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.

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➢5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM

FURANPYRROLE

THIOPHENE

Pyrrole

➢Pyrrole is an important five membered heterocyclic compound possessing a nitrogen atom as hetero atom.

➢plays important role in the chemistry of livingorganisms.

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The essential structural feature of hemeis porphyrin, which consists of four Pyrrole rings

held together by bridges.

Pyrrole

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Hemoglobin

Heme

Porphyrin Ring in Heme

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Hemoglobin

➢ Porphin rings are common biological ligands.

➢ Chlorophyll, the photosynthetic pigment of green plants, is a porphyrin with Mg2+ at the center of the porphin ring.

➢ Vitamin B12 has Co3+ at the center of the porphin ring.

Porphin rings

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Hemoglobin

Porphin rings are common biological ligands.

Porphin rings

vitamin B12chlorophyll

Pyrrole

The amino acids, prolin and hydroxyproline are

tetrahydropyrrole (pyrrolidine) derivatives.

Proline Pro - P

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➢5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM

FURAN

Derivatives of furan:

Vitamin C (ascorbic acid)

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➢5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS

PYRAZOLE IMIDAZOLE OXAZOLE ISOXAZOLE THIAZOLE

THIAZOLE

Among few naturally occurring productsthat contain the thiazole nucleus arevitamin B1 and the pencillins.

Vitamin B1

(Thiamine)General pattern of the penicillins

➢5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS

THIAZOLE

Among few naturally occurring productsthat contain the thiazole nucleus arepencillins.

➢5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS

➢5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS

IMIDAZOLE

Among the few naturally occurring productsknown to contain the imidazole nucleus areamino acids (histidine), purines, uric acid.

Histidine His - H

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➢6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM

PYRIDINE PIPERIDINE

PYRIMIDINE PYIRIDAZINE PYRAZINE

➢6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS

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➢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.

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➢6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM

PYRIDINE

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PYRIMIDINE

➢6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS

PyrimidinesThe pyrimidines are heterocyclic compounds whose basic structure is a six-membered ring containing carbon and nitrogen atoms as illustrated by the parent compound, pyrimidine.

Pyrimidines

Thymine, cytosine, and uracil are substituted pyrimidines found in nucleic acid. Their structural formulas are as follows:

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➢CONDENSED HETEROCYCLIC COMPOUNDS.

INDOLEPURINE

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➢CONDENSED HETEROCYCLIC COMPOUNDS

INDOLE

Tryptophan- Indole group

PurinesPurines

The parent substance, purine,consists of pyrimidine ring attached toimidazole ring. The structural formulaof the purine is as follows:

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

Purine Bases

➢Purine has a 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

6-amino purine 2-amino, 6-oxy purine

H

HH

Pyrimidine Bases

•The pyrimidine bases present in nucleic acids are

➢cytosine,

➢thymine and

➢uracil

Pyrimidine Bases

•Cytosine is present in both DNA and RNA.

Structures are shown in Figure.

2-oxy, 4-amino pyrimidine

H

Pyrimidine Bases

•Thymine is present in DNA and uracil in RNA.

Structures are shown in Figure.

5-methyluracil2-oxy-4-oxy pyrimidine

H H

H H

numbering scheme

THYMINE is the base present in DNA

THIAMINE is vitamin B1, named as the "thio-vitamine"("sulfur-containing vitamin") is a vitamin of theB complex

These two words are often confused

Nucleosides

•Nucleosides are formed when bases are attached to the pentose sugar, D-ribose or 2-deoxy-D-ribose.

Sugar groups in nucleic acids

O OH

OHOH

CH2

OH

O OH

OH

CH2

OH

Ribose Deoxyribose

The only difference in the two compounds is that deoxyribose is lacking an oxygen atom (second carbon atom).

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 nucleotide or nucleoside monophosphate.

Composition of Nucleotides

•When a second phosphate gets esterified to theexisting phosphate group, a nucleoside diphosphateis generated.

•The attachment of a 3rd phosphate group results inthe formation of a nucleoside triphosphate.

•The nucleic acids (DNA and RNA) are polymers ofnucleoside monophosphates

•The universal currency of energy, namely ATP,is a nucleotide derivative.

•Nucleotides are also components of importantco-enzymes like:

- NAD+ and FAD, and

- metabolic regulators such as cAMP and cGMP.

Nucleosides and nucleotidesFunctions

Bases Present in the Nucleic Acids

•Two types of nitrogenous bases;

- the purines and pyrimidines are present in

nucleic acids.

Nucleosides and nucleotidesFunctions

•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.

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 N9 of a purine or N1 of 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 andsugar groups.

