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U ovom radu sintetizirana su i strukturno karakterizirana četiri nova harmicina 15-18, hibridna spoja β-karbolina i derivata cimetnih kiselina, povezana 1,2,3-1H-triazolom, kao i prekursori potrebni za njihovu sintezu, cimetni azidi 7-10 i alkin β-karbolina 14. Cimetni azidi sintetizirani su iz odgovarajućeg CAD u 4 reakcijska koraka. U reakciji s tionil-kloridom nastali su kiselinski kloridi. Slijede esterifikacija i redukcija estera. Nastali primarni alkoholi s ADMP uz DBU u THF-u daju cimetne azide 7-10. Sinteza alkina u poloţaju C6 β-karbolinskog prstena započinje iz 5-metoksitriptamina Pictet-Spenglerovom kondenzacijom, nakon koje slijedi aromatizacija tetrahidro-β-karbolina. Nastali β-karbolin podvrgnut je kiseloj hidrolozi uz nastanak fenola koji s propargil-bromidom daje alkin 14.Za povezivanje cimetnih azida 7-10 i β-karbolinskog alkina 14 u hibridne spojeve, harmicine 15-18, korištena je bakrom(I) katalizirana azid-alkin cikloadicija koja rezultira uvođenjem triazolskog prstena, bioizostera amidne skupine, u strukturu hibridnog spoja. Strukture sintetiziranih spojeva potvrđene su uobičajenim spektroskopskim metodama (1H i 13C NMR, MS, IR). Sva četiri spoja zadovoljavaju Lipinskijeva i Veberova pravila, a dobru oralnu bioraspoloţivost predviđa im i alat SwissADME. Sintetiziranim derivatima će u daljnjim istraţivanjima biti ispitano biološko djelovanje. Four novel harminines 15-18, hybrid compounds consisting of β-carboline and cinnamic acid derivative, linked via 1,2,3-triazole, have been synthesized and structurally characterized, as well as their precursors, cinnamic acid azides 7-10 and β-carboline alkyne 14. Cinnamyl azides 7-10 were sythesized from corresponding CAD in a four step procedure. Reaction with thionyl chloride, followed by esterification and ester reduction led to formation of alcohols. In the final step, alcohols and ADMP formed cinnamic acid azides 7-10. Synthesis of alkyne 14 started from 5-methoxytryptamine by Pictet-Spengler condensation, followed by aromatization of tetrahydro-β-carboline ring. Generated β-carboline was exposed to acid hydrolisis resulting in the formation of a phenol, which was alkylated with propargyl bromide, to form an alkyne 14.The copper(I)-catalyzed azide-alkyne cycloaddition was used to link alkyne 14 and cinnamyl azides 7-10 into novel hybrid compounds, harmicines 15-18. As a result, triazole ring was formed, which is a bioisostere of the amide group. Structures of the newly prepared compounds were confirmed using conventional analytical and spectroscopic methods (1H i 13C NMR, MS, IR). All four novel derivatives meet all of the Lipinski's and Veber's criteria for good oral bioavailability of potential drugs. SwissADME tool predicts good oral bioavailability of all four derivatives. Further studies will investigate biological activity of the prepared harmicines. |
