WO2003086414A1 - Structural modification of resveratrol: sodium resverastatin phosphate - Google Patents
Structural modification of resveratrol: sodium resverastatin phosphate Download PDFInfo
- Publication number
- WO2003086414A1 WO2003086414A1 PCT/US2003/011008 US0311008W WO03086414A1 WO 2003086414 A1 WO2003086414 A1 WO 2003086414A1 US 0311008 W US0311008 W US 0311008W WO 03086414 A1 WO03086414 A1 WO 03086414A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- resveratrol
- och
- nmr
- max
- stilbene
- Prior art date
Links
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 title claims abstract description 70
- 229940016667 resveratrol Drugs 0.000 title abstract description 47
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 title abstract description 46
- 235000021283 resveratrol Nutrition 0.000 title abstract description 45
- 229910019142 PO4 Inorganic materials 0.000 title abstract description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title abstract description 7
- 239000010452 phosphate Substances 0.000 title abstract description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title abstract description 5
- 230000004048 modification Effects 0.000 title abstract description 5
- 238000012986 modification Methods 0.000 title abstract description 5
- 229910052708 sodium Inorganic materials 0.000 title abstract description 5
- 239000011734 sodium Substances 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 19
- 201000011510 cancer Diseases 0.000 claims abstract description 16
- 241000124008 Mammalia Species 0.000 claims abstract 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 9
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims 6
- NBEFMISJJNGCIZ-UHFFFAOYSA-N 3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C)=CC(C=O)=C1 NBEFMISJJNGCIZ-UHFFFAOYSA-N 0.000 claims 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 abstract description 24
- 230000015572 biosynthetic process Effects 0.000 abstract description 19
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 229960005537 combretastatin A-4 Drugs 0.000 abstract description 15
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 abstract description 15
- VLEUZFDZJKSGMX-ONEGZZNKSA-N pterostilbene Chemical compound COC1=CC(OC)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 VLEUZFDZJKSGMX-ONEGZZNKSA-N 0.000 abstract description 5
- 230000000845 anti-microbial effect Effects 0.000 abstract description 3
- GDHNBPHYVRHYCC-SNAWJCMRSA-N 1,3-dimethoxy-5-[(e)-2-(4-methoxyphenyl)ethenyl]benzene Chemical compound C1=CC(OC)=CC=C1\C=C\C1=CC(OC)=CC(OC)=C1 GDHNBPHYVRHYCC-SNAWJCMRSA-N 0.000 abstract description 2
- ULMJJZHWFJYIMM-ONEGZZNKSA-N 3-methoxy-5-[(e)-2-(4-methoxyphenyl)ethenyl]phenol Chemical compound C1=CC(OC)=CC=C1\C=C\C1=CC(O)=CC(OC)=C1 ULMJJZHWFJYIMM-ONEGZZNKSA-N 0.000 abstract description 2
- IHVRWFJGOIWMGC-NSCUHMNNSA-N 4-methoxyresveratrol Chemical compound C1=CC(OC)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 IHVRWFJGOIWMGC-NSCUHMNNSA-N 0.000 abstract description 2
- 230000000118 anti-neoplastic effect Effects 0.000 abstract description 2
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 abstract description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 abstract description 2
- ULMJJZHWFJYIMM-UHFFFAOYSA-N (E)-3-hydroxy-4',5-dimethoxystilbene Natural products C1=CC(OC)=CC=C1C=CC1=CC(O)=CC(OC)=C1 ULMJJZHWFJYIMM-UHFFFAOYSA-N 0.000 abstract 1
- GDHNBPHYVRHYCC-PLNGDYQASA-N 1,3-dimethoxy-5-[(z)-2-(4-methoxyphenyl)ethenyl]benzene Chemical compound C1=CC(OC)=CC=C1\C=C/C1=CC(OC)=CC(OC)=C1 GDHNBPHYVRHYCC-PLNGDYQASA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 229910052739 hydrogen Inorganic materials 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 35
- 239000000243 solution Substances 0.000 description 34
- 239000003921 oil Substances 0.000 description 31
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 27
- 229910052799 carbon Inorganic materials 0.000 description 26
- 235000021286 stilbenes Nutrition 0.000 description 23
