BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 1. STRUCTURE AND REACTIVITY OF BIOORGANIC COMPOUNDS

1.3. Selected classes of bioorganic compounds and their biological significance

1.3.6. Heterocyclic compounds

Heterocycles and their derivatives are widely represented among Biomolecules, low-molecular-weight physiologically active substances (including Alkaloids), and starting Materials for the synthesis of more complex bioorganic molecules. Heterocycles contain various heteroatoms and differ in ring size and degree of saturation. The numbering of atoms in heterocycles begins with the heteroatom. Examples of heterocycles common in biochemical systems include:

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Condensed heterocycles based on pyrrole include indole and its derivatives, which encompass The amino acid L-Tryptophan and its transformation products such as serotonin, tryptamine, indoxyl, and various alkaloids. Serotonin exhibits neurotransmitter properties, elevates Blood pressure, and activates the blood clotting cascade. Indoxyl (3-hydroxyindole) is a product of tryptophan biotransformation by intestinal microflora.

In the Liver, indoxyl is detoxified via The formation of the ester indoxyl sulfate; the latter is secreted by the Kidneys as a potassium salt known as indican. Therefore, urinary indican concentration serves as an indicator not only of protein putrefaction processes in the gut but also of the functional state of the liver. An example of an indole-based therapeutic agent is indomethacin, a derivative of β-indolylacetic acid with anti-inflammatory properties:

Tetrapyrrole compounds built from one pyrroline, one pyrrole, and two isopyrrole structures are called Porphyrins, and when complexed with metals (Fe, Cu, Mg), they are termed metalloporphyrins. The latter serve as prosthetic groups for redox Enzymes and transport Proteins. An example of a transport protein is Hemoglobin, whose prosthetic group is heme (Fe-protoporphyrin IX), a red pigment that determines the color of blood and erythrocytes.

Upon The breakdown of heme in the liver, linear tetrapyrrole structures are formed, such as bilirubin:

The five-membered heterocycle furan is chemically similar to pyrrole and is capable of electrophilic substitution reactions such as nitration, sulfonation, and acylation. 5-Nitrofurans with antiseptic activity are widely used in medical practice, with furacilin being a prominent example:

The furan ring (furanose cycle) is also a structural component of cyclic monosaccharide forms. The five-membered heterocycle thiophene, which is structurally analogous to furan, together with imidazole, forms the structural basis of biotin (vitamin H). Another imidazole derivative is the amino acid Histidine, which belongs to the 20 Proteinogenic Amino Acids, and its decarboxylation product is histamine, a biogenic amine with hormone-like activity:

Five-membered heterocycles containing two different heteroatoms include thiazole, oxazole, and isoxazole:

These rings, along with other cyclic structures, are incorporated into the molecules of Vitamins (B₁), Coenzymes, therapeutic agents (norsulfazole), and antiseptics (furazolidone), and serve as Structural components of Antibiotics, including cycloserine, an anti-tuberculosis agent.

The primary representative of six-membered heterocycles containing a single nitrogen atom is pyridine, which exhibits basic and nucleophilic properties. As a base, pyridine binds a free proton to form a pyridinium salt, whereas as a nucleophile, it attacks electrophilic centers in alkyl halide molecules to yield alkylpyridinium salts:

Amination (NH₂Na) and hydroxylation (KOH) of pyridine yield amino- or hydroxypyridines, which are utilized in the pharmaceutical industry. A biologically important derivative of hydroxypyridines is vitamin B₆ (pyridoxine, pyridoxol). Reduction of the aromatic pyridine ring yields the saturated heterocycle piperidine, which is part of the molecular Structure of several alkaloids and is used in the Synthesis of the narcotic analgesics promedol and cyclodol. Oxidation of alkyl substituents in pyridine homologs yields three isomeric pyridinecarboxylic acids:

Biologically active derivatives of nicotinic acid include nicotinamide, also known as Vitamin PP. N,N-diethylamide (coramine) is used to treat cardiovascular diseases, while isonicotinic acid hydrazides are employed in tuberculosis therapy. Partial reduction products of pyridine, namely 1,4-dihydropyridines, act as Cell/33.html">Plasma Membrane calcium channel blockers and are prescribed for Hypertension and cerebral Circulation disorders (e.g., nifedipine, nimodipine).

Pyridine derivatives, which are condensed heterocycles, include quinoline, isoquinoline, and acridine:

The first two are Aromatic Compounds with very similar chemical properties. Their derivatives are utilized in the synthesis of Pharmaceuticals such as nitroxoline (5-HOK) and enteroseptol. The isoquinoline structure is incorporated into the molecules of alkaloids like papaverine, narcotine, morphine, and codeine. An important acridine derivative is 9-aminoacridine—a precursor in the synthesis of substances with antiseptic (rivanol) and antimalarial (atebrin) activities—as well as acridine orange, a widely used dye that serves as a mutation indicator in microorganisms (by intercalating between DNA Base Pairs, it disrupts information reading):

Six-membered heterocycles containing oxygen atoms include α- and γ-pyrans, which exist primarily in derivative forms. Important derivatives of these heterocycles are oxy-derivatives that form part of many natural compounds, namely α- and γ-pyrones:

Coumarins (1,2-benzopyrans and their derivatives) are condensed heterocycles based on the α-pyrone core. They exhibit anticoagulant properties, as seen in dicoumarol, for example:

Condensed heterocycles based on the γ-pyrone and benzene rings form Flavonoids, which are plant pigments including quercetin, widely used in medical practice. Quercetin is a hydroxy derivative of flavone—a yellow pigment found in the flowers of many plants. Tocopherols (Vitamin E Group), which will be discussed in Chapter 8, also belong to γ-pyrone derivatives.

