Cytotoxin Inhibits DNAtopoisomerase enzymes Happy Tree China CO301

Cytotoxin- Inhibits DNA-topoisomerase enzymes Happy Tree (China) CO-301 Heterocyclic Chemistry Convenor Dr. Fawaz Aldabbagh http: //www. nuigalway. ie/chemistry/level 2/staff/f_aldabbagh/Fawaz. htm

Definition: Heterocyclic compounds are organic compounds that contain a ring structure containing atoms in addition to carbon, such as sulfur, oxygen or nitrogen, as the heteroatom. The ring may be aromatic or nonaromatic Significance – Two thirds of all organic compounds are aromatic heterocycles. Most pharmaceuticals are heterocycles. Examples Pfizer: Viagra Quinine Treatment of malaria for 400 years (Peru) Erectile dysfunction

Treating stomach & intestinal ulcers Camptothecin Analogues Pfizer - Irinotecan GSK - Topotecan Ovarian & lung cancer More soluble & less side-effects

When Is A Molecule Aromatic? • For a molecule to be aromatic it must: • • Be cyclic Have a p-orbital on every atom in ring Be planar Posses 4 n+2 p electrons (n = any integer) Erich Hückel

Six Membered Heterocycles: Pyridine replaces the CH of benzene by a N atom (and a pair of electrons) Hybridization = sp 2 with similar resonance stabilization energy Lone pair of electrons not involved in aromaticity Pyridinium ion: p. Ka = 5. 5 1 H NMR: d Piperidine: p. Ka = 11. 29 diethylamine : p. Ka = 10. 28 Pyridine is a weak base Pyridine is -electron deficient Electrophilic aromatic substitution is difficult Nucleophilic aromatic substitution is easy

Pyridine as a nucleophile Use Pyridine as a solvent to make esters E. g. Acyl pyridinium ion Reactive intermediate

DMAP (Dimethyl. Amino. Pyridine) Whereas acylations “catalyzed” by pyridine are normally carried out in pyridine as the reaction solvent. Only small amounts of DMAP are required to do acylations Attempted Electrophilic Aromatic Substitution Unreactive, Stable

How can we nitrate pyridine? We now have an activating and protecting group Mechanism

Third Period ; n 2 = 32 = 9 orbitals Ar [Ne]; 3 s 2, 3 px 2, 3 py 2, 3 pz 2 3 d 0 3 d 0 n=3

Nucleophilic Substitution at 2 - and 4 -positions of pyridine is most favoured E. g.

Five Membered Heterocycles: Pyrrole Aromatic: Thus, 6 electrons 1 H NMR: d Sp 2 hybridised and planar Lone pair tied up in aromatic ring Pyrrole is -electron excessive Thus, Electrophilic Aromatic Substitution is Easy Nucleophilic Substitution is Difficult

Electrophilic Aromatic Substitution preferred at the 2 -position Normal acidic nitration causes polymerization Vilsmeier Reaction Electron-withdrawing group allows substitution at the 3 -position

Organic Synthesis with Pyrrole should avoid strong acids i i; 1 X SO 2 Cl 2, Et 2 O ii; 4 X SO 2 Cl 2, Et 2 O ii

Indole Aromatic due to 10 -electrons Benzene part is non-reactive Electrophilic aromatic substitution occurs at the 3 -position Indole Alkaloids Lysergic acid (LSD) Strychnine Mitomycin C

Other Five Membered Heterocycles The least aromatic: The O atom is too electronegative Least reactive More aromatic than Furan Less reactive than pyrrole, but substitution always at 2 position Electrophilic Substitution, not addition Can give addition, as well as substitution products when reacted with E+ Thiophene has similar reactivity to benzene

Electrophilic Aromatic Substitution of Thiophene Avoid concentrated mineral acids or strong Lewis acids, e. g. Al. Cl 3

