1. ВАЖНИ ТЕРМИНИ И РЕАКЦИИ ВО ОРГАНСКАТА ХЕМИЈА Огромен број на органски соединенија се присутни во Човечкиот организам. Покрај тоа, голем број на главно органски соединенија Секојдневно внесуваме преку храната или преку третман со лекарства. Најчести групи кај физиолошки важните соединенија се: COOH, NH 2, OH; SH; S-S; C=O; „ = „; N=O; ( карбоксилна амино алкохол тиол дисулф кето двојна нитро Орг. киселини) ам.кисел врска Најголем дел од лекарствата и од органските Соединенија, во физиолошки услови се јонизирани!

2. Aspirin ( a pain killer)

3. Paracetamol (fever reliever)

4. Insulin (hormone), се лачи од панкреасот

6. 6 1- Растворливост на органските соединенија Зошто е важно: (1) Поради транспорт и биодостапност на физиолошки важните супстанци (апсорпција, дистрибуција, екскреција, метаболизам реактивност). Важни термини што се поврзани со растворливоста на органските супстанци хидрофилни....................сакаат вода (добро се раствораат во вода) ♣ липофобни.....................мразат масти и масла ♣ липофилни.......................сакаат масла ♣ хидрофобни..................мразат вода АМФИФИЛНИ......сакаат и вода и масло

7. ЛИПОФИЛНИОТ ДЕЛ НА ЕДНО СОЕДИНЕНИЕ Го прават АРОМАТИЧНИТЕ ПРСТЕНИ или Долгите алифатични ланци R-R-R...CH3-CH2-CH2-CH2-CH2.... ХИДРОФИЛНИТЕ ДЕЛОВИ потекнуваат од функционалните групи Што може да јонизираат (дисоцираат) како што се COOH; OH; NH2; S-H

8. ХИДРОФИЛНИ СОЕДИНЕНИЈА ЛИПОФИЛНИ СОЕДИНЕНИЈА Амфифилно соединение

9. Важни реакции на орг. Соедненија: 1Реакции на АДИЦИЈА: Овие реакции се одвиваат кај НЕЗАСИТЕНИ органски Соединенија што во својот состав имаат двојна „ = „ врска CH3-CH2-CH=CH 2 + I 2  CH3-CH2-CH-CH 2 I I НО, што ако имаме адиција на пример на HI? CH3-CH2-CH=CH 2 + HI  CH3-CH2-CH-CH 3 I Правило на Марковников: Водородот оди на тој С-атом од Двојната врска кој има повеќе Н-атоми

10. Реакции на OH групата Оваа група се нарекува и АЛКОХОЛНА група кога е во состав на Алифатични соединенија), или ФЕНОЛНА група со КИСЕЛИ СВОЈСТВА (кога е директно Поврзана на ароматичен бензенски прстен) Оксидација на алкохоли- се оксидираат до алдехиди, кетони (или органски киселини) CH3-CH2-OH + O2  CH3-CH2-CHO-алдехид CH3-CHOH-CH3 + O 2  CH 3 -C-CH 3 -кетон ( ацетон ) O

11. Реакции на алкохолите со органските киселини: --  ОН групата од алкохолите може да реагира со СООН групата од органски киселини и притоа се добиваат ЕСТРИ. -  Бидејќи голем број на лекови содржат СООН група, Лековите НЕ СМЕАТ да се примаат во присуство На алкохол, бидејќи ќе се естерифицираат и го Губат нивното дејство !!!

12. + HO-C2H5  C2H5 +H2O Реакција на естерификација на аспирин Во присуство на етанол НЕ ЗЕМАЈ ЛЕКАРСТВА И АЛКОХОЛ!!!

13. Други реакции Супституција (замена): –поларни –неполарни

14. Реакции на елиминација

15. Реакции на фенолите: Кога ОН групата е директно поврзана на бензенски прстен-ФЕНОЛИ ФЕНОЛИТЕ ИМААТ КИСЕЛИНСКИ СВОЈСТВА!!! Тие се слаби или умерени органски киселини!!! Важни антиоксиданти во живите организми, хелатори....

