Synthesis,structure Characterization And Properties Of Unsaturated Bis-norcantharimides

Cantharidin can be isolated from Chinese blister beetles and is in fact the active ingredient of this kind of popular traditional Chinese medicine.It is well known that cantharidin is the inhibitor of protein phosphatases 1(PP1)and 2A(PP2A)and shows good anticancer activities.For example,recent reports indicated that this compound is an apoptosis inducer in multiple melanoma cells by interaction with proteins of JAK/STAT.Similarly,cantharidin possesses cytotoxicity to a series of normal cells,including gastrointestinal tract,urethra and kidney.Now the high renal toxicity has precluded cantharidin’s use in modern medicine,which has on the other hand promoted lots of investigations in the synthesis of less renal cytotoxic and more selective cantharidin analogs with a similar or improved anticancer profile.Among various cantharidin derivatives,norcantharimides display modest anticancer activity and have proved to be interesting lead compounds in the search for new anticancer agents.A number of investigations focused upon their synthesis and structure-activity relationships have been carried out worldwide.As part of our ongoing study we have developed a series of six UNCI dimers: UDMC-EDA,UDMC-PDA,UDMC-BDA,UDMC-HDA,UDMC-DETA and UDMC-TETA.All the synthesized compounds were well characterized by IR,UV–Vis,1H and 13 C NMR as well as single crystal X-ray diffraction.UDMC-DETA and UDMC-TETA are new while the other four were reported previously but their structures and properties had not been determined.Introduction of various lengths of single bond chains provides too much conformational flexibility and then various building blocks for UNCI dimers crystal.Among the six dimers,three twisted into helicate,but crystallize into centrosymmetric lattice;one adopts approximately centrosymmetric conformer,but packs into non-centrosymmetric polar space group(P21).Supramolecular synthons via conventional hydrogen bonds have been analylized and the common feature is that two dimensional layer structures are formed.The structural elucidation and the complete NMR assignment of the six dimers were performed.A contradiction that the incorporation of an electron-donating substituent was observed to cause shielding of remote carbons,including remote ones situated on other cycles,but deshielding of nearby carbonyl occurs in six UNCI dimers.In this paper,we explained the shielding/deshielding contradiction,which is attributed to a decrease of coplanarity in the O=C-N(O)-C=O p-π electron conjugated system.In addition,theoretical studies have been investigated to compare with the experimental findings.Inspection of the six experimental IR spectra and comparison with the starting material and with their corresponding theoretical spectra leads quite readily to the conclusion that these UNCI dimers can be easily distinguished based on four strongest peaks,i.e.1771-1767 cm-1 for symmetric stretches of C=O bond,1721-1697 cm-1 for antisymmetric stretches of C=O bond,1412-1398 cm-1 for C-N-C symmetric vibrations and 1203-1165 cm-1 for C-N-C anti-symmetric vibrations.UV-Vis absorption spectra of the six UNCI dimers were reproduced from TD-DFT calculations,which match the experimentally obtained spectra.Attempts to understand the nature of electronic transitions were carried out through the method of Frontier Molecular Orbital Theory.All dimers were evaluated for their in vitro cytotoxic activity against two cancer cell lines: A549(human lung cancer),4T1(mouse breast cancer).Unfortunately,all six dimers are cytotoxically inactive.Only one saturated NCI dimer(DMC-HDA)showed modest cytotoxicity.By comparing with the relevant results obtained from literatures,we deduced that the antitumor properties of UNCI/NCI dimers depends mainly on the length of link chains and have relationship with the double bond(in most cases,NCI derivatives suppress tumor growth more effectively than UNCI analogues),but this hypothesis requires more experiments.