N-substituted Arcyriarubin A: Study On The Efficient Syntheses And Properties

Owing to their special core structure and remarkable biological activities,bisindolylmaleimides (abr. BIMs) have attracted wide attentions in the fields ofmaterials science and drug discovery. The fundamental structure-activity-relationship studies reveal that keeping NH moiety in maleimide ring while NH inindole ring substited was important to possess potent inhibitions to protein kinase C(PKC), glycogen synthase kinase3β (GSK-3β) and some of the other enzymes.However, for the high-performance materials, it is crucial to keep all of the three NHgroup substituted. The synthesis of bisindolylmaleimides usually adopts protectinggroups strategy and the yield of preparing N,N’,N’’-trisubstituted BIMs are usuallylow. Thus, it will make great sence to carry out the flexible and highly efficientsynthesis of the above mentioned BIMs.In this thesis, the efficient preparation of Arcyriarubin A was achieved in largescale (66.9g) via modified Faul’s procedure, although the Steglich protocol wastried and proved to be less efficient.After careful investigation on the reaction between Arcyriarubin A and alkylbromide in different reaction conditions, we found that highly selective N-alkylationof Arcyriarubin A could be realized. The N’-monoalkylation, N’,N’’-dialkylation andN,N’,N’’-trialkylation of Arcyriarubin A was achieved by the conditions ofNaH/THF and NaH/DMF respectively. Furthermore, the synthesis towardsGF109203X and LY333531was carried out based on the above reaction selectivity.In order to comfirm the non-planar character of BIMs, the single-crystals ofN’,N’’-dialkylated Arcyriarubin A163,181and182were cultured, and single-crystal X-Ray diffraction data of them were collected, which showed the existencesof torsion angle between the indole rings. And, different substituent led to differentdihedral angles between two indole rings. Furthermore, the BIMs molecules arefound to be connected by pairs of N-H…O hydrogen bonds. Afterwards, the UV-Visand Fluorescence spectra of the above mentioned N-substituted Arcyriarubin A weremeasured, which showed that (1) all the N-derived BIMs’ maximum absorptionwavelength and maximum emmision wavelength were red shifted comparedArcyriarubin A, and (2) the maximum emmision wavelength had big difference insolvent and solid. In order to get the information about the influence of chain lengthon N-alkylated BIMs’ thermostabilities, we measured the TG and DSCs of thecompounds. We found the initial degradation temperature of BIMs derivatives roseand the glass transition temperature went down with the chain length went longer(except189and190). And the coupound181and182could crystallize in the process of cooling.In summary, a highly selective N-alkylation of Arcyriarubin A was achieved toprovide the molecular diversity of BIMs, which was very useful forstructure-property-relationship studies. This research will accerlerate the relatedpharmaceutical and functional materials based BIMs.