Synthesis, Crystal Structure And Antiproliferative Activity Of Norcantharidin Sulferhetero-cyclicring Amic Acid And Transition-metal Complexes

Cancer has been a chronic disease that creates serious threat to humanity health. It's reported that there has been more than 3,000,000 cancer suffers in China and about 1,400,000 die of cancer every year. Cancer has become a worldwide disease harming humanity health and life safety. Therefore, synthesizing high efficient, broad-spectrum and low toxic anticarcinogen and studying their anticancer activity is becoming a strategic task of new drug development. Cantharidin has been used as an anticancer drug for a long time. However, the use of it has been restricted when it is put to clinical use because of its hepatotoxicity and nephrotoxicity. Improper use of it could sometimes cause poisoning even death. Norcantharidin (NCTD) is an analogy of cantharidin. It not only has great anticancer activity and could raise the number of leucocyte but also has less toxicity. It's of great significance to design and synthesize some cantharidin derivatives that could inhibit tumor cells selectively, have little toxicity and have no effect on the immune response of organisms. Scholars from different countries have synthesized a great number of norcantharidin derivatives since decades ago, a few of which exhibit better biological activity and are put to clinical use. In this paper, novel norcantharidin sulfurheterocyclicring derivatives and norcantharidin transitional metal complexes were synthesized. Their interactions with macromolecules were studied as well as antiproliferative activity in order to obtain compounds with high activity against in-vitro cancer cells.The main content of this paper: 1. Two norcantharidin sulfurheterocyclicring derivatives were synthesized: compound 1 (norcantharidin thiazoline amic acid, C₁₁H₁₄N₂O₄S) and compound 2 (norcantharidin benzothiazole amic acid, C₁₅H₁₄N₂O₄S). They were characterized by elemental analysis, IR and ¹HNMR. Their interaction with bovine serum albumin (BSA) was studied by fluorescence spectra and sychronous fluorescence spectrometry. Their interaction with DNA was studied by fluorescence spectra and viscosity measurements. The antiproliferative activity of compound 1 against SMMC7721 cells were carried out to reveal that compound 1 coud inhibit SMMC7721 cells more efficiently than NCTD.2. Three novel norcantharidin transition-metal polymers were synthesized: compound 3 (norcantharidin manganese complex, [Mn(C₈H₈O₅)(H₂O)₂]_n), compound 4 (norcantharidin nickele complex, [Ni(C₈H₈O₅)(H₂O)₂]_n), compound 5 (norcantharidin copper complex, [Cu(C₈H₈O₅)(H₂O)₂]_n). They were characterized by X-ray single crystal diffraction. The inhibition effect of compounds 3 and 4 against human lung cancer cells and human hepatoma cells were studied. The results revealed that both compounds 3 and 4 have inhibition effect on SMMC7721 and A549 cells as NCTD, especially compound 3 against SMMC7721. Compound 3 exhibits strong inhibition against A549 cells when at a high concentration. Compound 4 has stronger inhibition than NCTD at a low concentration, but weaker than NCTD at a high concentration.3. Three novel norcantharidin-imidazole ternary complexes were synthesized: compound 6 (norcantharidin-imidazole cobalt(â…¡) complex, [Co(C₈H₅O₅)(C₃H₄N₂)(H₂O)₂]·2H₂O), compound 7 (norcantharidin-triimidazole cobalt(â…¡) complex, [Co(C₈H₅O₅)(C₃H₄N₂)₃]·3.35H₂O), compound 8 (norcantharidin-triimidazole nickel(â…¡) complex, [Ni(C₈H₅O₅)(C₃H₄N₂)₃]·3.35H₂O). They were characterized by X-ray single crystal diffraction. The interaction of compound 6 with DNA was studied by fluorescence spectra and viscosity measurements, which indicate that compound 6 can bind DNA through a partially intercalative mode. The anti-proliferation activity test indicates that the compound has high antiproliferative ability against human hepatoma cells SMMC7721 and human lung cancer cells A549, which is better than NCTD.