Chemistry of Lipids - zakladbiochemii-2wl.wum.edu.pl · Number of drugs in pharmaceutical science...

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.

FURAN PYRROLE

THIOPHENE

Pyrrole

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

plays important role in the chemistry of living organisms.

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The essential structural feature of heme is 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 B12 chlorophyll

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 products that contain the thiazole nucleus are vitamin 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 products that contain the thiazole nucleus are the pencillins.

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 products known to contain the imidazole nucleus are amino 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

Niacin, nicotinamide and isoniazide – derivatives of piridine Niacin (nicotinic acid), also known as Vitamin PP (Vitamin B3). Nicotinamide - it is an amide of nicotinic acid 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.

INDOLE PURINE

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CONDENSED HETEROCYCLIC COMPOUNDS.

INDOLE

Tryptophan- Indole group

Purines

Purines The parent substance, purine, consists of pyrimidine ring attached to imidazole ring. The structural formula of the purine is as follows:

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.

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+ and FAD, and

- metabolic regulators such as cAMP and cGMP.

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

•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 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

Nucleotide

Nucleoside

Base

Phosphate

Sugar

X=H: DNA X=OH: RNA

Sugars have five carbons 1’ to 5’ (pentose) and they can be either a ribose or a 2’-deoxyribose (ribose without the oxygen attached to C2’). C1’ binds the nitrogenous base C2’ lacks the oxygen in the case of deoxyribose C5’ binds the phosphate group

Components of a nucleotide

Bases Present in the Nucleic Acids

•Two types of nitrogenous bases;

- the purines and pyrimidines are present

in nucleic acids.

Basic structure of pyrimidine and purine

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Bases are numbered in a conventional manner, with purine and pyrimidine numbered in opposite directions.

Pyrimidines

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Purines

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Purine Bases

• The purine bases present in RNA and DNA are the same;

- adenine and guanine.

• Adenine is 6-amino purine and guanine is 2-amino-6-oxopurine.

• The numbering of the purine ring with the structure of adenine

and guanine are shown in Figure.

Purine Bases

Adenine is 6-amino purine 2-amino -6-oxo purine

H

H H

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 –oxo-4-amino pyrimidine)

H

Pyrimidine Bases

• Thymine is present in DNA and uracil in RNA. Structures are

shown in Figure.

5-methyluracil

2,4-dioxo-5 methylpyrimidine 2,4-dioxo-pyrimidine

H H

H H

These two words are often confused

•THYMINE is the base present in DNA

•Thiamine (B1) is a member of vitamin B complex

Nucleosides

• Nucleosides are formed when bases are attached to the

pentose sugar, D-ribose or 2-deoxy-D-ribose.

Sugar groups in nucleic acids

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 and sugar groups. Atoms in sugar is denoted with primed numbers.

Nucleosides

•Nucleosides with purine bases have the suffix

-sine, while pyrimidine nucleosides end with

-dine. vi.

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.

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

• Moreover, a base can combine with either ribose or deoxy

ribose, which in turn can be phosphorylated at 3' or 5'

positions.

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.

Nucleotides • Many co-enzymes are derivatives of adenosine monophosphate.

• Examples are NAD+, NADP+, FAD and Co-enzyme A.

Flavin adenine dinucleotide (FAD) is a prosthetic group that participates in several intracellular oxidation -reduction reactions. B 2 (Riboflavin)

FAD

Flavin adenine dinucleotide (FAD) is a prosthetic group that participates in several intracellular oxidation -reduction reactions.

B 2 (Riboflavin)

B 2 (Riboflavin)

The nicotinamide adenine dinucleotide (NAD)

The nicotinamide adenine dinucleotide (NAD+)

molecule. The portion shown in purple is the nicotinamide molecule.

The nicotinamide adenine dinucleotide (NAD)

Vitamin B3

(niacin)

Vitamin PP

Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B3. Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP).

The nicotinamide adenine dinucleotide (NAD)

Nicotinamide adenine dinucleotide exists in two forms: an oxidized

and reduced form abbreviated as NAD+ and NADH respectively. In

metabolism, nicotinamide adenine dinucleotide is involved in redox

reactions, carrying electrons from one reaction to another.

NAD+ + 2e- + 2H+ -----> NADH + H+

2H + H +

The nicotinamide adenine dinucleotide (NAD)

NAD+ + 2e- + 2H+ -----> NADH + H+

One hydrogen is removed with 2

electrons as a hydride ion (H-) while the

other is removed as the positive ion (H+).

Usually the metabolite is some type of

alcohol which is oxidized to a ketone.

This is an oxidation reaction where 2

hydrogen atoms (or 2 hydrogen ions and

2 electrons) are removed from the organic

metabolite. (The organic metabolites are

usually from the citric acid cycle and the

oxidation of fatty acids).

Reaction: CH3CH2OH + NAD+ --> CH3CH=O + NADH + H+

The nicotinamide adenine dinucleotide (NADP)

NADPH acts as a reducing agent during the synthesis of nucleic acids and lipids.

Co-enzyme A

B5 (pantothenic acid)

Coenzyme A (CoA, CoASH, or HSCoA) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle.

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

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

•ATP is the universal energy currency.

Adenosine triphosphate (ATP)

Nucleoside Triphosphates

• It 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.

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 AMP or cAMP

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 or UTP.

uridine pseudouridine

Different attachment of uracil to sugars

DNA

•DNA - a polymer of deoxyribo nucleotides •found in chromosomes and mitochondria • carries the genetic information

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DNA structure

The primary structure of DNA is the sequence

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 wrap around the periphery. Bases (A, T, C and G) occupy the core, forming complementary A · T and G · C Watson-Crick base pairs.

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Two hydrogen bonds between A:T pairs Three hydrogen bonds between C: G paired

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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

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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Compaction of DNA in a eukaryotic chromosome

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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

The Genetic Code How do 64 different codons produce 20 different amino acids?

Protein coding

The sequence provided in the form of a double-stranded DNA molecule:

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

provided 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