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Heterocyclic compounds

with biological meaning

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Heterocyclic compounds

Cyclic, organic compounds which besides carbon

atoms have one or more heteroatom (other elements than

C).

Heterocyclic atoms:

– nitrogen, N

– sulphur, S

– oxygen, O

– phosphorus, P

– barium, Ba

– zinc, Zn

– silicon, Si.

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From the biological point of view, the most important are heterocyclic

compounds with 5- and 6-membered rings, containing: S, N, O.

Most of the heterocyclic compounds have their common names.

Substituent’s position in the ring is described by :

– number – position of heteroatom – no. 1

– Greek letter – describes carbon atom the closest to heteroatom as a, then β and γ, respectively.

Heterocyclic compounds

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Heterocyclic compounds are:

• widespread in nature

• biologically active

• some of them are toxic (e.g. coniine, coumarin and derivatives).

Occurrence in:

• natural dyes - heme, chlorophyll

• alkaloids – atropine and nicotine

• amino acids such as tryptophan and histidine

• enzymes, nucleoproteins, antibiotics

• vitamins

• many synthetic pharmaceuticals.

Heterocyclic compounds

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Aromatic character of heteroatom-containing ring comes from

aromatic sextet which consists of:

• „not bound” electron pairs of heteroatoms

• four electrons π from carbon atoms

Heterocyclic compounds

Pyrrole Furane Thiophen

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5- membered ring heterocyclic compounds with

one heteroatom

5-membered rings:

• contain mostly oxygen, sulphur and nitrogen

• are flat

• are aromatic

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5- membered ring heterocyclic compounds with

two heteroatoms

oxazole imidazole thiazole pyrazole

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5- membered ring heterocyclic compounds

Condensation products with benzene

With one heteroatom

With two heteroatoms

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Pyrrole and derivatives

• Pyrrole derivatives:

• pyrroline

• pyrrolidone

• proline,

• Hydroksyproline.

• Condensation’s products of pyrrole with benzene:

– indole,

– tryptophan,

– serotonin.

• Condensation’s products of pyrrole with formaldehyde:

– heme

– hemoglobin

– billirubin

– porphyrins

– Biliverdin.

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Pyrrole and derivatives. Porphyrin structure

Heme: cyclic tetrapyrrole containing iron atom. Present as prostetic group of hemoglobin, mioglobin, and cytochromes.

Chlorophylls are cyclic tetrapyrrole compounds

containing magnesium atom:

• photosynthesis center in plants

• light-absorbing dyes

Terapyrrols belong to a family of “dyes”

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Pyrrol derivatives. Porphyrins structure and

metabolism

degradation

Bilirubin + albumin is transported to liverwhere it combines with glucuronic acid whichincreases its solubility.

Porphyrin

arrangement

(yellow dye)

(green dye)

Tetrapyrrols have character of dyes.

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5-membered rings with one heteroatom

5-hydroxytryptophan serotonin (5-hydroxytryptamine)

biologicaly activ amine

hormon which is also neurotransmitter in central nervous system and in gastrointestinal tract

necessary for sleep - the intermediate product is converted in enzymaticreaction to melatonin (animals with blocked serotonin production are sleepless)

deficiency causes apathy or agression, depression, increasedappetite for carbohydrates

may also be a cause of Sudden Infant Death Syndrome

(SIDS)

Serotonin (5-hydroksytryptamine):

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5-membered ring with two heteroatoms

histaminehistidine

decarboxylation

HistidineStructural element of hydrolytic enzymes.

Histamine (tissue hormone) : present in plant and animal tissues natural factor increasing permeability of veins leading to edema (swelling) causes angiectasia (dilation of a lymphatic or blood vessel)

causes decreasing of blood pressure when binding to H2 receptors, causes vasodilation, stimulation of gastric acid secretion

- CO2

oxazole thiazole imidazole

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5-membered ring with two heteroatoms

Thiamine – Vitamin B1 - two-rings system:

Pyrimidine and thiazole rings connected by methylene group

Thiamine pyrophosphate (cocarboxylase):

•coenzyme of pyruvate dehydrogenases (citiric acid cycle)

•recommended in Beri-beri disease (nerves inflammation caused

by B1 deficiency.)