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical class C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 239000012965 benzophenone Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 102000004243 Tubulin Human genes 0.000 description 12
- 108090000704 Tubulin Proteins 0.000 description 12
- PJANXHGTPQOBST-QXMHVHEDSA-N cis-stilbene Chemical compound C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 description 12
- 239000012230 colorless oil Substances 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 11
- 150000001299 aldehydes Chemical class 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 229960001338 colchicine Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 150000001629 stilbenes Chemical class 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- -1 p- phenylenevinylene Chemical group 0.000 description 9
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical compound COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 7
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 240000006365 Vitis vinifera Species 0.000 description 6
- 235000014787 Vitis vinifera Nutrition 0.000 description 6
- 150000008366 benzophenones Chemical class 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000001472 cytotoxic effect Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 5
- LWYUGNUUEVXQBO-UHFFFAOYSA-N 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]benzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OC1=CC(O[Si](C)(C)C(C)(C)C)=CC(C=O)=C1 LWYUGNUUEVXQBO-UHFFFAOYSA-N 0.000 description 5
- AGLIDWFTVLFVQU-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxy-5-methoxybenzaldehyde Chemical compound COC1=CC(O[Si](C)(C)C(C)(C)C)=CC(C=O)=C1 AGLIDWFTVLFVQU-UHFFFAOYSA-N 0.000 description 5
- PYIXHKGTJKCVBJ-UHFFFAOYSA-N Astraciceran Natural products C1OC2=CC(O)=CC=C2CC1C1=CC(OCO2)=C2C=C1OC PYIXHKGTJKCVBJ-UHFFFAOYSA-N 0.000 description 5
- NDVRQFZUJRMKKP-UHFFFAOYSA-N Betavulgarin Natural products O=C1C=2C(OC)=C3OCOC3=CC=2OC=C1C1=CC=CC=C1O NDVRQFZUJRMKKP-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- IHPVFYLOGNNZLA-UHFFFAOYSA-N Phytoalexin Natural products COC1=CC=CC=C1C1OC(C=C2C(OCO2)=C2OC)=C2C(=O)C1 IHPVFYLOGNNZLA-UHFFFAOYSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 230000005484 gravity Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000280 phytoalexin Substances 0.000 description 5
- 150000001857 phytoalexin derivatives Chemical class 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 4
- VADKRMSMGWJZCF-UHFFFAOYSA-N 2-bromophenol Chemical compound OC1=CC=CC=C1Br VADKRMSMGWJZCF-UHFFFAOYSA-N 0.000 description 4
- DOXSRAMHAZLQFA-UHFFFAOYSA-N 4-[tert-butyl(diphenyl)silyl]oxybenzaldehyde Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)OC1=CC=C(C=O)C=C1 DOXSRAMHAZLQFA-UHFFFAOYSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 240000001341 Reynoutria japonica Species 0.000 description 4
- 235000018167 Reynoutria japonica Nutrition 0.000 description 4
- 229940034982 antineoplastic agent Drugs 0.000 description 4
- 230000002113 chemopreventative effect Effects 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- JMJMXUZILDIHQD-UHFFFAOYSA-M (3,5-dimethoxyphenyl)methyl-triphenylphosphanium;bromide Chemical compound [Br-].COC1=CC(OC)=CC(C[P+](C=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 JMJMXUZILDIHQD-UHFFFAOYSA-M 0.000 description 3
- QJPJQTDYNZXKQF-UHFFFAOYSA-N 4-bromoanisole Chemical compound COC1=CC=C(Br)C=C1 QJPJQTDYNZXKQF-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 241000219094 Vitaceae Species 0.000 description 3
- 235000009754 Vitis X bourquina Nutrition 0.000 description 3
- 235000012333 Vitis X labruscana Nutrition 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 230000000702 anti-platelet effect Effects 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 235000021021 grapes Nutrition 0.000 description 3
- 102000054896 human PML Human genes 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- HSTZMXCBWJGKHG-OUUBHVDSSA-N (2S,3R,4S,5S,6R)-2-[3-hydroxy-5-[2-(4-hydroxyphenyl)ethenyl]phenoxy]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(C=CC=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-OUUBHVDSSA-N 0.000 description 2
