugs in cancer treatment
1.4.1. Seizures and cancer
1.4.2. Hydantoins in cancer treatment
2. Aim and scope of the thesis
3. Methods
3.1. Electronic apsorption spectroscopy
3.2. Luminescence studies
3.3. Computational studies
3.3.1. Geometry optimalization and molecular orbitals energy calculations
3.3.2. Electronic absorption spectra simulation
3.4. Synthesis
3.5. Spectrofluorimetric titration of human serum albumin with ruthenium complex
4. Results and discussion
4.1. General strategy of ruthenium(II) polypyridyl complexes synthesis
4.2. Synthesis of 2,2’-bipyridine ligands modified with pyridine-2-carboxyaldehyde semicarbazone and the linker – various approaches Synthesis of ligand L1 – 5-(4-{4’-methyl-[2,2’-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone
4.3. Synthesis of 3-(5-{4’-methyl-[2,2’-bipyridine]-4-yl}pentyl) -imidazolidine-2,4-dione (L2),
5,5-dimethyl-3-(5-{4’-methyl-[2,2’-bipyridine]-4-yl}pentyl) -imidazolidine-2,4-dione (L3) and [1-(5-{4’-methyl-[2,2’-bipyridine]-4-yl}pentyl) -2,5-dioxoimidazolidin-4-yl]urea (L4) – General procedure
4.4. Ruthenium complexes synthesis
4.4.1. Synthesis of cis-bis(polypyridine)dichlororuthenium(II)
4.4.2. Synthesis of ruthenium(II) complexes with ligand L1
4.4.3. Synthesis of ruthenium(II) complexes with ligands L2, L3 and L4
4.5. Photophysical properties of ruthenium complexes
4.5.1. Absorption properties
4.5.2. Emission properties
4.6. Computational studies
4.6.1. Geometry calculations
4.6.2. Natural Bond Orbitals (NBO) analysis
4.6.3. Electronic absorption spectra
4.7. Ruthenium complexes intractions with Human Serum Albumin
4.7.1. Human Serum Albumin properties
4.7.2. Interactions with ruthenium complexes
5. Summary
5.1. Preliminary cytotoxic studies – Future perspectives
6. Synthetic procedures
6.1. Synthesis of Ligand L1
6.1.1. Synthesis of 4-(3-(trimethylsilyl)prop-2-yn-1-yl)-4’-methyl-2,2’-bipyridine (1)
6.1.2. Synthesis of 4-(prop-2-yn-1-yl)-4’-methyl-2,2’-bipyridine (2)
6.1.3. Synthesis of 5-bromopyridine-2-carboxyaldehyde (3)
6.1.4. Synthesis of 5-bromopyridine-2-carboxyaldehyde semicarbazone (4)
6.1.5. Synthesis of 5-(4-{4’-methyl-[2,2’-bipyridine]-4-yl}but-1-yn-1-yl)pyridine-2-carbaldehyde semicarbazone (L1)
6.2. Synthesis of Ligand L2, L3 and L4
6.2.1. Synthesis of 4-(5-bromopentyl)-4’-methyl-2,2’-bipyridine (6)
6.2.2. Synthesis of 3-(5-{4’-methyl-[2,2’-bipyridine]-4-yl}pentyl)- -imidazolidine-2,4-dione (L2)
6.2.3. Synthesis of 5,5-dimethyl-3-(5-{4’-methyl-[2,2’-bipyridine]-4-yl}pentyl)- -imidazolidine-2,4-dione (L3)
6.2.4. Synthesis of [1-(5-{4’-methyl-[2,2’-bipyridine]-4-yl}pentyl)- -2,5-dioxoimidazolidin-4-yl]urea (L4)
6.3. Ruthenium complexes synthesis
6.3.1. General procedure for synthesis of cis-Ru(NN)2Cl2
6.3.2. Synthesis of [Ru(bpy)2(L1)]Cl2 (16)
6.3.3. Synthesis of [Ru(Mebpy)2(L1)]Cl2 (17)
6.3.4. Synthesis of [Ru(tBbpy)2(L1)]Cl2 (18)
6.3.5. Synthesis of [Ru(Phbpy)2(L1)]Cl2 (19)
6.3.6. Synthesis of [Ru(dip)2(L1)]Cl2 (20)
6.3.7. Synthesis of [Ru(SO3dip)2(L1)]Cl2 (21)
6.3.8. Synthesis of [Ru(bpy)2(L2)](PF6)2 (22)
6.3.9. Synthesis of [Ru(bpy)2(L3)](PF6)2 (23)
6.3.10. Synthesis of [Ru(bpy)2(L4)](PF6)2 (24)
6.4. Other synthesis
6.4.1. Synthesis of 2-bromo-4-methylpyridine (25)
6.4.2. Synthesis of 4-methylpyridine-2-carboxyaldehyde (26)
6.4.3. Synthesis of 2-(1,3)-dioxolan-2-yl-4-methylpyridine (27)
6.4.4. Synthesis of 4-(7-bromoheptyl)-4’-methyl-2,2’-bipyridine (28)
6.4.5. Synthesis of 2-bromo-4-[6-(2-bromopyridin-4-yl)hexyl]pyridine (29)
6.4.6. Synthesis of 2-bromopyridine-5-carboxyaldehyde (30)
6.4.7. Synthesis of (2-bromopyridin-5-yl)methanol (31)
6.4.8. Synthesis of ({4’-methyl-[2,2’-bipyridine]-4-yl}pentyl)triphenylphosphonium bromide (32)
6.4.9. Synthesis of diethyl ({4’-methyl-[2,2’-bipyridine]-4-yl}pentyl)phosphonate (33)
References