Chemistry of Heterocyclic Compounds

Transcription

1 Chemistry of Heterocyclic Compounds Porphyrins Purines and pyrimidines Nucleosides and nucleotides Introduction to Heterocyclic Compounds Cyclic compounds with one or more other elements along with carbon atoms are heterocyclic compounds. Non carbon atoms are the hetero atoms. Common hetero atoms are the N, S, O etc. Number of drugs in pharmaceutical science are heterocyclic compounds. 5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM PYRROLE FURAN THIOPHENE 3 1

2 Pyrrole Pyrrole is an important five memberedheterocyclic compound possessing a nitrogenatom as hetero atom. plays important role in the chemistry of living organisms. 4 Pyrrole The essential structural feature of heme is porphyrin, which consists of fourpyrrole rings held together by bridges. 2

3 Heme Hemoglobin 7 Porphyrin orphyrinring in Heme Porphin rings Porphin rings are common biological ligands. Chlorophyll, the photosynthetic pigment of green plants, is a porphyrin with Mg 2+ at the center of the porphin ring. Vitamin B 12 has Co 3+ at the centerof the porphin ring. Hemoglobin 9 3

4 Porphin rings Porphin rings are common biological ligands. vitamin B 12 chlorophyll Hemoglobin 10 Pyrrole The amino acids, prolin and hydroxyproline are tetrahydropyrrole(pyrrolidine) derivatives. 5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM FURAN Derivatives of furan: Vitamin C (ascorbic acid) 12 4

5 5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS PYRAZOLE IMIDAZOLE OXAZOLE ISOXAZOLE THIAZOLE 13 5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS Among few naturally occurring products that contain the thiazole nucleus are vitaminb 1 andthepencillins. THIAZOLE Vitamin B 1 (Thiamine) General pattern of the penicillins 5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS Among the few naturally occurring products known to contain the imidazole nucleus are amino acids(histidine), purines, uric acid. IMIDAZOLE 5

6 6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM PYRIDINE PIPERIDINE 6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS PYRIMIDINE PYIRIDAZINE PYRAZINE 16 6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM PYRIDINE Nicotinamide and isoniazide derivatives of piridine. Nicotinamide, also known as niacin, is a vitamin. Isoniazid is biologically active and proved to be highly effective in the treatment of tuberculosis MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM PYRIDINE 18 6

7 6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS PYRIMIDINE Pyrimidines The pyrimidines are heterocyclic compounds whose basic structure is a six-membered ring containing carbon and nitrogen atoms as illustrated by the parent compound, pyrimidine. 19 Pyrimidines Thymine, cytosine, and uracil are substituted pyrimidines found in nucleic acid. Their structural formulas are as follows: CONDENSED HETEROCYCLIC COMPOUNDS. INDOLE PURINE 21 7

8 CONDENSED HETEROCYCLIC COMPOUNDS INDOLE Tryptophan- Indole group 22 Purines Purines The parent substance, purine, consists of pyrimidine ring attached to imidazole ring. The structural formula ofthepurineisasfollows: Nucleosides and nucleotides Functions Nucleotides are precursors of the nucleic acids, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The nucleic acids are concerned with the storage and transfer of genetic information. 8

9 Nucleosides and nucleotides Functions The universal currency of energy, namely ATP, is a nucleotide derivative. Nucleotides are also components of important co-enzymes like: - NAD + andfad,and - metabolic regulators such as camp and cgmp. Composition of Nucleotides A nucleotide is made up of 3 components: -a. Nitrogenous base (a purine or a pyrimidine) - b. Pentose sugar, either ribose or deoxyribose - c. Phosphate groups esterified to the sugar. Composition of Nucleotides When a base combines with a pentose sugar, a nucleoside is formed. When the nucleoside is esterified to a phosphate group, it is called a nucleotideor nucleoside monophosphate. 9