Atoms in sugar isdenoted with primednumbers.

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 ofthe differentnucleosides aregiven in Table.

Nucleotides

•These are phosphate esters of nucleosides.

Base plus pentose sugar plus phosphoric acid

is a nucleotide

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.

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+)

Nucleotides – NADH

Nucleotides – NADP+

Nicotinamide adenine dinucleotide phosphate, abbreviated NADP+

NADP+ differs from NAD+ inthe presence of an additionalphosphate group on the2' position of the ribose ringthat carries the adeninemoiety.

Nucleotides – FAD

Flavin adenine dinucleotide (FAD)

Riboflavin (vitamin B2) is part ofthe vitamin B group. It is thecentral component of thecofactors FAD

Nucleotides – Co-enzyme A

Co-enzyme AIn humans, CoA biosynthesisrequires cysteine, pantothenic acid.

Pantothenic acid is also calledvitamin B5 (a B vitamin).

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

•ATP is the universal energy currency.

•Nucleoside diphosphate contains one high energy bond and triphosphates have 2 high energy bonds.

Adenosine triphosphate (ATP)

Nucleoside Triphosphates

•High energy 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 is a major

metabolic regulator.

• Cyclic GMP also behaves similarly.

• These are second messengers

in mediating the action of several hormones.

3',5'-cyclic AMPor cAMP

Cyclic adenosine

monophosphate

Nucleotides

•Deoxy ribonucleotides are used for synthesis ofDNA and ribonucleotides for RNA.

• In pseudouridylic acid (found in tRNA) uridine isattached to ribose phosphate in a C-C bond insteadof C-N bond in UMP (uridine monophospate).

UMP

Nucleotides

Different attachment of uracil to sugars

1 3

5

1

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The structure of DNA

• DNA - a polymer of deoxyribo nucleotides

• found in chromosomes and mitochondria

• carries the genetic information

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Deoxyribonucleic Acid

Nucleotide

Nucleoside

Base

Phosphate

Sugar

X=H: DNAX=OH: RNA

Deoxyribonucleic Acid

Basic structure ofpyrimidine and purine

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Pyrimidines

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Purines

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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

The primary structure of DNA is the sequence

of nucleoside monophosphates

5’ end

3’ end

5’

3’

Phosphodiester

linkage

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Traditionally, a DNA sequence is drawn from 5’ to 3’ end.

A shorthand notation for this sequence is ACGTA

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The secondary structure of DNA is the double helix

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The secondary structure of DNA

Two anti-parallel polynucleotide chains wound around the same axis.

Sugar-phosphate chains wraparound the periphery.

Bases (A, T, C and G) occupy thecore, forming complementary A · Tand G · C base pairs.

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Two hydrogen bonds between A : T pairsThree hydrogen bonds between G : C paired

Three hydrogen bonds between G : C pairedTwo hydrogen bonds between A : T pairs

Base Stacking

The bases in DNA are planar

and have a tendency to

"stack".

Major stacking forces:

➢hydrophobic interaction

➢van der Waals forces.

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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

Normally hydrated DNA: B-form DNA

10 ångströms (1.0 nanometre)

In eukaryotic cells,

DNA is folded into chromatin

Nucleosomes

any of the repeating globular subunits of chromatin that consist of a complex of DNA and histone

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Structure of nucleosome core

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DNA is wound aroundhistone proteins to producenucleosomes

Histone octamer consists of2 copies each of the corehistones H2A, H2B, H3, andH4

Compaction of DNA in a eukaryotic chromosome

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Protein coding

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From the genetic code, we have the following amino acid

sequence:

AGU CUC UGU CUC CAU UUG AAG AAG GGG AAG GGG

Ser - Leu - Cys - Leu - His - Leu - Lys - Lys - Gly - Lys - Gly

Protein coding

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Protein coding

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The sequence of a double-stranded DNAmolecule:5' TCGTTTACGATCCCCATTTCGTACTCGA 3'

3' AGCAAATGCTAGGGGTAAAGCATGAGCT 5’

The sequence of the complementary strand is (notice the 5’ 3’

orientation):

5' TCGAGTACGAAATGGGGATCGTAAACGA 3’

The RNA sequence obtained after the transcription of the DNA sequence

will be identical to the sequence of the complementary strand, with the

exception of the presence of uracil in place of thymine:

5' UCGAGUACGAAAUGGGGAUCGUAAACGA 3’

The amino acid sequence is obtained after first separating the mRNA

sequence into codons:5' UCG AGU ACG AAA UGG GGA UCG UAA ACG A 3'

Ser-Ser-Thr-Lys-Trp-Gly-Ser-Stop

Protein coding

Protein coding