16. РЕАКЦИИ НА ФЕНОЛИТЕ:

17. Важни соединенија во медицината на некои хемиски елементи V AV B N азот V ванадиум P Phosphorus Nb As арсен Ta Sb антимон Bi бизмут

18. АЗОТ- N (Nitrogenium) N 2 78% of the atmosphere- chemically rather inert -principal bioelement: organic compounds ( "NH 3 derivatives" ) амино киселини  ПРОТЕИНИ влегува во состав на голем број ХЕТЕРОЦИКЛИЧНИ соединенија pyrimidine purine  uracil, thymine, cytosine  adenine, guanine НУКЛЕИНСКИ КИСЕЛИНИ (DNA, RNA)

19. NH 3 ammonia - остар мирис NH 4 + ammonium ion N 2 ONitrous oxide [ Dinitrogen oxide ] = “смешен гас" - при операции: inhalation  insensibility to PAIN = anaesthetic и аналгетски ефекти (without muscle relaxation) obstetrics - pain relief during childbirth NONitric oxide [ Nitrogen monoxide ] NO 2 Nitrogen dioxide - reddish-brown gas Токсични за животните in the environment -toxic gases (Photochemical smog)

20. Biological functions of NO = important gaseous signaling molecule !!! EDRF = endothelium-derived relaxing factor= NO NO synthesis Endothelial cell relaxation Smooth muscle cell NO diffusion Nitroglycerin = glyceryl trinitrate - oily explosive liquid[ DYNAMITE ] NO Nitroglycerin  vasodilator - treatment of angina pectoris (a lack of blood suply of heart muscle  chest pain)

21. Biochemical formation of NO Arginine (amino acid) Citrulline NO enzyme: NO synthase Functions of NO: 1) dilation of blood vessels  vasodilator ( = EDRF ) 2) neurotransmitter 3) in macrophages and neutrophils – immune response (NO is toxic to bacteria) 4) role in penile erection halflife: ~ 4 sec.

22. HNO 2 Nitrous acid (INN: Acidum nitrosum) - weak acid, not stable salts: nitrites NaNO 2 Sodium nitrite (INN: Natrii nitris) - toxic ! food additive: alters the color of preserved meat prevents growth of Clostridium botulinum (botulinum toxin  botulism) organic nitrites = esters of nitrous acid HNO 3 Nitric acid (INN: Acidum nitricum) - strong acid - oxidazing agent ! salts: nitrates AgNO 3 Silver nitrate (INN: Argenti nitras) Amyl nitrite – treatment of angina pectoris

23. Toxicity of NO 2 - (NO 3 - ) intestinal bacteria can reduce nitrates to nitrites : NO 3 - NO 2 - Limits for drinking water: NO 3 - 50 mg/l adults 15 mg/l infants 1) Methemoglobinemia "blue baby syndrom" HEMOGLOBIN Fe II METHEMOGLOBIN Fe III nitrites unable to transfer O 2 methemoglobin reductase "protective enzyme" - insufficient in infants !

24. 2) Nitrosamines Nitrites can react with secondary amines  Nitrosamines CARCINOGENS ! Nitrites in food - meat and cheese products preserved with nitrite pickling salt !!!

25. Phosphorus P -principal bioelement H 3 PO 4 Phosphoric acid (INN: Acidum phosphoricum) - in biochemistry: "phosphates" = esters of H 3 PO 4 1)Bone and tooth mineral: hydroxyapatite Ca 5 (PO 4 ) 3 OH 2)Anions in body fluids: H 2 PO 4 - / HPO 4 2- 3)Nucleotides, DNA, RNA 4)Structural lipids (phospholipids) - membranes ! 5)Metabolic intermediates (Glucose–6–phosphate,...) 6)High energy compounds ATP

26. ATP = adenosine triphosphate phosphoanhydride bonds ester bond ATP + H 2 O ADP + P i + energy ATP + H 2 O AMP + PP i + energy pyrophosphate  E = - 30.5 kJ/mol

27. ATP = adenosine triphosphate ATP is used to drive many energy consuming reactions ! ATP is used as "energy" for active transport ("pumps") ATP is often used to "activate metabolites": ATP ADP hexokinase glucose glucose-6-P ATP is formed from ADP when "fuel molecules" are oxidized. glucose  CO 2 + H 2 O up to 36-38 ATP / molecule of glucose (majority of this ATP production: oxidative phosphorylation in mitochondria)

28. Organophosphate neurotoxins Sarin Parathion Sarin, soman, tabun - "nerve gases" - extremely toxic substances !!! - chemical weapons of mass destruction very potent insecticid also highly toxic ! inhibition of the enzyme acetylcholinesterase !

