LECTERE 4LECTERE 4

Heterocycles. Nucleic acids, classification, structure and biological role.

Lecturer: Dmukhalska Ye. B.

PLAN1. Heterocyclic compounds. Classification.2. Five-ring heterocyclic compounds. Their properties and structure. Properties of pyrole, imidazole, thiazole.3. Six-ring and seven-ring heterocyclic compounds. Their properties and structure. Properties of pyridine, diazines.4. Bicyclic heterocyclic compounds, their biological role (purine, and its derivative).5. Alkaloids. Biological functions of alkaloids. Classes of alkaloids.6. Nucleic acids Types of nucleic acids. Nucleic acids composition. 7. Levels of structural organization DNA. Biological functions. Levels of structural organization RNA. Biological functions.8. Use of synthetic nucleic acid bases in medicine.

• Heterocyclic compounds are cyclic compounds in which one or more ring atoms are not carbon (that is, hetero atoms).

• As hetero atom can be N, О, S, В, Al, Si, P, Sn, As, Cu. Bat common is N, О, or S.

Classification • Heterocycles are conveniently grouped into two

classes, nonaromatic:

and aromatic

• By size of ring

• Three-membered four-membered

• five-membered six-membered

Furan, Pyrrole, and Thiophene. • These heterocycles have characteristics associated with

aromaticity. From an orbital point of view, pyrrole has а planar pentagonal structure in which the four carbons and the nitrogen have sp2 hybridization. Each ring atom forms two sp2—sp2 bonds to its neighboring ring atoms, and each forms one sp2 – s bond to а hydrogen. The remaining рz, orbitals on each ring atom overlap to form а molecular system in which the three lowest molecular orbitals are bonding. The six electrons (one for each carbon and two for nitrogen) fill the three bonding orbitals and give the molecule its aromatic character. Furan and thiophene have similar structures.

• The aromatic character of these heterocycles may also be expressed using resonance structures, which show that а pair of electrons from the hetero atom is delocalized around the ring.

• The most general is the Paal-Кnоp synthesis, in which а 1,4-dicarbonyl compound is heated with а dehydrating agent, ammonia, or an inorganic sulfide to produce the furan, pyrrole, or thiophene, respectively.

Reaction:

• The most typical reaction of furan, pyrrole, and thiophene is electrophilic substitution.

• Pyrroles are polymerized by even dilute acids, probably by a mechanism such as the following:

• Thiophen and furan are more stable and do not undergo hydrolysis

• Reduction of pyrrole:

Condensed of thiophenes • Pyrrole compounds occur widely in living systems. One of the

more important pyrrole compounds is the porphyrin hemin, the prosthetic group of hemoglobin and myoglobin. А number of simple alkylpyrroles have played an important role in the elucidation of the porphyrin structures. Thus, drastic reduction of hemin gives а complex mixture from which the four pyrroles, hemopyrrole, cryptopyrrole, phyllopyrrole, and opsopyrrole, have been isolated.

Tetrapyrrole compounds

• Azoles are five-membered ring aromatic heterocycles containing two nitrogens, one nitrogen and one oxygen, or one nitrogen and one sulfur. They may be considered as aza analogs of furan, pyrrole, and thiophene, in the same way that pyridine is an aza analog of benzene.

 

• Pyridine is an analog of benzene in which one of the СН units is replaced by nitrogen. The nitrogen lone pair is located in an sp2 hybrid orbital which is perpendicular to the system of the ring. Various values have been deduced for the empirical resonance energy of pyridine, but it would appear to be roughly comparable to benzene. The resonance stabilization is shown by the two equivalent Kekule structures and the three zwitterionic forms with negative charge on nitrogen.

 

• Derivatives of pyridine are biological active compounds, such as nicotine amide, nicotinic acid (vitamin PP).

nicotinic acid

• Diazines• In this section, we shall take а brief look at another class of

heterocycles, the diazines. The three types of diazabenzenes are:

• In addition to these three diazines, the bicyclic tetraaza compound, purine, is an important heterocyclic system.

• These ring systems, particularly that of pyrimidine, occur commonly in natural products. The pyrimidines, cytosine, thymine, and uracil are especially important because they are components of nucleic acids, as are the purine derivatives adenine and guanine.

• The рininе nucleus also occurs in such compounds as caffeine (coffee and tea) and theobromine (cacao beans).

• Alkaloids constitute а class of basic, nitrogen containing plant products that have complex structures and possess significant pharmacological properties. The name alkaloid, or "alkali-like," was first proposed by the pharmacist W. Meissner in the early nineteenth century before anything was known about the chemical structures of the compounds.

Nucleic acids A most remarkable property of living cells is their ability to produce exact replicas of themselves. Furthermore, cells contain all the instructions needed for making the complete organism of which they are а part. The molecules within а cell those are responsible for these amazing capabilities are nucleic acids.The Swiss physiologist Friedrich Miescher (1844 – 1895) discovered nucleic acids in 1869 while studying the nuclei of white blood cells. The fact that they were initially found in cell nuclei and are acidic accounts for the name nucleic acid. Although are now know that nucleic acids are found throughout а cell, not just in the nucleus, the name is still used for such materials.

Types of nucleic acids.

Two types of nucleic acids are found within cells of higher organisms: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nearly all the DNA is found within the cell nucleus. Its primary function is the storage and transfer of genetic information. This information is used (indirectly) to control many functions of a living cell. In addition, DNA is passed from existing cell to new cells during cell division RNA occurs in all parts of a cell. It functions primarily in synthesis of proteins, the molecules that carry out essential cellular functions.

