Heterocycles 4 PowerPoint PDF

Fused Rings with More than One Nitrogen The Purines – C5H4N4 6 7 1N 5 N pyrimidine 8 imidazole 2 N 4 N9 3 H...

Fused Rings with More than One Nitrogen The Purines – C5H4N4 6 7 1N 5 N pyrimidine 8 imidazole 2 N 4 N9 3 H purine Purines are possibly the most widely distributed of all heterocycles. Constituents of DNA & RNA. Act as hormones & neurotransmitters  The 4 Tautomers of Purine H N H N N N N N N N N N N N N N H N N H Undergo both electrophilic and nucleophilic attack at C in the 5- membered ring. Undergo only nucleophilic attack at C in the 6-membered ring.  Biological Significance NH2 H2N H2N N N N N N N N N N N N N H O O Adenine (A) HO H2N OH O OH N HO P O N O OH Adenosine N N Cyclic AMP (Nucleoside) O RO O O OH HO N N O HN HN AMP R= O P OH OH H2N N N H2N N N nucleotides O O H O ADP R= O P O P OH HO OH OH Guanine (G) OH O O O HO ATP R= O P O P O P OH Guanosine OH OH OH  O O P RNA/DNA HO O Base thymine adenine O Me O H NH N O OH O P HO O O Base N H N N O OH N N backbone O P backbone O HO O Base O HO OH cytosine guanine HN H O N N H N N N N backbone O H NH backbone  RNA/DNA DNA and RNA are polynucleotides DNA consists of two strands of nucleic acid with the sugar-phosphate backbone on the outside and the bases on the inside. The two strands are held together by H-bonds. Adenine always pairs with Thymine Guanine always pairs with Cytosine. This is called complimentary base pairing. In RNA thymine is replaced with uracil (U).  Other Important Purines O O Me O Me H Me N N N HN N HN N O N N O N N O N H Me Me Xanthine – degradation Caffeine – stimulant Theobromine – stimulant product from DNA Found in tea/coffee Found in chocolate O H Uric acid – a way of excreting N HN excess nitrogen (mainly by birds). O When crystals deposit O N N in joints, it is known as gout. H H  Pharmaceutical Importance S O O N N N HN HN HN N N H2N N N OH N N H O O 6-Mercaptopurine – HO Leukemia, Crohn’s Acyclovir – disease Most commonly used Dideoxyinosine (DDI) – antiviral for Herpes AIDS (zovirax, zovir, herpex) N NO2 N S Me N Azathioprine - organ transplantation and HN autoimmune disease (IBS, Crohn's disease, MS). N A prodrug of 6-mercaptopurine. N H  Pteridine – C6H4N4 Bicyclic – consider as a fused 4 5 N pyrimidine and pyrazine ring system 3 N 6 Analogue of naphthalene 2 7 N N 10 π electron ring system – aromatic 1 8 pteridine Weak base Natural occurrence Pteridine is found in folic acid (Vit B9) and folate (water soluble form). Vitamin B9 is essential to numerous bodily functions and is particularly important during periods of rapid cell division and growth. Both adults and children require folic acid to produce healthy red blood cells and prevent anaemia.  Pharmaceutical Importance OH N p-aminobenzoic acid (paba) N NH H2N N N Pteridine + paba = Pteroic acid CO2H pteridine O N CO2H glutamic Folic Acid H acid NH2 NH2 N R N N N N R' H2N N N H2N N N NH2 Anti cancer drugs R R’ Action Triamterene (diuretic) Methotrexat CH3 paba + Inhibits folic hypertension and edema. e glut. acid metabolism Aminopterin H paba + Antifolate  Benzopteridine Tricyclic ring system (cf anthracene) – 4 nitrogen atoms O N N N HN N N O N N H Natural occurrence Isoalloxazine (flavin) Vitamin B2 (Riboflavin) a micronutrient found O in dairy, leafy green veg, kidney, etc. Key role in maintaining health in humans and N HN animals through energy metabolism. Central component of the cofactors FAD O N N (flavine adenine dinucleotide) and FMN OH (flavine mononucleotide). HO + H ,e - H+, e- OH + FADH FAD FADH2 oxidised free radical reduced HO Riboflavin  Other heterocyclic systems of pharmaceutical interest Phenothiazine (tranquillisers). This class of antipsychotic drugs is so large it is classified into three main groups depending on the substituent on the Nitrogen. These groups are the aliphatic, piperidine and piperazines. S S N Cl N S Thioridazine Chlorpromazine N (CPZ) – oldest typical N N antipsychotic N Dibenzazepines: (antidepressents), tricyclic antidepressents Imipramine Benzodiazepines (sedatives). First introduced onto the market in the early 1960’s. They are a commonly prescribed class of psychoactive drugs that result in a slowing down of the central nervous system. They can be used in alcohol withdrawal and prior to certain medical procedures. R O N R R’ X Diazepam CH3 H Cl R' N Nitrazepam H H NO2 X Oxazepam H OH Cl tamazepam CH3 OH Cl