Synthesis And Antiproliferative Activity Of Phenyl-A Desmosdumotin Canalogues

Cancer is a serious disease to human health. In the past20years, the tumor patientswere younger and the trend of morbidity and mortality was higher in China.According to an estimate from China Cancer Registration Center, China’s newlydiagnosed cancer patients was approximately3.12million cases annually, Average of8550people diagnosed with cancer in one day,6people diagnosed with cancer everyminute, Cancer mortality was180.53/10million, and2.7million cases died due tocancer every year by the data of “2012China Cancer Registration Annual Report”.Recent progress in cancer drug discovery have been impeded due to severe sideeffects, development of resistance to the current drug and limited available chemicalspace, which have fueled high demands for new chemotherapeutic agents with newscaffolds and prompted us to discover new biologically active chemical entities. Inthis continuing study, we have reported the design and synthesis of novel derivativesof Desmosdumotin C as potential antitumor agents.The analogues were designed and synthesized from2,4,6-trihydroxyacetand through a three-step sequence and their structures were identified by1H-NMR,13C-NMR, and HR-ESI-MS spectra. Firstly, Selective methoxylation of7wasaccomplished by using TMSCHN2at-78℃to obtain8in37%yield,2,4,6-trihy-droxyacetophenone reacted with sulfonyl chloride to provide1-(3-chloro-2,4,6-trihydroxyphenyl)ethanone, secondly treated with equivalent ofmethyl iodide in the presence of potassium methoxide give1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)ethanone, then followed by condensation witharomatic aldehydes in30%KOH aqueous solution to obtain the target compounds1-19:(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(2-chlorophenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(2-nitrophenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(3-isopropylphenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(2,3-difluorophenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(2-fluorophenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(3,4-dibromophenyl)prop-2-en-1-one(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(2,5-difluorophenyl)prop-2-en-1-one,(E)-3-(4-bromophenyl)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(3-chlorophenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(3,4-dichlorophenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)prop-2-en-1-one,[(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(pyridin-2-yl)prop-2-en-1-one,[(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(pyridin-3-yl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one,(E)-3-(anthracen-9-yl)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)prop-2-en-1-one,(E)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)-3-(naphthalen-2-yl)prop-2-en-1-one,(E)-3-(5-bromofuran-2-yl)-1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)prop-2-en-1-one.The anti-proliferation evaluation of19compounds using the human acutepromyelocytic leukemia cell line (HL-60), human lung adenocarcinoma cell line (A549), human prostate cancer cell lines (DU-145), human oral epithelial carcinomacell line (KB), human colon cancer cell lines (HCT-8), the human hepatoma cell line(HEPG-2). The activity of three compounds were better than that of Des-C, and theactivities of ten compounds were comparable to that of Des-C. Limited SAR could beconcluded from the results of anti-proliferation of tumor cell: To preserve phenyl of Aring, chloride ion on C-3position makes crucial contribution to the anti-proliferationactivities, and B replaced by a furan ring is good for the increasing activities.