Study On The Synthesis Of Coenzyme Q Analogues And Antioxidant Activity

Coenzyme Q (CoQ or CoQn), also known as the ubiquinones, occur naturally in all cells and possess several important functions that include acting as mobile mediators for electron transfer in the electron transport chain of mitochondria respiratory systems and acts as an anti-oxidant by reducing free radicals that can cause damage to structural lipids or proteins in membranes. CoQ10, the main homologue of CoQ existing in humans, is widely used in the treatment of cardiovascular disease, hepatitis and cancer, and in the improvement of immunotherapy. The metabolites of CoQ homologues, and a number of synthetic CoQ analogues have shown significant biological activities related to its therapeutic effects.In this paper, we use the theory of bioisostere and drug metabolism to design CoQ analogoues, which were synthesized by three different original nucleus of CoQ with Side chain extension method and Side chain structure modification. A total of45compounds were synthesized including15CoQ analogues and15new compounds, Most of them were verified by IR spectrum,1HNMR spectrum,13CNMR spectrum, MS spectrum (HRMS). In addition, we studied on the antioxidant capacity of several CoQ analogues with DPPH essay in vitro.The paper was combined with three sections as follows.Part One The synthesis of three original nucleus compounds1. The TEMT compound was prepared in excellent yield (89%) by a reaction sequence starting from3,4,5-trimethoxy-benzadehyde via Wolff-Kishner reduction, selective bromination and methoxylation.2. CoQo was synthesized by3,4,5-trimethoxy-toluene via oxidation with30%H2O2in Formic acid-HOAc system in a yield of50%.3. The DMMCQ compound was prepared in high yield (52%) by a reaction sequence starting from3,4,5-trimethoxy-toluene via Wolff-Kishner reduction, Vilsmeier-Haack reaction, Blanc chloromethylation reaction, Dakin reaction and oxidation. Part Two Introducing of side chain1. A series of2,3-dimethoxy-5-methyl-1,4-benzoquinones substituted at the C-6position with alkoxy methyl groups were prepared by a reaction sequence starting from2,3,4,5-tetramethoxytoluene via Blanc chloromethylation reaction, Williamson reaction and oxidation in a yield of over64%.2. The direct alkylation of heterocyclic compound (N-benzylpiperazine, N-benzoylpiperazine, morpholine) with DMMCQ produced corresponding Heterocyclic-Coenzyme Q analogues in70%Yield.3. Based on radical alkylation of CoQo with10-Hydroxydecanoic acid in the presence of AgNO3and K2S2O4to afford Idebenone analogue in60%Yield.Part Three Study on the antioxidant activity of several CoQ analogues with DPPH asay in vitroTo investigate the eliminating free radical ability in vitro of Coenzyme Q analogues using DPPH essay and calculate IC50value, founding that most of Coenzyme Q analogues show comparative antioxidant activity of Coenzyme Q10. What's more, the antioxidant activity of F4, F5, F8were better than Coenzyme Q10, which provided the foundation for studying on the structure-activity relationship of Coenzyme Q analogues and further pharmacological activity research.