chemistry ofheterocyclic compounds€¦ · number of drugs in pharmaceutical science are...

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Chemistry of Heterocyclic Compounds

Porphyrins

Purines and pyrimidines

Nucleosides and nucleotides

Introduction to Introduction to Introduction to Introduction to

Heterocyclic CompoundsHeterocyclic CompoundsHeterocyclic CompoundsHeterocyclic 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

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PyrrolePyrrolePyrrolePyrrole

�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.


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7777

HemoglobinHemoglobinHemoglobinHemoglobin

Heme

PPPPorphyrinorphyrinorphyrinorphyrin Ring in Ring in Ring in Ring in HemeHemeHemeHeme

9999


� 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 Porphin rings Porphin rings Porphin rings

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10101010


Porphin rings are common biological ligands.

Porphin rings Porphin rings Porphin rings Porphin rings

vitamin B12chlorophyll


The amino acids, prolin and hydroxyproline are

tetrahydropyrrole (pyrrolidine) derivatives.

12121212

�5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE

HETERO ATOM

FURAN

Derivatives of furan:

Vitamin C (ascorbic acid)

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13131313

�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





IMIDAZOLE

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

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16161616

�6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING

ONE HETERO ATOM

PYRIDINE PIPERIDINE

PYRIMIDINE PYIRIDAZINE PYRAZINE



17171717


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.

18181818


ONE HETERO ATOM

PYRIDINE

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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.

Pyrimidines

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

21212121

�CONDENSED HETEROCYCLIC COMPOUNDS.

INDOLEPURINE

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22222222

�CONDENSED HETEROCYCLIC COMPOUNDS

INDOLE

Tryptophan- Indole group

Purines

PurinesThe parent substance, purine,

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

Nucleosides and nucleotidesNucleosides and nucleotidesNucleosides and nucleotidesNucleosides and nucleotidesFunctionsFunctionsFunctionsFunctions

• 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.

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• 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 nucleotidesNucleosides and nucleotidesNucleosides and nucleotidesNucleosides and nucleotidesFunctionsFunctionsFunctionsFunctions

Composition of NucleotidesComposition of NucleotidesComposition of NucleotidesComposition 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.


• 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.

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• 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

Bases Present in the Nucleic AcidsBases Present in the Nucleic AcidsBases Present in the Nucleic AcidsBases Present in the Nucleic Acids

• Two types of nitrogenous bases;

- the purines and pyrimidines are present in

nucleic acids.

Purine BasesPurine BasesPurine BasesPurine 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

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�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.


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

H

HH

Pyrimidine BasesPyrimidine BasesPyrimidine BasesPyrimidine Bases

• The pyrimidine bases present in nucleic acids are

�cytosine,

�thymine and

�uracil

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• Cytosine is present in both DNA and RNA.

Structures are shown in Figure.

2-oxy, 4-amino pyrimidine

H


• Thymine is present in DNA and uracil in RNA.

Structures are shown in Figure.

5-methyluracil2-oxy-4-oxy pyrimidine

H H

H H

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

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NucleosidesNucleosidesNucleosidesNucleosides

• 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 thatdeoxyribose is lacking an oxygen atom (second carbon atom).


• 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.


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.

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• 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.


The names ofthe differentnucleosides aregiven in Table.

NucleotidesNucleotidesNucleotidesNucleotides

• These are phosphate esters of nucleosides.

Base plus pentose sugar plus phosphoric acid

is a nucleotide

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• 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.

NucleoNucleoNucleoNucleotidestidestidestides


• 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.

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• Many co-enzymes are derivatives of adenosine

monophosphate.

• Examples are

NAD+, NADP, FAD and Co-enzyme A

NucleotidesNucleotidesNucleotidesNucleotides –––– NADNADNADNAD++++

• 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)

NucleotidesNucleotidesNucleotidesNucleotides –––– NADNADNADNAD++++

Nicotinamide adenine dinucleotide (NAD+)

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NucleotidesNucleotidesNucleotidesNucleotides –––– NADHNADHNADHNADH

NucleotidesNucleotidesNucleotidesNucleotides –––– NADPNADPNADPNADP++++

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.

NucleotidesNucleotidesNucleotidesNucleotides –––– FADFADFADFAD

Flavin adenine dinucleotide (FAD)

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

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NuNuNuNucleotidescleotidescleotidescleotides –––– CoCoCoCo----enzyme Aenzyme Aenzyme Aenzyme A

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

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

Nucleoside TriphosphatesNucleoside TriphosphatesNucleoside TriphosphatesNucleoside Triphosphates

• Corresponding nucleoside di- and triphosphates are formed by esterification of further phosphate groups to the existing ones.

• In general, any nucleoside triphosphate is abbreviated as NTP or d-NTP.


• ATP is the universal energy currency.

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

Adenosine triphosphate (ATP)Adenosine triphosphate (ATP)Adenosine triphosphate (ATP)Adenosine triphosphate (ATP)

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• 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.

CCCCyclic yclic yclic yclic NNNNucleotidesucleotidesucleotidesucleotides

• 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 AMP

or cAMP

Cyclic adenosinemonophosphate


• 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).

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Different attachment of uracil to sugars

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

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Basic structure of

pyrimidine and purine

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Pyrimidines

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Purines

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Nomenclature of Nucleic Acid Components

Base Nucleoside Nucleotide Nucleicacid

PurinesAdenine Adenosine Adenylate RNA

Deoxyadenosine Deoxyadenylate DNAGuanine Guanosine Guanylate RNA

Deoxy guanosine Deoxyguanylate DNA PyrimidinesCytosine Cytidine Cytidylate RNA

Deoxycytidine Deoxycytidylate DNAThymine Thymidine Thymidylate DNA

(deoxythymidine) (deoxythymidylate)Uracil Uridine Uridylate RNA

The primary structure of

DNA is the sequence

of nucleoside

monophosphates5’ end

3’ end

5’

3’

Phosphodiesterlinkage

65

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 wrap

around the periphery.

Bases (A, T, C and G) occupy the

core, forming complementary A · T

and G · C base pairs.

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Two hydrogen bonds between A : T pairs

Three hydrogen bonds between G : C paired

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Three hydrogen bonds between G : C paired

Two 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)

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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

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Compaction of DNA in a eukaryotic chromosome

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