The monomers for nucleic acid polymers, nucleotides, have а more complex structure than polysaccharide monomers (monosaccharides) or protein monomers (amino acids). Within each nucleotide monomer are three subunits. А nucleotide is, а molecule composed of a pentose sugar bonded to both a group and a nitrogen-containing hetero-cyclic base.

• Pentose sugars. • The sugar unit of а nucleotide is either the

pentose ribose or the 2-deoxyribose.

ribose 2-deoxyribose

Nitrogen-containing bases. • Five nitrogen-containing bases are nucleotide

components. Three of them are derivatives of pyrimidine, а monocyclic base with а six-membered ring, and two are derivatives of purine, а bicyclic base with fused five- and six-membered rings.

AdenineAdenine GuanineGuanine

UracilUracilCytosineCytosine ThymineThymine

AdeninosineAdeninosineGuaninosineGuaninosine

                                                                   

CytidineCytidine ThymidineThymidineUridineUridine

Nucleotide formation. • The formation of а nucleotide from sugar, base, and phosphate

can be visualized as occurring in the following manner:

Nucleotide nomenclature. Base Sugar Nucleotide name

Nucleotide abbreviation

DNA Nncteothles

Adenine Deoxyribose Deoxyadenosine-5’-monophosphate dAMP

Guanine Deoxyribose Deoxyguanosine-5’-monophosphate dGMP

Cytosine Deoxyribose Deoxycytidine-5’-monophosphate dCMP

Thymine Deoxyribose Deoxythymidine – 5’-monophosphate dTMP

RNA Nncteothles

Adenine Ribose Adenosine-5’-monophosphate AMP

Guanine Ribose Guanosine-5’-monophosphate GMP

Cytosine Ribose Cytidine-5’- monophosphate CMP

Uracil Ribose Uridine UMP

Structure • Primary nucleic acid structure is the sequence of nucleotides in

the molecule.

• The amounts of the bases А, Т, G, and С present in DNA molecules were the key to determination of the general three-dimensional structure of DNA molecules. Base composition data for DNA molecules from many different organisms revealed а definite pattern of base occurrence. The amounts of А and Т were always equal, and the amounts of С and G were always equal, as were the amounts of total purines and total pyrimidines.

• The relative amounts of these base pairs in DNA vary depending on the life form from which the DNA is obtained. (Each animal or plant has а unique base composition.) However, the relationships:

• %А =%Т and %C=%G• always hold true. For example, human DNA contains

30% adenine, 30% thymine, 20% guanine, and 20% cytosine.

• А physical restriction, the size of the interior of the DNA double helix, limits the base pairs that can hydrogen-bond to one another. Only pairs involving one small base (а pyrimidine) and one large base (а purine) correctly "fit" within the helix interior. There is not enough room for two large purine bases to fit opposite each other (they overlap), and two small pyrimidine bases are too far apart to hydrogen-bond to one another effectively. Of the four possible purine – pyrimidine combinations (А – Т, А – С, G – Т, and G – С), hydrogen-bonding possibilities are most favorable for the А –Т and G – С pairings, and these two combinations are the only two that normally occur in DNA.

• DNA molecules are the carriers of the genetic information within а cell; that is, they the molecules of heredity. Each time а cell divides, an exact copy of the DNA of the present cell is needed for the new daughter cell. The process by which new DNA molecule generated is DNA replication DNA replication is the process by which DNA molecules produce exact duplicates of themselves. The key concept in understanding DNA replication is the base pairing associated with the DNA double helix.

• We can divide the overall process of protein synthesis into two steps. The first step is called transcription and the second translation. Transcription is the process by which DNA directs the synthesis of RNA molecules that carry the coded information needed for protein synthesis. Translation is the process by which the codes within RNA molecules are deciphered and а particular protein molecule is formed. The following diagram summarizes the relationship between transcription and translation.

Replication

transcription of DNA to form RNA

• Ribonucleic acids. • Four major differences exist between RNA molecules and DNA

molecules.• 1.  The sugar unit in the backbone of RNA is ribose; it is

deoxyribose in DNA.• 2.  The base thymine found in DNA is replaced by uracil in RNA

(Figure.1). Uracil, instead of thymine, pairs with (forms hydrogen bonds with) adenine in RNA.

• 3.  RNA is а single-stranded molecule; DNA is double-stranded (double helix). Thus RNA, unlike DNA, does not contain equal amounts of specific bases.

• 4.  RNA molecules are much smaller than DNA molecules, ranging from as few as 75 nucleotides to а few thousand nucleotides.

Types of RNA molecules.• Through transcription, DNA produces four types of RNA, distinguished

by their function. The four types are ribosomal RNA (rRNA), messenger RNA (mRNA), primary transcript RNA (ptRNA), and transfer RNA (tRNA).

• Ribosomal RNA combines with а series of protein to form complex structures, called ribosomes that serve as the physical sites for protein synthesis. Ribosomes have molecular masses on the order of 3 million. The rRNA present in ribosomes has no informational function.

• Messenger RNA carries genetic information (instructions for protein synthesis) from DNA to the ribosomes. The size (molecular mass) of mRNA varies with the length of protein whose synthesis it will direct. Each kind of protein in the body has its own mRNA.

• Primary transcript RNA in the material from which messenger RNA is made.

• Transfer RNA delivers specific individual amino acids to the ribosomes, the sites of protein synthesis. These RNAs are the smallest of the RNAs, possessing only 75-99 nucleotide units.