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6-membered ring - heterocyclic

compounds

pyran pyridine pyrazine pyrimidine

The most important derivatives of pyrane are monosaccharides:• glucopyranose• galactopyranose• mannopyranose

Pyridine derivatives – biologically active compounds:• vitamin B6

• nicotine• vitamin PP

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Vitamin PP –

nicotinic acid derivative

It participates in:

• redox processes in human body (as coenzymes)

• regulation of sugar level in blood

• regulation of cholesterol level

• regulation of blood flow in veins

• maintaining appropriate skin condition (deficiency of vit. PP –pellagra, from latin: pella agra – rough skin)

• hormones synthesis (estrogen, progesterone)

Nicotinic acid nicotine vitamin PP

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Vitamin B6 –

pyridoxine, pyridoxal phosphate

• Vitamin B6– water soluble

– part of three natural pyridine compounds

– coenzyme for 50 different enzymes

• Takes part in :

– protein transformation (coenzyme of transaminases)

– transformation of tryptophan to serotonin

– protein and nucleic acid synthesis

Its necessary for hemoglobin synthesis.

Pyridoxine piridoxalPyridoxal phosphate

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Pyrimidine bases and their derivatives

Pyrimidine:1,3- diazine – aromatic heterocyclic compound containing two atoms of nitrogen at position 1 and 3

cytosine uracyl thymine

Derivatives:

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Pyrimidine bases and derivatives

In physiological conditions quantitatively dominant tautomeric form:• in thymine and uracyl is lactam• in cytozine is lactim

Keto-enol tautomerism: result of hydrogen atom migration, due to it, pirimidine bases are

present in the following forms:• Lactam, keto structure (=O) • Lactim, enol structure (-OH)

cytozine uracyl thymine

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Condensed rings with heteroatoms

Vitamin H

• Participate in:

– proteins and fats metabolism

– fatty acids synthesis

– vitamin C absorption

– amino acid and sugars metabolism

• resistant to heating, acids and bases.

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Purine base and their derivatives

Purine have pyrimidine ring combined with imidazol ring.

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Purine bases and derivatives

Purines contain pyrimidine ring combined with imidazol ring

In nature purine does not exist in free form but as amino and keto derivatives

Amine groups attached to aromatic ring of purine

act similarly to amine group from amino acids, i.e.

can transform into cationic form after H+ addition.

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Purine bases and derivatives

Adenine Guanine Hypoxanthine

In physiological conditions main tautomeric forms are:• for guanine and hypoxanthine - lactam• for adenine – lactim –amino form

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Purine bases and derivatives

Uric acid

easily undergos keto-enol transformations

mammals have uric acid in small quantities in blood, liver, spleen and urine

in humans uric acid is a final product of purine bases metabolism of food as well as of degradation of endogenous

nucleic acids

about 75% is excreted with urine and 25% goes to gastrointestinal tract where it is decomposed by gut microflora

slightly soluble in water and therefore has a tendency to accumulate in kidneys (uric stones) and in joints

in basic environment creates easily soluble urates.

xanthin uric acid

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Purine bases and derivatives

Teophilin Caffeine Theobromine(1,3-dimethylxanthine) (1,3,7-trimethylxanthine) (3,7-dimethylxanthine)

• Methylated purines are present in plants as plant’s bases (alcaloids)

• caffeine is present in coffee beans

• teophilin is present in tea leaves

• theobromine is present in cacao beans (harmful for dogs

and horses)

All of them have pharmacological application

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Condensed rings with heteroatoms

Riboflavin - vitamin B2

• mononucleotide consisting of :

– nitrogenous base called isoalloxazine

(polycyclic heterocyclic compound )

– ribitol esterified by isoalloxazine (flavin)

rybitol

Isoalloxazine (flavin)

B2 participate in:

- oxydo/reduction processes,

- normal functioning of nervous system,

eyes, mucous membranes, respiratory

system,

- amino acids and lipids transformation

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Active forms of riboflavin

pyrophosphate

adenine

D-ribose

D-ribitol

flavin

riboflavin mononucleotide (FMN)- created as a result of ATP-dependent

phosphorylation of riboflavin

flavin adenine dinucleotide (FAD)- adenine nucleotide is attached to FMN

(requires ATP):

FMN + ATP → FAD + PPi (pirophosphate)

orthophosphate

- represent flavoprotein prosthetic groups connected with an apoenzyme – enzymes from

oxyreductases family (ex. participating in Krebs’ cycle)

- participate in electron transfer and H+ ions (reduced forms: FADH2 and FMNH2)

AMP

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Structure of nucleosides

H

Nucleosides consist of nitrogenous base (A,G,C,T,U) and

ribose or deoxyribose.