Six-membered heterocycles with two nitrogen atoms (diazines) comprise several groups of substances (pyridazine, pyrazine, pyrimidine), among which Pyrimidines and their derivatives are the most important. These are predominantly amino- and hydroxypyrimidines that constitute DNA, RNA, vitamins, coenzymes, and pharmaceutical drugs. The pyrimidine components of NUCLEOTIDES include uracil (2,4-dihydroxypyrimidine), thymine (2,4-dihydroxy-5-methylpyrimidine), and cytosine (2-hydroxy-4-aminopyrimidine):

Barbituric acid derivatives—barbiturates possessing strong hypnotic, sedative, and anticonvulsant properties, such as phenobarbital and veronal—serve as prime examples of pyrimidine-derived pharmaceuticals. Cinnarizine and flunarizine, which normalize cerebral blood vessel circulation, are synthesized based on pyrazines (1,4-diazine).

A large and vital group of substances consists of compounds featuring two heterocyclic rings: pyrimidine and imidazole. These are Purines and their derivatives, which are Components of nucleic acids, their metabolic products (hypoxanthine, xanthine, uric acid), and various alkaloids.

Acidic sodium and potassium salts of uric acid have low Water solubility; therefore, when their concentration in urine rises, they form precipitates, which serve as the BIOCHEMICAL BASIS OF urolithiasis (Kidney stone disease). Methylated xanthine derivatives are plant alkaloids (caffeine as 1,3,7-trimethylxanthine, theophylline as 1,3-dimethylxanthine, and theobromine as 3,7-dimethylxanthine) used in beverage preparation and as medications. Pteridines (a condensed pyrazine-pyrimidine system) form The basis of the vitamin B_c coenzyme (folic or pteroylglutamic acid). The chemical properties of pyridazines closely resemble those of pyrimidine. Their practically important derivatives include sulfapyridazine, which exhibits high antibacterial activity, and the herbicide phenazone.

Six-membered heterocycles containing two different heteroatoms include thiazine derivatives—phenothiazines, which are condensed systems consisting of a thiazine ring and benzene rings. Phenothiazine derivatives are used in the Treatment of Mental Disorders, particularly Schizophrenia (e.g., chlorpromazine). Another phenothiazine derivative, methylene blue, is widely used as a biological stain and as a topical antiseptic in alcoholic solutions.

Seven-membered heterocycles—diazepines—do not occur in a free state. Diazepine derivatives are commonly used as sedatives. Their biochemical MECHANISM OF ACTION involves interaction with receptors for γ-aminobutyric acid, the primary inhibitory receptor of the Central Nervous system.

Thus, biological chemistry studies bioorganic molecules and their derivatives that drive the life processes of All living organisms. These molecules are fundamentally hydrocarbon derivatives—compounds composed of carbon and hydrogen atoms. Hydrogen atoms can be substituted by specific functional groups such as -CH₃, -OH, -COOH, -NH₂, etc., conferring new polyfunctional properties upon these compounds.

A carbon atom can form four covalent bonds with other atoms (or functional groups), building chains, rings, and branched polymers. When a carbon atom in a molecule has four different substituents, it is considered an asymmetric atom, and the molecule exhibits stereoisomers (enantiomers). The orientation of atomic groups, determined by their rotation around single C–C bonds, allows a molecule to be classified into a specific conformation—a three-dimensional structure. Biomolecular conformation is a critical parameter, particularly regarding enzyme-substrate and hormone-receptor interactions.

In biochemistry, Hydrogen Bonds and hydrophobic interactions hold special significance among non-covalent bonds. Specifically, hydrogen bonds participate in stabilizing the secondary and tertiary structures of proteins and in forming the DNA double helix, making them essential for the normal functioning of enzyme proteins, structural proteins, The Genome, and more. Hydrophobic interactions, which drive the aggregation of water-repellent regions in amphiphilic compounds, play a crucial role in vital biological activities, given that most cellular components—such as Phospholipids, proteins, and Nucleic Acids—possess amphiphilic properties.

Based on their carbon Skeleton structure, all Organic compounds are divided into three groups: acyclic, carbocyclic (alicyclic and aromatic) Hydrocarbons and their derivatives, and heterocyclic substances. Within these groups, depending on the presence of functional groups and carbon skeleton architecture, distinctions are made among classes of carboxylic acids, alcohols and phenols, aldehydes and ketones, ethers and esters, amines, amides, nitro compounds, nitriles, thiols, thioethers, sulfonic acids, and halogenated CARBOHYDRATES. Numerous representatives of these organic classes play pivotal roles in key biochemical processes occurring within the living Organism.