29. neuronal synapse  neurotransmitter  receptor  effect vesicles with neurotransmitter synaptic cleft receptor Neurotransmitter must be removed from the synaptic cleft (after its job is done) ! 1) REUPTAKE 2) Enzymatic breakdown into inactive fragments - ACETYLCHOLINE (acetylcholinesterase) 1) 2)

30. Cholinergic synapses ( neurotransmitter = acetylcholine ) ACH receptor vesicles with acetylcholine (ACH) acetylcholine choline acetic acid * synaptic cleft botulinum toxin (release of ACH is blocked) ATROPINE (ACH receptor is blocked) organophosphates (acetylcholinesterase is blocked) * * acetylcholinesterase

31. As Arsenicum- toxic in all forms dentistry – root canal therapy (devitalisation of tooth)  arsenic compounds SALVARSAN - organic compound containing As - drug that was used to treat syphilis ! - the first effective "chemotherapeutic agent" before penicillin (1940s) - severe side effects

32. Elements of group VI VI AVI B O Oxygenium Cr Chromium S Sulfur Mo Molybdaenum Se Selenium W Wolframium Te Tellurium Po Chalcogens

33. Oxygen O (Oxygenium) O 2 21% of the atmosphere -principal bioelement: H 2 O many functional groups in biomolecules - OH "hydroxyl group" alcohols, phenols "carbonyl group" aldehydes, ketones - COOH "carboxyl group" carboxylic acids C O electron acceptor in biologically important oxidations ! O 2 + 4 e - 2 O 2- 2 H 2 O + 4 H +

34. Реактивни честички на кислород Toxicity of oxygen) Многу реактивни  им штетат на сите органски соединенија!! O 2 + e - O 2 - superoxide radical O 2 Hperhydroxyl radical (hydroperoxyl) H 2 O 2 + e - OH - + OHhydroxyl radical ROS = reactive oxygen species "free radicals" + H 2 O 2,.... + H +

35. Штетни ефекти од слободните радикали

36. Sulphur S (Sulfur) -principal bioelement H 2 S Hydrogen sulphide- strong poison - gas with odour of rotten eggs - SH sulfhydryl groups in organic structures ( often: active groups of proteins – enzymes) protein SH Toxic heavy metals ( Pb, Hg, As,...) - block sulfhydryl groups !

37. H 2 SO 3 Sulphurous acid (INN: Acidum sulfurosum) - weak acid salts: sulphites (........ sulfis ) H 2 SO 4 Sulphuric acid (INN: Acidum sulfuricum) - strong acid salts: sulphates (........ sulfas ) H 2 S 2 O 3 Thiosulphuric acid (INN: Acidum thiosulfuricum) salts: thiosulphates (........ thiosulfas ) H 2 S Hydrogen sulphide (INN: Acidum hydrosulfuricum) salts: sulphides (........ sulfuridum )

38. Amino acids containing sulphur cysteine ( Cys ) methionine ( Met ) - essential amino acids - in proteins

39. Redox reactions R SHR S R‘ SH R‘ S - 2 H + 2 H disulfide bond - S – S - disulfide bonds stabilize the folded form of a protein SSSS SSSS SSSS intramolecular -S-S- bond intermolecular -S-S- bonds R SH R S OH O O "sulfates" oxidation

40. sulfate groups - modification of polysaccharides (heparine, chondroitin sulfate, keratan sulfate,...) ------------------------------------------------------------------------------ Vitamins containing S lipoic acid biotin vitamin B 1 (thiamin) important COENZYMES

41. coenzyme A Acetyl-CoA important molecule in metabolism Coenzyme A - thiol ("high energy bond") - acyl group carrier thiol + carboxylic acid  thioester pantothenic acid

42. Selenium Se trace element - in enzymes: glutathion peroxidase (destruction of peroxides) - chemically related to sulphur  analogous amino acids selenocysteine = "rare amino acid" in some proteins : thyroid hormone deiodinases