Name depends on the type of purine or pyrimidine bases.

(A,G,T,C,U)

(ribose or deoxyribose)

A nitrogenous base

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Structure of nucleotides

A phosphate group

Nucleotides have three characteristic components:a nitrogenous base, a five-carbon sugar (ribose or deoxyribose)

and at least one phosphate group.

A nitrogenous base(pyrimidines or purine base)

(ribose or deoxyribose)

A, G,T,C,U

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Nucleotides and nucleic acids

Nucleotides are the building blocks of nucleic acids

NucleotideDNARNA

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Roles of nucleotides

• building blocks of nucleic acids (RNA, DNA)

(like amino acids in proteins);

• ATP: adenosine triphosphate - "molecular unit of

currency" of intracellular energy transfer; energy

source;

• structural components of many enzyme cofactors

(NAD+/NADH: nicotinamide adenine dinucleotide)

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Nucleic acids are biopolymers with molecular weight about 106 daltons

RNA - contains ribose (D-ribose)

DNA – contains deoxyribose ( D-2-deoxyribose)

DNA: contains adenine, guanine, cytosine , thymine

RNA: contains adenine, guanine, cytosine, and uracil

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Nucleotide nomenclature

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DNA structure

• DNA consists of two helical

chains wound around the

same axis in a right-handed

fashion aligned in an

antiparallel way.

• There are 10.5 base pairs, or

36 Å, per turn of the helix.

• Alternating deoxyribose and

phosphate residues on the

backbone form the outer part

of the helix.

• The planar purine and

pyrimidine bases of both

strands are stacked inside the

helix.

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DNA structure

• Nucleotides in polynucleotide strands

are joined to one another by the a

covalent bond between sugar of one

nucleotide and phosphate of the next

one (phosphodiester bond)

• Nitrogenous bases of the two strands

are bound together with hydrogen

bonds

• Major and minor grooves: different

sizes, as a result of asymmetrical

alignment of the two strands (with

respect to each other);

- major groove: 22 Å wide

- minor groove: 12 Å wide.

Transcription factors usually bind to

DNA in the major groove.

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DNA strands

• the antiparallel strands of DNA are not identical, but are complementary.

• complementary base pairs: C pairs with G, and A with T

• the sequence of one strand can be predicted when the sequence of its complementary strand is given.

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Causes of DNA modifications

• physical factors ex.:

– gamma radiation– UV

• effect of carcinogenic chemicals

• changes in cell metabolism

• the oxidation of nitrogenous bases by free radicals:

hydroxyl (.OH) and singlet oxygen (1O2)

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cleavage of

phosphodiester bonds

modification to nitrogenous bases

A,G,C,T

cleavage of the glycosidic bond

conversion of sugar residue

DNA damage by the hydroxyl radical and singlet oxygen

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Adenine

Guanine

.OH attacks at N7 and C8 in

adenine and guanine leading to

disruption of the imidazole ring

Modifications of nitrogenous bases in addition

reaction of the hydroxyl radical

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The reaction products of thymine with ROS under

aerobic conditions

thymine

5-hydroxy-6-hydrothymine

thymine glycol

5,6-dihydrothymin

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Pyrimidine bases – cytosine and uracil – high sensitivity to .OH

uracil

5-hydroxyuracil

5,6-dihydroxyuracil

5-hydroxymethyluracil

cytosine

5,6-dihydroxycytosine5-hydroxycytosine

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• High levels of oxidative damage to DNA may cause :– carcinogenesis,

– blockage, or

– decelerating of DNA replication.

DNA repair mechanisms:

• Oxidised products are removed by:

– excision of modified DNA nucleobases by: formamidopyrimidineDNA glycosylase (repaired by: AP endonucleases and DNA polymerase)

• Bulky (helix-distorting) damage: removed by endonucleases.

• Double-strand breaks: “stitching" with the participation

of ligases

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