Lecture 5 Heterocyclic Compounds. Structure, Properties and Biological Function of Nucleic Acids

1. Kharkiv National Medical University Department of Medical and Bioorganic chemistry «Biological and Bioorganic Chemistry» Lecture 5 Heterocyclic Compounds. Structure, Properties and Biological Function of Nucleic Acids Lecturer: As. Professor, Department of Medical and Bioorganic Chemistry,, Ph.D. Kozub S.M.

2. ACTUALITY OF THE LECTURE Heterocyclic structures are in the basis of numerous natural and biologically active substances and drugs. Heterocyclic molecules (indol, imidazole...) are included in some essential amino acids. A lot of drugs also contain heterocycles: non-narcotic analgesics contain pyrazolon-5, anti-tuberculosis drugs contain pyridine.

3. Outline of the lecture • Classification of heterocycles. • Aromaticity of heterocycles. • Biologically important compounds with five-membered heterocycles. • Biologically important compounds with six-membered heterocycles. • The structure and biochemical functions of nucleosides, nucleotides and nucleic acids.

4. HETEROCYCLIC COMPOUNDS are cyclic compounds in which an element other than carbon is present in the ring: Thiazole Furan Pyrrole

5. 1. Classification of heterocycles а) Five-membered heterocycles • containing one heteroatom S O N Pyrrole Thiophene Furan • containing two heteroatoms (azoles) N N N S N N Imidazole Pyrazole Thiazole

6. c) Six-membered heterocycles: • containing one heteroatom O N Pyrane Pyridine • containing two heteroatoms N N N N N N Pyridazine Pyrimidine Pyrazine

7. в) condensed heterocycles: 1 N N 1 N 9 N 1 N N Indole Quinoline Purine Usually trivial names are used. Numeration of ring atomsbegins with heteroatoms.

8. AROMATICITY OF HETEROCYCLES Hückel’s rule N = 4n + 2 where isn (number of cycles) = 1,2, etc. N - number of conjugate -electrons

9. Pyridine is basic in nature; it reacts with water and acids. The nitrogen atom is more electronegative as compared with the carbon itself. It pulls electron density from the ring. Therefore, the system with the pyridine nitrogen is called  -deficiency. PYRIDINE NITROGEN N Pyridine

10. Pyridine is -deficiency sistem p-orbitalisinvolved inconjugation sp2 - orbital lone pair of electrons Pyridine

11. PYRROLE NITROGEN • Pyrrole is slightly acidic. • The system with the pyrrole nitrogen is called  -excess. N Pyrrol

12. Pyrrole is -excess system p orbitallone pair of electrons involved in conjugation sp2 - orbital forms σ- bond Pyrrole

13. AMPHOTERIC COMPOUNDS Pyridine nitrogen (basic properties) Imidazole Pyrrole nitrogen (acidic properties ) Pyrazole

14. 3. Biologicallyimportantcompounds withfive-memberedheterocyclesPorphine - tetrapyrrolearomaticringconstructedofpyrroline (I), pyrrole (III) andtwoizopirrolnyhnuclei (II, IV), connectedby a methinegroup = CH- Porphyrins (substitutedporphine) - prostheticgroupsofcomplexproteins: hemoglobin, myoglobin, mitochondrialrespiratoryenzymes - cytochrome, catalaseandperoxidase, chlorophyll, vitamin B12. 14 N N N N N N N N Porphine Porphyrine

15. USE IN MEDICINE Serotonin and tryptamine are biogenic amines, the products of the biochemical conversion of tryptophan in the body: N N 5-hydroxy triptophan Serotonin N Triptophan N Tryptamine

16. The final products of metabolism of serotonin and tryptamine in the body are: 5-hydroxy-  -indoleacetic acid and • -indoleacetic acid N N • -indoleacetic acid 5-hydroxy-  -indoleacetic acid

17. Five-membered heterocycles containing two heteroatoms (azoles): pyrazole, imidazole, and thiazole. N N Pyrazole N N N N N N Amidopyrine Antipyrine Analgin

18. The structure of the imidazole part of many biomolecules and drugs IMIDAZOLE N N N Histidine N N N Imidazole N N Purine

19. The main biologically active derivatives of imidazole are histidine and histamine N N N N

20. In the organism Vitamine B1 is converted into its active form - thiamine pyrophosphate (TPP): + N N S N TPP

21. 4. Biologically important compounds with six-membered heterocycles:pyridine, pyrimidine, purine. N N N Picolinic acid Nicotinic acid Isonicotinic acid