10 Composition of Nucleotides When a second phosphate gets esterified to the existing phosphate group, a nucleoside diphosphate is generated. The attachment of a 3rd phosphate group results in the formation of a nucleoside triphosphate. The nucleic acids (DNA and RNA) are polymers of nucleoside monophosphates Bases Present in the Nucleic Acids Two types of nitrogenous bases; -the purines and pyrimidines are present in nucleic acids. Purine Bases The purine bases present in RNA and DNA are the same; -adenine and guanine. Adenine is 6-amino purine Guanine is 2-amino, 6-oxy purine 10

11 Purine Bases Purine hasa numbering scheme that does not match rules, and represents a historical numbering pattern. The numbering of the purine ring with the structure of adenine and guanine are shown in Figure. Purine Bases H H H 6-amino purine 2-amino, 6-oxy purine Pyrimidine Bases The pyrimidine bases present in nucleic acids are cytosine, thymine and uracil 11

12 Pyrimidine Bases Cytosineis present in both DNA and RNA. Structures are shown in Figure. 2-oxy, 4-amino pyrimidine H Pyrimidine Bases Thymineis present in DNA and uracilin RNA. Structures are shown in Figure. H H H 2-oxy-4-oxy pyrimidine H 5-methyluracil These two words are often confused THYMINEisthebasepresentinDNA THIAMINE is vitamin B 1, named as the "thio-vitamine" ("sulfur-containing vitamin") is a vitamin of the Bcomplex 12

13 Nucleosides Sugar groups in nucleic acids Nucleosides are formed when bases are attached to the pentose sugar, D-ribose or 2-deoxy-D-ribose. OH CH 2 O OH OH CH 2 O OH OH Ribose OH OH Deoxyribose Theonlydifference inthetwocompoundsisthat deoxyribose is lacking an oxygen atom(second carbon atom). Nucleosides All the bases are attached to the corresponding pentose sugar by a beta-n-glycosidic bond between the 1st carbon of the pentose sugar and N9of a purine or N1of a pyrimidine. The deoxy nucleosides are denoted by adding the prefix d- before the nucleoside. Nucleosides The carbon atoms of the pentose sugar are denoted by using a prime number to avoid confusion with the carbon atoms of the purine or pyrimidine ring. Numbering in base and sugar groups. Atoms in sugar is denoted with primed numbers. 13

14 Nucleosides Nucleosides with purine bases have the suffix -sine, while pyrimidine nucleosides end with -dine. Uracil combines with ribose only; and thymine with deoxy ribose only. Nucleosides The names of the different nucleosides are given in Table. Nucleotides These are phosphate esters of nucleosides. Base plus pentose sugar plus phosphoric acid is a nucleotide 14

15 Nucleotides The esterification occurs at the 5th or 3rd hydroxyl group of the pentose sugar. Most of the nucleoside phosphates involved in biological function are 5'-phosphates. Nucleotides Nucleotides Since 5'-nucleotides are more often seen, they are simply written without any prefix. For example, 5'-AMP is abbreviated as AMP; but 3' variety is always written as 3'-AMP. Moreover, a base can combine with either ribose or deoxy ribose, which in turn can be phosphorylated at 3' or 5' positions. 15

16 Nucleotides Many co-enzymes are derivatives of adenosine monophosphate. Examples are NAD+, NADP, FAD and Co-enzyme A Nucleotides NAD + Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. The compound is a dinucleotide, because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide. Nicotinamide adenine dinucleotide exists in two forms, an oxidized and reduced form abbreviated as NAD+ and NADH respectively(in metabolism is involved in redox reactions) Nucleotides NAD + Nicotinamide adenine dinucleotide (NAD + ) 16

17 Nucleotides NADH Nucleotides NADP + Nicotinamide adenine dinucleotide phosphate, abbreviated NADP + NADP + differs from NAD + in the presence of an additional phosphate group on the 2' position of the ribose ring that carries the adenine moiety. Nucleotides FAD Riboflavin (vitamin B2) is part of the vitamin B group. It is the central component of the cofactors FAD Flavin adenine dinucleotide (FAD) 17

