Synthesis And Antimicrobial Activity Of Tetrahydro-β-Carboline Diketopiperazines

Tetrahydro-β-carboline diketopiperazines is a member of the indolealkaloids that block cell cycle progression are attracting much attention aspotential therapeutic agents. Recently, a series of tetrahydro-β-carbolinediketopiperazines were isolated. Due to their broad range of bioactivities,especially antimicrobial activities and anti-tumor activities, synthesis of suchsubstance has attracted great attention. In this theis, we mainly focus on thesynthesis and antimicrobial activity of tetrahydro-β-carboline diketopiperazines.Although total syntheses of tetrahydro-β-carboline diketopiperazines ofnatural forms have been completed and reported, an efficient synthesis oftetrahydro-β-carboline diketopiperazines faces a challenge. Tetrahydro-β-carboline ring is the basic structure unit of tetrahydro-β-carbolinediketopiperazines because of its unique structure. The first problem to be solvedwas the construction of the1,3-disubstituted-1,2,3,4-tetrahydro-β-carbolineframework of tetrahydro-β-carboline diketopiperazines with the establishment ofthe C-1stereocenter, but many methods inevitably led to the diastereomericmixtures of tetrahydro-β-carboline ring, the mixture of cis-and trans-aredifficult to be separated. Recently, the asymmetric Pictet-Spengler reaction andthe crystallization-induced asymmetric transformations (CIAT) have attractedmuch attention, because it is an imporant and useful tool to construct synthonscontaining tetrahydro-β-carbolines structural moieties and is able to obtain asingle enantiomer.In this study, we have reported a concise and efficient synthetic route togenerate a series of single enantiomer tetrahydro-β-carboline diketopiperazines.Firstly, starting from optically pure L-tryptophan methyl ester hydrochloride withvarious aldehydes in isopropanol by refluxing to obtain an epimeric mixture ofthe hydrochloride salts of cis-and trans-1,3-disubstituted tetrahydro-β-carbolines, and then a process of crystallization-induced asymmetric transforinmation (CIAT)was taken place in a mixed solvent with different ratios of nitromethane andtoluene to obtain a single enantiomer. Secondly, the synthesis of protecteddipeptide was completed under the two-phase Schotten-Baumann condition bytetrahydro-β-carboline and the Fmoc-L-Pro-Cl. Finally, under theFmoc-deprotection condition (morphine,10mL), the desired tetrahydro-β-carboline diketopiperazines were readily formed as sole products. Sixtetrahydro-β-carboline diketopiperazines were synthesized through this route,four compounds among which are new compounds have not been reported.All compounds were characterized by NMR, IR, LC-ESI-MS, In order todetermine their absolute configurations, the X-ray diffraction study of asingle-crystal was taken place, and the single crystal of tetrahydro-β-carbolinediketopiperazines have also been prepared by using solvent volatilization method.Finally, two single crystals of these compounds were obtained.Four bacterias (Escherichia coli, Pseudomonas aeruginosa, Staphylococcusaureus, Bacillus subtilis) and four fungi (Colletotirchum gloeosporioides, Valsamali, Alternaria alternata, Alternaria brassicae) were selected to measure theantimicrobial activities of target compounds. The results of activity test indicatedthat all the six tetrahydro-β-carboline diketopiperazines have the antimicrobialactivities for these test microorganism with different degrees, The antitumoractivity and other bioactivities of this six target compounds need to be futherstudied.