22. Derivative of nicotinic acid is nicotinamide (Vitamin PP) Cashews Peanuts Turkey meat Liver Tomatoes

23. Nicotinamide (Vit PP(B5)) is a structural component and reactive site of the coenzyme NAD+ Nicotinamide Structure of nicotinamide adenine dinucleotide, oxidized (NAD+)

24. ANTITUBERCULAR DRUG. N N Isoniazid Phthivazid

25. Derivatives of pyrimidine called nitrogen bases. N N N N N N Uracil Thymine Cytosine

26. PYRIMIDINE DERIVATIVES Among the medicines - pyrimidine derivatives - important are preparations which are synthesized on the basis of barbituric acid

27. Barbituric acid (2,4,6-trihydroxypyrimidine) in water solutions can exist being in some tautomeric forms: • Lactam-lactim tautomerism, • keto-enol tautomerism: N N N N

28. BARBITURATES are drugs synthesized on the basis of barbituric acid. Phenobarbital (Luminal): R1 = C2H5; R2 = C6H5 Barbital (Veronal): R1 = R2 =C2H5 N N

29. Purine – is a fused aromatic system consisting of pyrimidine and imidasole Hydroxy purines are formed in the organism in the nucleic acid metabolism: 30 7 N 1 N N N Purine N N N N N N N N N N N N Xanthine Hypoxanthine Uric acid

30. TAUTOMERISM For purine containing compounds lactim-lactam tautomerism is typical (prototropic tautomerism): N N N N N N N N N N N N Prototropic tautomerism of hypoxanthine Lactim-lactam tautomerism of hypoxanthine

31. URIC ACID Uric acid is dibasic, poorly soluble in water, but well soluble in bases with formation of acidic and neutral salts – urates: H N N N N N N N N N N N N

32. IMPORTANT HETEROCYCLIC COMPOUNDS OF AMINOPURINES 6-aminopurine (adenine) 2-amino-6-hydroxypurine (guanine)

33. NUCLEIC ACIDS • Were discovered in 1868 by Swiss chemist F. Miescher • First found in the nucleus Friedrich Miescher

34. The role of nucleic acids People, animals, plants, and more all are connected by genetic material. Every living thing may look different and act different, but deep down — way deep down in the nucleus of cells — living things contain the same chemical “ingredients” making up very similar genetic material.

35. 5.The structure and biochemical functions of nucleosides and nucleotidesnucleic acid The structure of nucleic acids, monosaccharides are included in the β - furanose form:

36. SUGAR 2’ Ribose

37. SUGAR 2’ H deoxyribose 2’ -

38. NITROGEN BASES HN HN N 1 N N N 5

39. LACTIM-LACTAM TAUTOMERISM Lactim form Lactam form

40. NUCLEOSIDES • The heterocyclic base of a nucleotide is attached through an N-glycosidic linkage to C1’ of the ribose or deoxyribose unit and this linkage is always β. • The phosphate group of a nucleotide is present as a phosphate ester and may be attached at C5’ or C3’. (In nucleotides, the carbon atoms of the monosaccharide portion are designated with primed numbers, i.e. 1’, 2’, 3’, etc.) • Removal of the phosphate group of a nucleotide converts it to a compound known as a nucleoside.

41. NUCLEOSIDES

42. NAMING OF NUCLEOSIDES In naming of nucleosides have suffix : • -idine for pyrimidine bases: (uridine (U), thymidine(Т), cytidine (C), deoxycytidine (dC)), • -osinefor purine bases: аdenosine (А), deoxyаdenosine (dА), guanosine (G), deoxyguanosine (dG).

43. NUCLEOTIDES 5’ 1’ 3’

44. The position of the phosphate group is sometimes explicitly noted by use of the names uridine 5’-monophosphate or 5’-uridylic acid.

45. Nikotinamidnukleotide NAD+ nicotinamide adenine dinucleotide

46. Adenine macroergic bonds ribonucleotide ATP adenosine triphosphate

47. cAMPcyclic adenosine monophosphate Cyclic AMP

48. Primary structure of DNA 5’ 1’ 4’ 3’ 2’

49. THE STRUCTURE OF DNA 1950 Chargaff's rule Erwin Chargaff

50. 1953 Open structure of DNA Джеймс Уотсон Фрэнсис Крик