| Cantharidin(CAN)derived from the dried body of the Chinese Mylabris(blister beetles),is the principle active ingredient of this traditional Chinese medicine.Furthermore,cantharidin is also a natural toxin.As the protein phosphatase inhibitors,cantharidin expresses strong antitumor properties and has been used worldwide as an anticancer agent since 1264.However,cantharidin also possesses cytotoxicity to a series of normal cells,such as gastrointestinal tract,urethra and kidney.As a result,this agent is restricted in clinical applications.The activity and cytotoxicity of cantharidin are closely related to its structure.In order to obtain the derivatives with high activities and less toxicity profiles,researchers have synthesized thousands of analogues and derivatives based on the structure of cantharidin.The structure modification of cantharidin includes the following methods:skeleton modification,anhydride modification and combination modification.Among various cantharidin derivatives,norcantharidin has the similar anticancer activity with cantharidin and lower cytotoxicity,as well as easier preparation,which make it become the focus of new derivatives.Norcantharimide is one of the important norcantharidin derivatives due to the possibility to incorporate any kinds of substituent in the nitrogen,as well as essentially equipotent inhibitory activity of the serine/threonine protein phosphatases 1 and 2A(PP1 and PP2A)with cantharin.In this paper,we synthesized six norcantharimides through norcantharidin(UNC)[also can be named as demethyl-cantharidin(DMC)]with ethanediamine(EDA),1,3-propanediamine(PDA),1,4-butanediamine(BD A),1,6-Hexanediamine(HDA),Diethylenetriamine(DETA),and triethylenetetramine(TETA),respectively.Their structures are confirmed by elemental analysis,IR and NMR.Moreover,in vitro cytotoxic activities of these novel compounds have been evaluated with MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]assays.Attracted by the interesting structure of 2,2'-(1,3-propanediyl)bis[3a,4,7,7a-te-trahydro-4,7-epoxy-1,3-bishydroisoi-ndole-1,3-dione],we synthesized three dimers based on it in order to study the conformations of propylene linking groups.The synthesis,NMR and single-crystal structures of three propylene linking dimers related with the hydrolytic degradation of 5,6-dehydronorcantharimide dimer have been studied.Of course,special attentions were paid to their conformations in order to understand their changes throughout the reaction.Statistical analysis of CSD database revealed that anti-anti,gauche-anti and gauche-gauche conformations may have similar stability in most cases and various complicated unpredictable non-covalent interactions may play important role in the formation of final rotamers.In order to reproduce all stable conformations and the energy barriers separating them,full range two-dimensional fully relaxed potential-energy surfaces(PES)scans of six 'propylene linker9 dimers were calculated starting from the most stable crystal structures.The PES were scanned along both bridge C-C single bond torsional angles(denoted as ?1 and ?2),while all other internal coordinates were optimized at the DFT/B3LYP/3-21G*level in gas phase.Then all energy minima were re-optimized again at the DFT/B3LYP/6-311+G(d,p)level both in gas and ethanol solutions in order to evaluate the really stable rotamers.At last,1D or 2D relaxed PES scans were performed between local stable rotamers to get reliable energy barriers.This method represents a less time-consuming and more reliable approach to the determination of conformational stability of propanediyl bridging chains.The combination of experimental,statistical and theoretical results shows that the observed conformation is jointly determined by the energy levels of the minima,energy barriers separating them,non-covalent interactions and somewhat randomness. |
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