The Research Of Pa-catalyzed Novel Tranesterification And Synthesis, Antitumor Activity And TRAIL Sensitization Of Novel Ceramide Analogues

Recently, transition-metal catalyzed C-H activation bring about great change to traditional organic functional group reaction. Synthesized a series of reports for transition-metal catalyzed reactions of aldehydes and esters, we engaged to utilize aldehydes as acyl donors to develop a new type of transesterification for the efficient synthesis of a broad scope of esters under neutral and mild conditions.A new type of transesterification reaction of N-heteroarene-2-carboxylates 1 with aldehydes 2 by C-H and C-O bond activations has been developed for the synthesis of a broad scope of carboxylic esters 3 under neutral and mild conditions. By using Pd(OAc)2 as a catalyst and TBHP as an oxidant, various aryl, heteroaryl, alkyl N-heteroarene-2-carboxylates la-p could perform the transesterification smoothly with aromatic, heteroaromatic and aliphatic aldehydes 2a-o to furnish versatile carboxylic esters 3 with up to 90% yield. The transesterification reaction has good generality, and tolerates various functional groups, such as nitro, cyno, hydroxy, acetyl, fluoro, chloro, bromo, trifluromethyl and methoxy group. 18O-Isotopic labeling and radical inhibiting experiments indicate that the mechanistic pathway may undergo the two key steps of oxidative addition of acyl-O bond in parent ester 1 and radical cleavage of sp2 C-H bond in aldehyde 2. Nitrogen in N-heteroarene-2-carboxylates 1 is neccessary in the reaction, and could control the acyl-oxygen cleavage with the aid of Pd(OAc)2. Combined these results, a possible mechanism via Pd (IV) intermediates is proposed.Our another work is design, synthesis and antitumor activity of ceramide analogues. A group of novel ceramide analogues, replaced L-serine with L-threonine as the original material, (2’S,3’R)-N-(3-Hydroxy-1-oxo-1-(alkylamino)butan-2-yl)-he teroaryl carboxamides were synthesized as potential antitumor lead compounds. These ceramide analogues are shown to be effective at inducing apoptosis in various types of tumor cells. Further, these ceramide analogues are shown to be effective at sensitizing multiple types of tumor cells to TRAIL-induced apoptosis. Among them, 3e which include indole ring, showed the significant anti-proliferation effect with IC50 values of 6.81 μM in MCF-7 and 4.80μM in SiHa, respectively. When provided in combination with TRAIL,2b,2a,2f,3g, 1g, 1c, and 1h are observed to sensitize HELA cells to TRAIL-induced apoptosis. Taken together, our results suggest that these group of novel ceramide analogues might be as potent apoptosis inducers or sensitizers with great promise for further development as an adjuvant agent to overcome drug resistance in human cancer therapy.