- ZICXUWQPVOZNHU-UHFFFAOYSA-N (3,5-dimethoxyphenyl)-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC(OC)=CC(OC)=C1 ZICXUWQPVOZNHU-UHFFFAOYSA-N 0.000 description 2
- HSTZMXCBWJGKHG-UHFFFAOYSA-N (E)-piceid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(C=CC=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-UHFFFAOYSA-N 0.000 description 2
- 0 *c1cc(*)ccc1 Chemical compound *c1cc(*)ccc1 0.000 description 2
- HAQLHRYUDBKTJG-UHFFFAOYSA-N 3,5-dihydroxybenzaldehyde Chemical compound OC1=CC(O)=CC(C=O)=C1 HAQLHRYUDBKTJG-UHFFFAOYSA-N 0.000 description 2
- IMUMNNFSYPVDEW-WAYWQWQTSA-N 5-[(z)-2-(3,4-dimethoxyphenyl)ethenyl]-2,3-dimethoxyphenol Chemical compound C1=C(OC)C(OC)=CC=C1\C=C/C1=CC(O)=C(OC)C(OC)=C1 IMUMNNFSYPVDEW-WAYWQWQTSA-N 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- 235000010777 Arachis hypogaea Nutrition 0.000 description 2
- 241001465180 Botrytis Species 0.000 description 2
- 241000375691 Combretum caffrum Species 0.000 description 2
- 101000921798 Crocosmia x crocosmiiflora Flavonoid 3'-monooxygenase CYP75B137 Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000194032 Enterococcus faecalis Species 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 2
- 101000919381 Oryctolagus cuniculus Cytochrome P450 2C5 Proteins 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 241000219095 Vitis Species 0.000 description 2
- 235000009392 Vitis Nutrition 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000719 anti-leukaemic effect Effects 0.000 description 2
- 230000002927 anti-mitotic effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 235000021028 berry Nutrition 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- NIFZYIXSCTYWKI-UHFFFAOYSA-N bromo-[(4-methoxyphenyl)methyl]-triphenyl-$l^{5}-phosphane Chemical compound C1=CC(OC)=CC=C1CP(Br)(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NIFZYIXSCTYWKI-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000003218 coronary vasodilator agent Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940032049 enterococcus faecalis Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- QVLMUEOXQBUPAH-UHFFFAOYSA-N p-hydroxystilbene Natural products C1=CC(O)=CC=C1C=CC1=CC=CC=C1 QVLMUEOXQBUPAH-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- HSTZMXCBWJGKHG-CUYWLFDKSA-N trans-piceid Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(\C=C\C=2C=CC(O)=CC=2)=C1 HSTZMXCBWJGKHG-CUYWLFDKSA-N 0.000 description 2
- 235000018991 trans-resveratrol Nutrition 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000009369 viticulture Methods 0.000 description 2
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 description 1
- QXRGOOONSJPVAX-UHFFFAOYSA-N (3,5-dihydroxyphenyl)-(4-hydroxyphenyl)methanone Chemical compound C1=CC(O)=CC=C1C(=O)C1=CC(O)=CC(O)=C1 QXRGOOONSJPVAX-UHFFFAOYSA-N 0.000 description 1
- LWVASFVCIHXYAK-UHFFFAOYSA-N (3-hydroxy-5-methoxyphenyl)-(4-hydroxyphenyl)methanone Chemical compound COC1=CC(O)=CC(C(=O)C=2C=CC(O)=CC=2)=C1 LWVASFVCIHXYAK-UHFFFAOYSA-N 0.000 description 1
- BUHLYXRGSCMHTQ-UHFFFAOYSA-N (3-hydroxy-5-methoxyphenyl)-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC(O)=CC(OC)=C1 BUHLYXRGSCMHTQ-UHFFFAOYSA-N 0.000 description 1
- NZRLNLVUUYPAGG-UHFFFAOYSA-N 1,4‐dimethyl‐2H‐pyrido[4,3‐b]indol‐3‐amine Chemical compound C1=CC=C2C3=C(C)NC(N)=C(C)C3=NC2=C1 NZRLNLVUUYPAGG-UHFFFAOYSA-N 0.000 description 1
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 description 1
- YKYWUHHZZRBGMG-JWTNVVGKSA-N 1-methyl-2-[[(1r,5s)-6-[[5-(trifluoromethyl)pyridin-2-yl]methoxymethyl]-3-azabicyclo[3.1.0]hexan-3-yl]methyl]benzimidazole Chemical compound C1([C@@H]2CN(C[C@@H]21)CC=1N(C2=CC=CC=C2N=1)C)COCC1=CC=C(C(F)(F)F)C=N1 YKYWUHHZZRBGMG-JWTNVVGKSA-N 0.000 description 1
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- YTVCXBVFGQEBAL-ARJAWSKDSA-N 2-methoxy-5-[(z)-2-(7-methoxy-1,3-benzodioxol-5-yl)ethenyl]phenol Chemical compound C=1C=2OCOC=2C(OC)=CC=1\C=C/C1=CC=C(OC)C(O)=C1 YTVCXBVFGQEBAL-ARJAWSKDSA-N 0.000 description 1
