chemistry ofheterocyclic compounds€¦ · number of drugs in pharmaceutical science are...
TRANSCRIPT
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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.
PyrrolePyrrolePyrrolePyrrole
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HemoglobinHemoglobinHemoglobinHemoglobin
Heme
PPPPorphyrinorphyrinorphyrinorphyrin Ring in Ring in Ring in Ring in HemeHemeHemeHeme
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HemoglobinHemoglobinHemoglobinHemoglobin
� 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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HemoglobinHemoglobinHemoglobinHemoglobin
Porphin rings are common biological ligands.
Porphin rings Porphin rings Porphin rings Porphin rings
vitamin B12chlorophyll
PyrrolePyrrolePyrrolePyrrole
The amino acids, prolin and hydroxyproline are
tetrahydropyrrole (pyrrolidine) derivatives.
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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
�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.
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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
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:
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�CONDENSED HETEROCYCLIC COMPOUNDS.
INDOLEPURINE
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�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.
Composition of NucleotidesComposition of NucleotidesComposition of NucleotidesComposition 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.
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Composition of NucleotidesComposition of NucleotidesComposition of NucleotidesComposition 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
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 BasesPurine BasesPurine BasesPurine 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 BasesPurine BasesPurine BasesPurine Bases
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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Pyrimidine BasesPyrimidine BasesPyrimidine BasesPyrimidine Bases
• Cytosine is present in both DNA and RNA.
Structures are shown in Figure.
2-oxy, 4-amino pyrimidine
H
Pyrimidine BasesPyrimidine BasesPyrimidine BasesPyrimidine 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
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).
NucleosidesNucleosidesNucleosidesNucleosides
• 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.
NucleosidesNucleosidesNucleosidesNucleosides
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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NucleosidesNucleosidesNucleosidesNucleosides
• 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.
NucleosidesNucleosidesNucleosidesNucleosides
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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NucleotidesNucleotidesNucleotidesNucleotides
• 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
NucleotidesNucleotidesNucleotidesNucleotides
• 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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NucleotidesNucleotidesNucleotidesNucleotides
• 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 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 TriphosphatesNucleoside TriphosphatesNucleoside TriphosphatesNucleoside Triphosphates
• 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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Nucleoside TriphosphatesNucleoside TriphosphatesNucleoside TriphosphatesNucleoside 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.
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
NucleoNucleoNucleoNucleotidestidestidestides
• 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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NucleoNucleoNucleoNucleotidestidestidestides
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
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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 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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