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Synthesis and Anti-Cancer Activities of Isoflavones Substituted with Fluorine-Containing Groups

Author: JinYe
Tutor: LiHongQi
School: Donghua University
Course: Organic Chemistry
Keywords: isoflavone perfluorobutylsulfonyl synthesis anti-cancer activity HL-60
CLC: R285
Type: Master's thesis
Year: 2007
Downloads: 93
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There has been growing interest to find anti-cancer drugs with high efficiency and low toxicity. Isoflavones have been found extensively in plants and have showed a broad range of pharmacological properties including anti-tumor activity. However, most isoflavonones showed only low anti-cancer activity because they were little or even not absorbed in intestines. The aims of the dissertation inlude design of novel isoflavonoid molecular structures by introduction of fluorine-containg groups that possess strong penetrating ability as well as synthesis and anti-cancer activity study of novel isoflavones substituted with fluorine-containing groups. The dissertation was divided into two parts. PartⅠ: Molecular structure design and synthesis of isoflavones substituted with fluorine-containing groupsIntroduction of hydroxy and methoxy groups into isoflavones can not only increase their solubilities but may also enhance their anti-cancer activities. Therefore we have selected and designed monohydroxy- isoflavones with 1-4 methoxy group(s) (2a and 2d-f), dihydroxyisoflavone (daidzein, 2b), and trihydroxyisoflavone (genistein, 2e) as the parent compounds for research. Considering that short fluorochains can readily penetrate human blood and brain barriers thus can be absorbed by human tissues to take their effect, we choose perfluorobutylsulfonyl and other groups as active groups. By introduction of the active groups into 7-or 4’-hydroxy on the designed parent isoflavones, we design to synthesis a series of isoflavones substituted with fluorine-containing groups, including substituted isoflavone-O-perfluoroalkylsulfonates and substituted isoflavone-O-fluorobenzoates.Five parent hydroxyisoflavones (2a, 2b and 2d-f), two of which (2e and 2f) are new, were synthesized by Vilsmeier-Haack reaction of hydroxydeoxybenzoins which were prepared by’two different mutes. One involves Friedel-Crafts acylation of resorcin with p-hydroxyphenylacetic acid or p-methoxyphenylacetic acid. The other involves Fries transposition of phenyl substituted phenylacetates, which may be synthesized by a five-step sequence starting from hydi’oxybenzaldehydes,Perfluoroalkylsulfonyl fluorides were used as electrophiles to introduce perfluoroalkylsulfonyl groups onto 7- or 4’-OH of three parent isoflavones (2a-e) to give substituted isoflavone-7-O-perfluoroalkylsulfonates or substituted isoflavone’4’-O-perfluoroalkylsulfonates. Six new isoflavones with perfluoroalkylsulfonyl group (3a-f) were synthesized. It was revealed that perfluoroalkylsulfonyl groups only reacted with the 4’-OH of daidzein or genistein to give regioselective products, or reacted with 7-OH of the monohydroxyl isoflavone 2a. This regioselective reaction of multihydroxyisoflavones was found for the first time. In addition, p-fluorobenzoyl was introduced onto 7, or 4’-OH of isoflavones (2a and 2b) to produce two new isoflavones with one or two p-fluorobenzoyl group(s),In the all, thirty-five compounds, nineteen of which are new compounds: including ten new isoflavonoids were synthesized and characterized in this work. The chemical structures of the new compounds were characterized by 1H 13C NMR, MS and IR spectra, and elemental analysis.PartⅡ: Study on anti-cancer activities of isoflavones substituted with fluorine-containing groupsAnti-cancer activities of six substituted isoflavone-O-perfluoroalkyl-sulfonates (3a-f) against the proliferation of human leukemia cell HL-60 and human liver tumor cell BEL-7402 were tested in vitro by Methyl-Thiazol-Tetrozolium (MTT) reduction method and Sulforhodamine B (SRB) albumen coloration method, respectively. The determination results indicated that two of the synthesized isoflavones 3e and 3f, with the perfluorobutylsulfonyl substituent on 4’-O position of isoflavones, displayed strong activity against HL-60 cells. The later (3f) displayed an inhibition ratio of 99.6% against HL-60 cells under a concentration of 10-8 mol/L and also showed weak activity against BEL-7402 cells. Study on structure-activity relationshi’p of substituted isoflavone-O-perfluoroalkylsulfonates (3a-f) against the proliferation of HL-60 indicates that isoflavone-7-O-perfluorobutylsulfonate (3d) is ineffective while isoflavone-4’-O-perfluorobutylsulfonates (3e and 30 are strong inhibitors. Isoflavones containing perfluorooctylsulfonyl (3a-e) have not showed activity towards HL-60. It is concluded that 5-and 7-hydroxy and perfluorobutylsulfonyl groups are active groups in isoflavonoids against HL-60.

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