Microwave-assisted Synthesis Of Tanshinone-imidazole Derivatives And Its Antitumor Mechanism

Tanshinone IIA(Tan IIA), one of extracts derived from the root of Traditional Chinese Medicine Danshen, possesses antitumor activity, antioxidant, anti-aging,preventing myocardial ischemia and myocardial infarction properties. However,tanshinone IIA possesses low the antitumor activity, poor water solubility and poor stability, both of which restrict its further development.Chemical modification of bioactive natural products is a kind of important way to develop new drugs. In order to get higher efficiency and less side effects of antitumor compounds, the C-ring structure of tanshinone IIA was chemically modified with various aldehydes to introduce imidazole group. In this paper,twenty-five tanshinone-imidazole compounds were synthesized and characterized by ESI-MS, NMR and X-ray crystal diffraction. And their antitumor activities and mechanism were preliminarily studied.The results of this study were shown as following:(1) Microwave-assisted synthesis technology was so efficiently and worked at a high rate of speed that twenty-five tanshinone IIA-imidazoles derivative were synthesized. Furthermore, the structure of tanshinone IIA-imidazoles derivatives were characterized by ESI-MS, NMR and single-crystal X-ray diffraction.(2) The anticancer activities of tanshinone IIA-imidazoles derivatives towards different tumor cells have been screened by MTT assay, with pirarubicin as positive comparison. The results showed that most of tanshinone IIA-imidazoles derivativesshowed potent growth-inhibitory effects on different tumor cells such as MDA-MB-231, HeLa and HepG2. And the anticancer activities of tanshinone IIA-imidazoles derivatives improved significantly as compared with those of tanshinone IIA. In addition, the structure-activity relationship for the anticancer activity of tanshinone IIA-imidazoles derivatives was studied, and the results indicated that the electron donating group substituted derivatives exhibit better anticancer activity than the electron attracting group substituted derivatives,meanwhile, the group in ortho and para position made more contribution than meta position for anticancer activity.(3) Cell biology techniques were utilized to study mechanism antitumor of tanshinone IIA-imidazoles derivatives. The results suggested that tanshinone IIA-imidazoles derivatives induced MDA-MB-231 cell cycle arrest in S phase and inhibit tumor cell metastasis, leading to tumor cell death.