43. Elements of group VII VII AVII B F Fluorum Mn Manganum Cl Chlorum Tc Br Bromum Re I Iodum At Halogens

44. Fluorine F (Fluorum) trace element F 2 yellowish very reactive gas Ca 5 (PO 4 ) 3 Ffluorapatite- bones, teeth compounds of fluorine ( NaF ) – toothpaste  to prevent dental caries excessive consumption of F -  "fluorosis" - damage of dental enamel (white spots, mottling of enamel) Freons ( chlorofluorocarbons) - destruction of O 3 layer Hydrofluorocarbon derivatives - inhalational general anaesthetics halothane (isofluran, sevofluran,...)

45. Chlorine Cl (Chlorum) Cl 2 pale green poisonous gas, suffocating odour World War I chemical weapon  destruction of lungs ! (it was soon replaced by more deadly gases – phosgene,...) Cl 2 + H 2 O HCl + HClO HClO HCl + O Chlorination of water - to KILL bacteria COCl 2 O Cl C Cl

46. Cl - important anion in body fluids the main EXTRAcellular anion (97 – 108 mmol/l) Physiologic saline solution (= isotonic = same osmolality as blood plasma) NaCl 0.9 % Inorganic acids HClHydrochloric acidAcidum hydrochloricum HClOHypochlorous acidAcidum hypochlorosum HClO 2 Chlorous acidAcidum chlorosum HClO 3 Chloric acidAcidum chloricum HClO 4 Hyperchloric acidAcidum hyperchloricum HCl - stomach !

47. CHCl 3 Chloroform- one of the first anesthetics (~ 1850) - inhaled vapour  insensibility  "painless sugrery" - hepatotoxic ! - 2 CHCl 3 + O 2 2 HCl + 2 COCl 2 CCl 4 Tetrachloromethane (Carbon tetrachloride) - solvent - hepatotoxic ! ( = liver damage ) CH 3 CH 2 ClEthyl chloride - boiling point 13 o C - evaporation  cooling down the skin  pain relief - local skin anesthesia (sport injuries,...) CH 2 CHClVinyl chloride - is used to produce its polymer: PVC phosgene ! (war gas)

48. DDT (dichloro-diphenyl-trichloroethane) contact poison for INSECTS only: lipids of insect cuticule  penetration to nervous ganglia  paralysis  death DDT was used with great effect to prevent insect-borne diseases ! (mosquitoes – MALARIA lice – spotted TYPHUS) environmental impact ! - long half life = persistent pollutant magnifying through the food chain  accumulation in fatty tissue (reproductive toxicity, carcinogen ?,...) 1960s USA - DDT - major reason for the decline of the bald eagle (impaired quality of eggshells) best known banned pesticide (insecticide) high solubility in lipids !

49. Polychlorinated biphenyls PCBs biphenyl good technical properties  were used as: insulating materials cooling fluids in transformers additives in plastics PROBLEM: very stable ! = persistent pollutants BANNED contamination of soil plants animals cumulation in lipids, milk (carcinogens ?)

50. DIOXIN tetrachlorodibenzo-1,4-dioxin TCDD (the most toxic dioxin) general poison LD 50 = 10 - 100  g/kg ("lethal dose") very stable, very resistant (up to 800 o C)  persistent pollutant accumulation in fatty tissues - teratogens, mutagens, carcinogens by-product of production of herbicides Vietnam War - Agent Orange (herbicide contaminated by TCDD) 1976 Seveso (Italy) - industrial accident – uncontrolled reaction  explosion of chemical reactor  cloud containing dioxin !

51. Iodine I (Iodum) trace element as element: purple – black solidsublimes into purple gas ! - solubility in water can be increased by addition of KI  Lugol‘s solution( I 2 KI water ) tincture of iodin = I 2 in ethanol starch + iodine complexes of deep blue color starch = mixture of  -amylose – linear polymer of glucose amylopectin – branched polymer of glucose - polysaccharide of PLANTS  in FOOD desinfectant

52. Thyroid hormones T4 thyroxine T3 triiodothyronine smaller quantity, greater activity ! deiodinases in tissues Se (selenocysteine) ! Function: stimulation of metabolism (act to increase the metabolic rate) essential to proper development (BRAIN !)

