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Chalkony a Jejich Analogy Jako Potenciální Léčiva

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Chalkony a Jejich Analogy Jako Potenciální Léčiva Universita Karlova v Praze Farmaceutická fakulta v Hradci Králové Katedra farmaceutické chemie a kontroly léčiv CHALKONY A JEJICH ANALOGY JAKO POTENCIÁLNÍ LÉČIVA disertační práce studijní program: farmacie studijní obor: farmaceutická chemie školitel: doc. RNDr. Jiří Hartl, CSc. školitel specialista: RNDr. Veronika Opletalová, Ph.D. Hradec Králové 2006 Mgr. Marta Chlupáčová Disertační práce Poděkování Ráda bych poděkovala svému školiteli doc. RNDr. Jiřímu Hartlovi, CSc. za jeho odborné vedení, rovněţ tak své školitelce RNDr. Veronice Opletalové, Ph.D. za neutuchající všestrannou pomoc, trpělivost a cenné připomínky při vypracovávání této práce. Děkuji také všem diplomantům a rigorosantům, kteří v období mého studia pracovali v laboratoři RNDr. Veroniky Opletalové, Ph.D. Můj dík patří všem pracovníkům Katedry farmaceutické chemie a kontroly léčiv za podporu a vytvoření příjemného pracovního prostředí. Děkuji také pracovníkům Laboratoře struktury a interakcí biologicky aktivních molekul za změření a interpretaci NMR spekter, paní Drahomíře Karlíčkové a paní Věnceslavě Hronové za změření elementárních analýz, paní Jitce Ţiţkové a paní Ivě Vencovské za změření IČ spekter a PharmDr. Viktorovi Voříškovi za změření MS spekter. Dále bych chtěla poděkovat pracovníkům mikrobiologické laboratoře Katedry biologických a lékařských věd vedené doc. RNDr. Vladimírem Buchtou, CSc. za zhodnocení mikrobiologické aktivity připravených látek, RNDr. Kataríně Kráľové, CSc. za stanovení a vyhodnocení inhibice fotosyntézy. Děkuji také doc. RNDr. Lubomír Opletalovi, CSc. a PharmDr. Danielu Junovi, Ph.D. za změření antiagregační aktivity chalkonů. Moje poděkování patří rovněţ prof. Dr. Michaelu Gütschowovi za přijetí a odborné vedení během studijního pobytu na Pharmazeutisches Institut, Friedrich-Wilhelms Universität in Bonn (SRN) v roce 2003 v rámci programu ERASMUS a během krátkodobého pracovního programu v roce 2005 tamtéţ a jeho skupině doktorandů za vytvoření motivujícího pracovního prostředí. Tato práce vznikla za finanční podpory Výzkumného záměru MSM 111600001, MSM 111600002 a MSM 0021620822 a grantu FRVŠ 2970/2003. Disertační práce Obsah Obsah Seznam zkratek .................................................................................................................................. 7 1 Úvod ...................................................................................................................................... 9 2 Cíl práce .............................................................................................................................. 10 3 Teoretická část .................................................................................................................... 11 3.1 Chalkony jako rostlinné metabolity a předlohové sloučeniny pro vývoj nových léčiv.......... 11 3.1.1 Antimikrobní účinky chalkonů .......................................................................... 13 3.1.2 Antifungální účinky chalkonů ........................................................................... 18 3.1.3 Antivirové účinky chalkonů .............................................................................. 21 3.1.4 Antiprotozoální účinky chalkonů ...................................................................... 26 3.1.4.1 Antimalarické působení chalkonů ..................................................................... 26 3.1.4.2 Antileishmaniosní a trypanocidní působení chalkonů ....................................... 28 3.1.4.3 Další antiparazitární účinky chalkonů ............................................................... 33 3.1.4.4 Působení chalkonů na cysteinové proteasy parazitů .......................................... 34 3.1.5 Anthelmintické účinky chalkonů ....................................................................... 37 3.1.6 Antineoplastické působení chalkonů ................................................................. 38 3.1.7 Chalkony jako chemosensitizéry ....................................................................... 48 3.1.8 Působení chalkonů na tyrosinkinasy .................................................................. 49 3.1.9 Působení chalkonů na enzymy........................................................................... 50 3.1.9.1 Působení chalkonů na aldosareduktasu ............................................................. 50 3.1.9.2 Působení chalkonů na monoaminooxidasu a katechol-O-methyltransferasu .... 50 3.1.9.3 Působení chalkonů na xathinoxidasu ................................................................. 52 3.1.9.4 Působení chalkonů na enzymy zasahující do metabolismu glutathionu ............ 