Synthesis And Biological Activity Of Natural Product-like With Structural Diversity Based On Arylketals

Natural lead compounds are the molecular basis for many drug innovations.However,the classical discovery model of natural lead compounds has some problems,such as long preparation cycle and low discovery rate of active compounds.The directional synthesis of natural products is suitable for the full synthesis of single lead compounds.Therefore,the research focus on natural organic synthetic chemistry has gradually shifted from the goal of "synthesis of a single natural product" to the guiding synthesis of "structurally diverse natural products".Especially in the field of drug research,small molecular compounds with diverse structures can provide opportunities to explore a wide range of biological targets,so diversity-oriented synthesis has rapidly become a new synthetic target in recent years.This paper takes a Arylglyoxals as the reaction material and organic unit reaction as the basis,realizes the construction of three kinds of functional groups or skeletons,and studies the biological activity of synthetic natural products,mainly including the following aspects:In the first part,polyhydroxychalcones was synthesized by aldol condensation based on the catalytic system SOCl₂/Et OH,including 2,2',4'-trihydroxychalcone?a1?,4,2',4'-trihydroxychalcone?a2?,2,3,2',4'-tetrahydroxychalcone?a3?,2,4,2',4'-tetrahydroxychalcone?a4?,3,4,2',4'-tetrahydroxychalcone?butein,a5?,3,2',4'-trihydroxy-4-methoxychalcone?a6?,2',4'-dihydroxy-3,4–dimethoxychalcone?a7?.2',4'-dihydroxy-2,5-dimethoxy chalcone?a8?,2',4'-dihydroxy-2,6-dimethoxychalcone?a9?,4-methoxy-2',4' dihydroxychalcone?a10?.The optimal reaction conditions of butein including the equivalent of 3,4-dihydroxybenzaldehyde,catalyst dosage as well as reaction time were investigated.The reaction result exhibited that when the concentration of SOCl₂ is 1 mol/L,the equivalent of 3,4-dihydroxybenzaldehyde is 1 as well as reaction time is 1 h,the yields of butein can reach to 88%.In the second part,a new method was developed for one-pot synthesis triarylmethane based on diversity oriented synthesis between 2,4-dihydroxyacetophenone and bromine-substituded benzaldehydes via Friedel-Crafts addition applying SOCl₂/Et OH as catalyst.The synthetic compounds are 1-{3-[?5-acetyl-2,4-dihydroxy-phenyl?-?2-brominephenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b1?,1-{3-[?5-acetyl-2,4-dihydroxy-phenyl?-?3-brominephenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b2?,1-{5-[?5-acetyl-2,4-dihydroxy-phenyl?-?3-brominephenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b3?,1-{3-[?5-acetyl-2,6-dihydroxy-phenyl?-?3-brominephenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b4?,1-{3-[?5-acetyl-2,4-dihydroxy-phenyl?-?4-brominephenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b5?,1-{5-[?5-acetyl-2,4-dihydroxy-phenyl?-?4-brominephenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b6?,1-{3-[?3-acetyl-2,6-dihydroxy-phenyl?-?4-brominephenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b7?,1-{3-[?5-acetyl-2,6-dihydroxy-phenyl?-?3,5-dibromophenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b8?,1-{3-[?5-acetyl-2,4-dihydroxy-phenyl?-?3,4-dibromophenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b9?,1-{5-[?5-acetyl-2,4-dihydroxy-phenyl?-?3,4-dibromophenyl?-methyl]-2,4-dihydroxy-phenyl}-ethanone?b10?respectively.Additionally,the plausible mechanism was preliminarily explained by Fridel-Crafts addition.In the third part,on the basis of diversity oriented synthesis,eight new bromo-substituted ?-hydroxyldihydrochalcones were synthesized.Their structures were elucidated on the basis of spectroscopic analyses,including ESI-MS,1D and 2D NMR techniques.The synthetic compounds are 2-bromine-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c1?,3-bromine-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c2?,4-bromine-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c3?,2,5-dibromine-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c4?,3,4-dibromo-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c5?,3,5-dibromine-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c6?,2-bromine-5-methoxy-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c7?,5-bromine-2-methoxy-2?,4?-dihydroxy-?-hydroxydihydrochalcone?c8?respectively.The CD values showed that eight ?-hydroxydihydrochalcones are raceme,which were non-selective synthetic.In the forth part,eighteen polyhydroxychalcones and its derivatives were evaluated the inhibitory activity on xanthine oxidase in vitro.The result displayed that butein has high inhibitory activity?IC50 = 2.93×10-6 mol/L?,which was close to that of allopurinol?IC50=1.1×10-6 mol/L?.Therefore,its potential inhibition of XO was discussed in aspect of inhibition kinetics,fluorescence titrations,synchronous fluorescence spectroscopy and molecular docking.The inhibition kinetics analysis showed that butein possessed a stronger inhibition on XO in an irreversible competitive manner.The results of fluorescence titrations and synchronous fluorescence spectroscopy indicated that butein was able to interact with XO at one binding site,and the fluorophores of XO were placed in a more hydrophobic environment with the addition of butein.Subsequently,the results of molecular docking between butein and XO protein revealed that butein formed hydrogen bonding with the amino acid residues located into the hydrophobic cavity of XO.All the results suggested that the inhibition mechanism of butein on XO activity may be the insertion of butein into the active site occupying the catalytic center of XO to avoid the entrance of xanthine and inducing conformational changes in XO.In the fifth part,the antimicrobial activities of eighteen polyhydroxychalcones and its derivatives were evaluated against Gram-negative bacteria?Esherichia coli,Pseudomonas aeruginosa,and Chromobacterium violaceum?,Gram-positive bacteria?Staphylococcus aureus?,as well as one fungi?Candida albicans?.All tested compounds showed only narrow-spectrum bacteriostasis against C.violaceum.Among them,?-hydroxydihrochalcones bearing one bromine substitution in the A-ring?c1-c3?were found to be the most potent with the MICs values of 33.6 ?g/m L against C.violaceum.In this paper,three types of natural product-like were synthesized by aldol condensation and Friedel-Crafts reaction with the raw matetials of 2,4-dihydroxy acetophenone and substituted-benzaldehyde,which enormously rich the compound libraries of triarylmethane,chalcone and ?-hydroxydihydrochalcone.In the aspect of biological activity,the interaction mechanism between butein and xanthine oxidase was studied in detail for the first time,which provided an important reference for the structural optimization in the future.