53. Disorders Deficiency of thyroid hormones = hypothyroidism metabolism  low body temperature intolerance to cold weight gain weakness, lethargy - children: mental retardation, short stature [ CRETENISM ] Excess of thyroid hormones = hyperthyroidism ( Grave‘s disease ) metabolism  intolerance to heat weight loss increased heart rate (tachycardia) GOITER (Latin STRUMA) = enlarged thyroid gland (function of the gland can be low, normal, high)

54. Iodine is necessary for the synthesis of the thyroid hormones !!! THYREOGLOBULIN hormone release into the blood proteolysis TSH (Thyroid-stimulating hormone) 2 I - I2I2 iodination thyroid peroxidase FOOD BLOOD THYROID GLAND very effective in uptake of I - from blood !!! I -, IO 3 -,...

55. Thyroid gland is composed of spherical "follicles" thyreoglobulin T4, T3 release into blood I2I2 uptake of I - I-I- follicular cells "Colloid" inside the follicles is rich in protein THYREOGLOBULIN

56. Iodine in food seafood - rich of iodine ! inland areas (Czech republic !!!) iodine deficiency  "endemic goiter"  "endemic cretenism" prevention: iodised SALT ( = table salt fortified with NaI, KI, or KIO 3 ) ( 25 mg KI / 1 kg of salt )

57. Elements of group VIII VIII AVIII B HeFe Co Ni NeRu Rh Pd ArOs Ir Pt Kr Xe Rn Ferrum Cobaltum Niccolum Noble gases

58. Iron Fe (Ferrum) important microelement human body: 4–5 g Fe a) functional form- heme iron proteinshemoglobin70 % myoglobin 5 % some enzymes - non-heme iron proteins b) tranport form (transferrin) c) storage of iron (ferritin, hemosiderin)20 % Fe in food 10-30 mg/day absorption: only 7-10%  ~ 1 mg/day

59. HEME iron proteins Hemoglobin - O 2 transport in blood - in red blood cells - tetramer = 4 subunits (each subunit: one heme + one globin) HbA ("adult")  2  2 HbF ("fetal")  2  2 Myoglobin - "O 2 store" in muscle cell Cytochromes - electron transport - their function is based on: Fe 2+ (reduced) Fe 3+ (oxidized) heme

60. Non-heme iron proteins Fe II or Fe III bound to protein SH iron–sulphur proteins (FeS proteins) Transferrin - blood plasma protein (  1 globulin ) - transport of Fe - 1 molecule of transferrin can carry 2 iron ions in form of Fe 3+ Ferritin - intracellular iron storage protein (liver, bone marrow) - 1 ferritin complex can store about 4500 Fe 3+ - ferritin without iron = apoferritin Hemosiderin - "damaged (Fe-overloaded) ferritin" - Fe from it is less available

61. Overview of iron metabolism liver FERRITIN HEMOSIDERIN blood plasma TRANSFERRIN bone marrow FERRITIN red blood cells HEMOGLOBIN spleen FERRITIN tissues CYTOCHROMES Fe-S proteins muscles MYOGLOBIN BLEEDING (Fe losses) FOOD

62. Iron metabolism = unique - reutilization ! (closed system) NO regulated excretion system for Fe ! Fe absorption must be "regulated" Loss of Fe  through loss of blood (females - mestrual bleeding) Iron deficiency - microcytic anemia "iron deficiency anemia" Iron overload - hemochromatosis = accumulation of iron in the body (depositions as hemosiderin) organ dysfunction (liver, heart,...)

63. Iron absorption FOOD Fe 3+ STOMACH HCl pH 1-2 ascorbic acid gastroferrin - iron binding protein Fe 2+ reduction INTESTINAL MUCOSA CELL Fe 3+ apoferritin ferritin (Fe 3+ ) BLOOD transferrin (Fe 3+ ) Fe 2+

64. Cobalt Co (Cobaltum) trace element -central atom of vitamin B 12 (cobalamin) (daily intake ~ 1  g "the liver store": 3–5 years !) Absorption of vit. B 12 gastric parietal cells intrinsic factor absorption in terminal ileum B 12 complex B 12 – intrinsic factor Vit. B 12 deficiency megaloblastic anemia pernicious anemia – due to impaired absorption !