54 3.1.9.5 Působení chalkonů na epoxidhydrolasy ............................................................. 56 3.1.9.6 Působení chalkonů na fosfodiesterasy ............................................................... 59 3.1.9.7 Působení chalkonů na COX a další enzymy v souvislosti s jejich protizánětlivým a antiulcerosním působením .................................................... 60 3.1.10 Ostatní účinky chalkonů .................................................................................... 65 3.1.11 Syntetický význam chalkonů ............................................................................. 65 3.2 2-Benzyl-2-hydroxybenzofuran-3(2H)-on ........................................................ 66 4 Metodická část .................................................................................................................... 69 4.1 Deriváty chalkonu .............................................................................................. 69 4.1.1 Syntéza chalkonů ............................................................................................... 69 4.1.1.1 Claisen-Schmidtova kondensace ....................................................................... 69 4.1.1.2 Friedel-Craftsova acylace .................................................................................. 70 4.1.1.3 Další syntézy chalkonů ...................................................................................... 70 4.1.2 Michaelova adice thiolů na chalkony ................................................................ 71 4.2 2-Benzyl-2-hydroxybenzofuran-3(2H)-on ........................................................ 71 4.2.1 Syntéza auronu (2-benzylidenkumaranonu) ...................................................... 71 4.2.1.1 Oxidativní cyklisace 2´-hydroxychalkonů ......................................................... 71 4.2.1.2 Benzofuranová cesta .......................................................................................... 73 4.2.1.3 Palladiový coupling a následná cyklisace diarylpropynonů .............................. 73 4.2.2 Syntéza epoxidu auronu ..................................................................................... 74 4.2.3 Syntéza 2-benzyl-2-hydroxybenzofuran-3(2H)-onu .......................................... 75 5 Experimentální část ............................................................................................................. 77 5.1 Syntézy a fyzikálně-chemické vlastnosti látek .................................................. 77 5.1.1 Deriváty chalkonu a jejich syntetické meziprodukty ......................................... 77 5.1.1.1 Příprava 5-alkylpyrazin-2-karbonitrilů (S1 – S11) radikálovou alkylací .......... 77 Disertační práce Obsah 5.1.1.2 Příprava 1-pyrazin-2-ylethanonu a 1-(5-alkylpyrazin-2-yl)ethanonů (S12 – S22) Grignardovou reakcí .......................................................................................... 81 5.1.1.3 Příprava 1-pyrazin-2-yl-3-arylprop-2-en-1-onů a 1-(5-alkylpyrazin-2-yl)-3- arylprop-2-en-1-onů (S23 – S66) Claisen-Schmidtovou kondensací ................. 85 5.1.1.4 Příprava 1-fenyl-3-subst.fenylprop-2-en-1-onů (S67 – S72) Claisen- Schmidtovou kondensací ................................................................................. 108 5.1.1.5 Příprava 3-alkylsulfanyl- a 3-arylsulfanyl-1,3-difenylpropan-1-onů (S73 – S79) Michaelovou adicí ............................................................................................ 111 5.1.1.6 Příprava 3-alkylsulfanyl- a 3-arylsulfanyl-1-pyrazin-2-yl-3-aryl-propan-1-onů (S81 – S85) Michaelovou adicí ........................................................................ 115 5.1.2 Syntéza 2-benzyl-2-hydroxybenzofuran-3(2H)-onu (S88) .............................. 118 5.1.2.1 Syntéza auronu (S86) ....................................................................................... 118 5.1.2.2 Syntéza trans-auronepoxidu (S87) ................................................................... 119 5.1.2.3 Štěpení epoxidového kruhu trans-auronepoxidu ............................................. 119 5.1.3 Spektra vybraných chalkonů v ultrafialové a viditelné oblasti ........................ 121 5.2 Biologické hodnocení ...................................................................................... 122 5.2.1 Antimykobakteriální testování ......................................................................... 122 5.2.2 Antifungální testování ...................................................................................... 125 5.2.3 Testování inhibice fotosyntézy ........................................................................ 131 5.2.4 Antiagregační hodnocení chalkonů .................................................................. 132 5.2.5 Testování chalkonů na inhibici papainu ..........................................................
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