18 Nucleotides cleotides Co-enzyme A In humans, CoA biosynthesis requires cysteine, pantothenic acid. Co-enzyme A Pantothenic acid is also called vitaminb 5 (abvitamin). Nucleoside Triphosphates Corresponding nucleoside di-and tri-phosphates are formed by esterification of further phosphate groups to the existing ones. In general, any nucleoside triphosphate is abbreviated as NTP or d-ntp. Nucleoside Triphosphates Adenosine triphosphate (ATP) ATP is the universal energy currency. Nucleoside diphosphate contains one high energy bond and triphosphates have 2 high energy bonds. 18

19 Nucleoside Triphosphates Highenergy bond is formed during oxidative processes by trapping the released energy in the high energy phosphate bond. A phosphodiester linkage may be formed between the 3' and 5' positions of ribose group. Such compounds are called cyclic nucleotides. Cyclic Nucleotides 3',5'-cyclic AMP or camp Cyclic adenosine monophosphate 3', 5'-cyclic AMP or camp is a major metabolic regulator. Cyclic GMP also behaves similarly. These are second messengers in mediating the action of several hormones. Nucleotides Deoxy ribonucleotides are used for synthesis of DNA and ribonucleotides for RNA. In pseudouridylic acid (found in trna) uridine is attached to ribose phosphate in a C-C bond instead of C-N bond in UMP (uridine monophospate). 19

20 Nucleotides Different attachment of uracil to sugars The structure of DNA Deoxyribonucleic Acid DNA -a polymer of deoxyribo nucleotides found in chromosomes and mitochondria carries the genetic information 59 Deoxyribonucleic Acid Base Phosphate Sugar X=H: DNA X=OH: RNA Nucleoside Nucleotide 20

21 Basic structure of pyrimidine and purine 61 Pyrimidines 62 Purines 63 21

22 Nomenclature of Nucleic Acid Components Base Nucleoside Nucleotide Nucleic acid Purines Adenine Adenosine Adenylate RNA Deoxyadenosine Deoxyadenylate DNA Guanine Guanosine Guanylate RNA Deoxy guanosine Deoxyguanylate DNA Pyrimidines Cytosine Cytidine Cytidylate RNA Deoxycytidine Deoxycytidylate DNA Thymine Thymidine Thymidylate DNA (deoxythymidine) (deoxythymidylate) Uracil Uridine Uridylate RNA 5 end The primary structure of DNA is the sequence of nucleoside monophosphates 5 3 Phosphodiester linkage 3 end 65 Traditionally, a DNA sequence isdrawn from 5 to 3 end. A shorthand notation for this sequence is ACGTA 66 22

23 The secondary structure of DNA is the double helix 67 The secondary structure of DNA Two anti-parallel polynucleotide chains wound around the same axis. Sugar-phosphate chains wrap around the periphery. Bases (A, T, C and G) occupy the core, forming complementary A T and G C base pairs. 68 Two hydrogen bonds between A:T pairs Three hydrogen bonds between G : Cpaired 23

24 Three hydrogen bonds between G : Cpaired Two hydrogen bonds between A:T pairs Base Stacking The bases in DNA are planar andhave a tendency to "stack". Major stacking forces: hydrophobic interaction van der Waals forces. 71 Normally hydrated DNA: B-form DNA Helical sense: right handed Base pairs: almost perpendicular to the helix axis; 3.4 Å apart One turn of the helix: 36 Å; ~10.4 base pairs Minor groove: 12 Å across Major groove: 22 Å across 10 ångströms(1.0 nanometre) 24

25 In eukaryotic cells, DNA is folded into chromatin Nucleosomes any of the repeating globular subunits of chromatin that consist of a complexof DNA and histone 74 Structure of nucleosome core DNA is wound around histone proteins to produce nucleosomes Histone octamer consists of 2 copies each of the core histones H2A, H2B, H3, and H

26 Compaction of DNA in a eukaryotic chromosome 76 26