Synthesis And Anti-Lung Cancer Activity Of Compounds Related To Protein EIF3a With Double Activity

Lung cancer is the most common cause of cancer mortality, overall global both male and female in patients with malignant tumors its mortality account for the first, the 5-year overall survival (OS) rate is about 16%.In eukaryotes,11 factors have been identified that participate in the translation initiation step.Among these factors, eIF3 is the largest and the most complex one. eIF3a is the largest subunit of eIF3. Recently, overexpression of eIF3a has been discovered to be associated with several human cancers, especially lung cancers. The mammalian eIF3a has also been identified to be a mediator of the effect of mimosine, a cell cycle blocker, on up-regulating synthesis of p27kip, aCDK inhibitor, and simultaneously down-regulating the synthesis of a-tubulin and ribonucleotide reductase M2(RRM2). This may be related to its fuctions, such as promoting of microtubule synthesis, regulating DNA synthesis and cell differentiation, which regulate cell growth.So it has enormous potential to develop new molecular drugs as eIF3a inhibitors for cancer therapy, especially lung cancers in which eIF3a is highly expressed in particular. However, there is no drug related to eIF3a that has been reported currently.For the first time this issue uses eIF3a protein as target and 1 substituted phenyl-5-methyl-pyridine-2-ones as the lead compound. And 30 compounds whose 5-position side chain modified to form similar Y-type structure compounds have been designed and synthesized. Their structures have been confirmed by MS,1HNMR,13CNMR,IR. Their anti-cancer and anti-fibrosis activity have been investigated by using MTT method. Compound27 has been found as the best anti-cancer active, and Compound 14 has been found as the best anti-fibrosis active, whose activity is 22.7 times of pirfenidone.This issue summarizes structure-activity relationship t of the similar Y-type structure compounds with anti-lung cancer and anti-fibrosis activity.1) The connection part of 5-position side chain is considered as the active center of similar Y-type structure compounds, while the 1 position benzene ring replaced with electron donor is unfavorable to both anti-cancer and anti-fibrosis activity.2) Different groups replacement in the two benzene rings of similar Y-type structure affects anti-cancer and anti-fibrosis activity differently, in which anti-cancer has best activity whenl-benzene ring is not substituted and 5-position side chain benzene ring is substituted by m-methyl; while anti-fibrosis has best activity whenl-benzene ring is substituted by F atoms,but there is no obvious rule for 5-position side chain benzene ring substituted by the simple groups, and it needs further study.For the first time this issue systematic synthesizes 1-substituted phenyl-5-methyl-pyridine-2-ones of 5-position side chain modified to form similar Y-type structure compounds. Their anti-lung cancer and anti-fibrosis activity have been evaluated and the structure-activity relationship has been described respectively. This issue preliminary investigates compounds'inhibition on the expression of eIF3a.These achievements provide important and basic information for the further study of designing novel structures of better anti-cancer and/or anti-fibrosis activity, especially with eIF3a protein inhibition.