Design, Synthesis And Activity Study Of Multi-targets Anti-tumor Agents Affecting On Ras/Raf/MEK/ERK Signaling Pathway

Ras/Raf/MEK/ERK signaling pathway exsits in all eukaryotic cells.This signaling pathway taked an important role in cell proliferation, differentiation, apoptosis, metastasis and metabolic and increases in most tumor cells.The important kinases Ras, Raf, MEK and ERK in this signaling pathway becomes the crucial targets for the investigation of anti-tumor agents. Tumor belongs to one of multifactorial diseases. Single targets agents that have a strong selectivity and efficacy on a particular enzyme or receptor usually have little effect on tumor therapy. It's difficult for single targets to achieve the pursose of tumor therapy. In the case that they contain efficacy structures affecting on multiple targets, multi-targets agents may produce a variety of pharmacological activities so as to cure cancer.The protein Ras is the crucial signaling protein in the Ras/Raf/MEK/ERK signaling transduction.This investigation chosed the Farnesyltransferase which can catslytic non-activated Ras-GDP to activated Ras-GTP as the main target and Raf-1 kinase which has a close relationship with Ras and plays an key role in this transduction simultaneously as the secondary target.Six multi-targets compounds which have an effect on FTase an Raf-1 kinases at the same time were designed by the use of computer aided drug design in the hope that they could have stronger inhibitory effect on tumor cells .The ultimate goal is to find the high activity and low toxicity multi-targets agents for specific cancer.A new pharmacophore model of Raf-1 kinase inhibitors were constructed by the sofeware catalyst in the investigation. The six targets compounds matched with phar–macophore model of FTIs and Raf-1 kinase very well and had good predictive acti–vity(none was reported).The targets compounds were screened in vitro by the use of MTT. Hepatoma cells HepG-2 and pancreatic cancer cells pcmc-1 were chosed because of their close relationship with the Ras/Raf/MEK/ERK signaling transduction. The target compounds had a good inhibition effect on these two kinds of tumor cells. The IC50 of compound B1 affecting on HepG-2 and pcmc-1 were 48.46μmol/ml and 15.43μmol/ml respectively. Comparising the actual activity with the predicted activity, it was found that their mutative trends were consistent. This result indicated that the pharmacophore model of FTIs and Raf-1 kinase inhibitors has a certain predictability and reliability. The investigation has some guiding significance in some degree to the design of new anti-tumor agents.The innovations of this investigation: (1) multi-targets anti-tumor agents which have effect on different targets take the advantages of strong activity and little side effects. The investigation designed multi-targets agents affecting on FTase and Raf-1 kinases by the use of CADD. (2) analysising the medicine of the guiding compounds increased their druggability. (3) the guiding compounds were easy to be synthesized and have not been reported in other literature. (4) the methods were proposed and confirmed that multi-targets anti-tumor agents can be designed by the use of CADD.