Palladiumkatalysoitu vinyylikloridien heteroarylointi

This master’s thesis describes a method to prepare heteroarene-linked cycloalkenones. The method is a previously underutilized palladium-catalyzed coupling reaction between vinyl chlorides and non-activated heteroarenes. The reaction type is essentially the reverse of the Heck reaction. The procedure was optimized using a reaction between imidazo[1,2-a]pyridine and 3-chloro-2-cyclohexenone. The optimized reagent system consists of Pd(OAc)2 as catalyst, PPh3 as ligand, K2CO3 as base, 2-ethylhexanoic acid as acid additive and toluene as solvent. A number of other heteroarenes and another chlorocycloalkenone were used to expand the scope of the reaction, with a total of 23 successfully synthesized products. By default, the syntheses were performed at 100 °C but some substrates required a higher temperature of 120 °C. Chlorocycloalkenones were used in a moderate excess. The most suitable substrates were fused imidazoles and substituted oxazoles and thiazoles. Yields of over 80% were obtained from several substrates and most yields ranged between 50% and 80%. Ester and nitrile functionalities were tolerated. Unsubstituted thiazole reacted unselectively at two sites. As such, the developed method has potential uses in small-scale medicinal chemistry and other fine chemical industries. The use of non-activated heteroarenes complies with the green chemistry principles. In addition, vinyl chlorides are conveniently synthesized and are relatively stable compared to other vinyl halides.Tässä diplomityössä esitellään menetelmä heteroareenikytkettyjen sykloalkenonien valmistamiseksi. Menetelmä on aiemmin vähän käytetty palladiumin katalysoima kytkentäreaktio vinyylikloridien ja aktivoimattomien heteroareenien välillä. Reaktiotyyppiä voi pitää käänteisenä Heck-reaktioon nähden. Menetelmä optimoitiin käyttäen reaktiota imidatso[1,2-a]pyridiinin ja 3-kloro-2-sykloheksenonin välillä. Optimoidussa reagenssiyhdistelmässä oli katalyyttina Pd(OAc)2, ligandina PPh3, emäksenä K2CO3, happolisäaineena 2-etyyliheksaanihappo ja liuottimena tolueeni. Yhteensä 23 tuotetta valmistettiin onnistuneesti käyttäen erilaisia heteroareeneja ja toista klorosykloalkenonia. Useimmat synteesit tehtiin 100 °C:n lämpötilassa, mutta osa lähtöaineista vaati 120 °C:n lämpötilan. Klorosykloalkenoneja käytettiin ylimäärin. Soveltuvimpia lähtöaineita olivat bisykliset imidatsolit sekä substituoidut oksatsolit ja tiatsolit. Useat reaktiot tuottivat yli 80 %:n saannon, ja useimmat saannot olivat 50 ja 80 %:n välillä. Esteri- ja nitriilifunktionaalisuudet kestivät reaktio-olosuhteissa. Substituoimaton tiatsoli reagoi epäselektiivisesti kahdesta paikasta. Menetelmä soveltuu sellaisenaan pienen mittakaavan lääkeainekemian ja muun hienokemian käyttöön. Aktivoimattomien heteroareenien käyttö on vihreän kemian periaatteiden mukaista. Lisäksi vinyylikloridit ovat helposti saatavilla ja ne ovat suhteellisen stabiileja muihin vinyylihalideihin verrattuna

Comparative Hepatic and Intestinal Efflux Transport of Statins

Previous studies have shown that lipid-lowering statins are transported by various ATP-binding cassette (ABC) transporters. However, because of varying methods, it is difficult to compare the transport profiles of statins. Therefore, we investigated the transport of 10 statins or statin metabolites by six ABC transporters using human embryonic kidney cell-derived membrane vesicles. The transporter protein expression levels in the vesicles were quantified with liquid chromatography-tandem mass spectrometry and used to scale the measured clearances to tissue levels. In our study, apically expressed breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transported atorvastatin, fluvastatin, pitavastatin, and rosuvastatin. Multidrug resistance-associated protein 3 (MRP3) transported atorvastatin, fluvastatin, pitavastatin, and, to a smaller extent, pravastatin. MRP4 transported fluvastatin and rosuvastatin. The scaled clearances suggest that BCRP contributes to 87%-91% and 84% of the total active efflux of rosuvastatin in the small intestine and the liver, respectively. For atorvastatin, the corresponding values for P-gp-mediated efflux were 43%-79% and 66%, respectively. MRP3, on the other hand, may contribute to 23%-26% and 25%-37% of total active efflux of atorvastatin, fluvastatin, and pitavastatin in jejunal enterocytes and liver hepatocytes, respectively. These data indicate that BCRP may play an important role in limiting the intestinal absorption and facilitating the biliary excretion of rosuvastatin and that P-gp may restrict the intestinal absorption and mediate the biliary excretion of atorvastatin. Moreover, the basolateral MRP3 may enhance the intestinal absorption and sinusoidal hepatic efflux of several statins. Taken together, the data show that statins differ considerably in their efflux transport profiles. SIGNIFICANCE STATEMENT This study characterized and compared the transport of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid and four atorvastatin metabolites by six ABC transporters (BCRP, MRP2, MRP3, MRP4, MRP8, P-gp). Based on in vitro findings and protein abundance data, the study concludes that BCRP, MRP3, and P-gp have a major impact in the efflux of various statins. Together with in vitro metabolism, uptake transport, and clinical data, our findings are applicable for use in comparative systems pharmacology modeling of statins.Peer reviewe