Some Reactions of Furan is more reactive than thiophene Wittig reaction Addition product Hydrolysis of acetal Furan is easily cleaved to dicarbonyls

Furan is a source of 1, 4 -dicarbonyls in Organic Synthesis

The Diels-Alder Reaction Diene 4 system dienophile 2 system 4+2 cycloaddition Otto Diels Electron rich Electron poor Kurt Alder Noble Prize in 1950

The configuration of the dienophile is retained Always reacts via the cis-diene Under kinetic control

Furan readily undergoes the Diels-Alder reaction with maleic anhydride Thermodynamic exo-product forms as the temperature is raised endo-product More stable due to less steric reasons Aromaticity prevents thiophene from taking part in the Diels-Alder reaction - SO 2 This sulfone is not aromatic & very reactive

Five-membered Rings with Two or More Nitrogens p. Ka = 14. 5 (imidazole) p. Ka = 16. 5 (pyrrole) Diazoles Pyrazole Imidazole is more basic than pyridine, but more acidic than pyrrole Imidazole + H+ Imidazole - H+ Na. OH - H 2 O Properties: Very stable cation and anion of imidazole is formed

Some Natural Imidazole Compounds Histidine Important ligand to many metalloproteins Is one of the essential amino acids. A relatively small change in cellular p. H can result in a change in its charge Body neurotransmitter & local immune response histamine histidine carboxylase Dipeptide in high concentrations in the brain & muscles - Improves social interactions & treatment of autism Carnosine

Synthesis of 2 - and 5 -Nitroimidazole Antibiotics 2 -Nitroimidazole, “azomycin” (i) (iii) 30% (i) Cl. CPh 3, NEt 3 (ii) Bu-Li, n-Pr. ONO 2 (iii) HCl (aq), Me. OH 5 -Nitroimidazoles, “metronidazole” is used to treat anaerobic protozoan infections 4 (i) 80% (i) HNO 3, H 2 SO 4 5 metronidazole inactive

Triazoles Weakly basic like pyridine, but more acidic than imidazole 1, 2, 4 -Triazole 1, 2, 3 -Triazole Tetrazoles p. Ka = 10. 3 Only one isomer now possible p. Ka ~ 5 ~ RCOOH

Tetrazoles are used in drugs as replacements for CO 2 H Indomethacin Tetrazole derivative Anti-arthritis drug - Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses

Synthesis of Indomethacin

Bioreductive Anti-Tumour Agents 10 1 Mitomycin C IC 50 ≈ 1. 0 µM Pyrrolo[1, 2 -a]benzimidazole (PBI) E. B. Skibo et al. , J. Med. Chem. , 2002, 45, 1211 K. Fahey, F. Aldabbagh, Tetrahedron Lett. , 2008, 49, 5235 More selective to hypoxia Hypersensitive to Fanconi Anemia IC 50 ≈ 0. 001 µM L. O’Donovan, F. Aldabbagh, Chem. Commun. , 2008, 5592. M. Lynch, S. Hehir, M. P. Carty, F. Aldabbagh, Chem. Eur. J. 2007, 13, 3218 S. Hehir, L. O’Donovan, M. P. Carty, F. Aldabbagh, Tetrahedron 2008, 64, 4196

Targeting Hypoxic Cells

Mitomycin C (MMC) SET - activation 10 1 + 1 e- steps - 1 e- . DNA alkylation CY P 450 reductase Two electron activation + 2 e+ 2 H+ DNA alkylation DT-diaphorase S. E. Wolkenberg and D. L. Boger, Chem Rev. , 2002, 102, 2477

Measuring the Effect of FANCD 2 Expression on Cell Viability ●, ● PD 20 i cells (lack FANCD 2) ▲, ▲ PD 20: RV (express FANCD 2) K. Fahey, L O’Donovan, M. Carr, M. P. Carty, F. Aldabbagh, Eur. J. Med Chem. 2010, 45, 1873 -1879