- XBHJTSIYYWRJFQ-UHFFFAOYSA-N 3-(2-phenylethenyl)phenol Chemical compound OC1=CC=CC(C=CC=2C=CC=CC=2)=C1 XBHJTSIYYWRJFQ-UHFFFAOYSA-N 0.000 description 1
- SVUHJMMOTKIXMR-ISLYRVAYSA-N 3-[(e)-4-(3-hydroxyphenyl)hex-3-en-3-yl]phenol Chemical compound C=1C=CC(O)=CC=1C(/CC)=C(\CC)C1=CC=CC(O)=C1 SVUHJMMOTKIXMR-ISLYRVAYSA-N 0.000 description 1
- RAKWQZBLEYPQHG-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxy-5-hydroxybenzaldehyde Chemical compound CC(C)(C)[Si](C)(C)OC1=CC(O)=CC(C=O)=C1 RAKWQZBLEYPQHG-UHFFFAOYSA-N 0.000 description 1
- INDBEAWZLMFYQL-UHFFFAOYSA-N 4-[(3,5-dimethoxyphenyl)-hydroxymethyl]phenol Chemical compound COC1=CC(OC)=CC(C(O)C=2C=CC(O)=CC=2)=C1 INDBEAWZLMFYQL-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- AZARHELIPHKHED-UHFFFAOYSA-N 5-ethyl-1,2,3-trimethoxybenzene Chemical compound CCC1=CC(OC)=C(OC)C(OC)=C1 AZARHELIPHKHED-UHFFFAOYSA-N 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- LLCGHTBIDOZWAN-ACGXKRRESA-N CC(C1)[C@H]1c1ccc(C=C)cc1 Chemical compound CC(C1)[C@H]1c1ccc(C=C)cc1 LLCGHTBIDOZWAN-ACGXKRRESA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 241001355260 Cissus Species 0.000 description 1
- 235000017003 Cissus Nutrition 0.000 description 1
- 235000017014 Cissus repens Nutrition 0.000 description 1
- 241000221032 Combretaceae Species 0.000 description 1
- 241000407877 Combretum Species 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000941690 Homo sapiens Cytochrome P450 1A1 Proteins 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 241000218657 Picea Species 0.000 description 1
- 235000008124 Picea excelsa Nutrition 0.000 description 1
- HSTZMXCBWJGKHG-CENDIDJXSA-N Piceid Natural products OC[C@@H]1O[C@@H](Oc2cc(O)cc(C=Cc3ccc(O)cc3)c2)[C@H](O)[C@H](O)[C@H]1O HSTZMXCBWJGKHG-CENDIDJXSA-N 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 241000907916 Vatica Species 0.000 description 1
- 241001170572 Veratrum formosanum Species 0.000 description 1
- YRCMMFQIBSEZSU-UHFFFAOYSA-N [3,5-bis[[tert-butyl(dimethyl)silyl]oxy]phenyl]-(4-methoxyphenyl)methanol Chemical compound C1=CC(OC)=CC=C1C(O)C1=CC(O[Si](C)(C)C(C)(C)C)=CC(O[Si](C)(C)C(C)(C)C)=C1 YRCMMFQIBSEZSU-UHFFFAOYSA-N 0.000 description 1
- XFHJEDJFFLSWJR-UHFFFAOYSA-N [3,5-bis[[tert-butyl(dimethyl)silyl]oxy]phenyl]-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC(O[Si](C)(C)C(C)(C)C)=CC(O[Si](C)(C)C(C)(C)C)=C1 XFHJEDJFFLSWJR-UHFFFAOYSA-N 0.000 description 1
- ZWUSDQGVSFYLPW-UHFFFAOYSA-N [3-[tert-butyl(dimethyl)silyl]oxy-4-methoxyphenyl]-(3-methoxyphenyl)methanone Chemical compound COC1=CC=CC(C(=O)C=2C=C(O[Si](C)(C)C(C)(C)C)C(OC)=CC=2)=C1 ZWUSDQGVSFYLPW-UHFFFAOYSA-N 0.000 description 1
- YKVOXTVWPRNYFP-UHFFFAOYSA-N [4-(bromomethyl)phenoxy]-tert-butyl-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)OC1=CC=C(CBr)C=C1 YKVOXTVWPRNYFP-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002790 anti-mutagenic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Substances OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 210000000069 breast epithelial cell Anatomy 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012627 chemopreventive agent Substances 0.000 description 1
- 229940124443 chemopreventive agent Drugs 0.000 description 1
- HRRAOGKGGZFKSW-UHFFFAOYSA-N combretastatin A2 Natural products COc1ccc(C=C/c2cc(O)c3OCOc3c2)cc1OC HRRAOGKGGZFKSW-UHFFFAOYSA-N 0.000 description 1
- 150000004814 combretastatins Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- IHVRWFJGOIWMGC-UHFFFAOYSA-N desoxyrhapontigenin Natural products C1=CC(OC)=CC=C1C=CC1=CC(O)=CC(O)=C1 IHVRWFJGOIWMGC-UHFFFAOYSA-N 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002066 eicosanoids Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000002532 grape seed extract Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 102000052268 human CYP1A1 Human genes 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940111688 monobasic potassium phosphate Drugs 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 description 1
- 150000004714 phosphonium salts Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- VLEUZFDZJKSGMX-UHFFFAOYSA-N pterostilbene Natural products COC1=CC(OC)=CC(C=CC=2C=CC(O)=CC=2)=C1 VLEUZFDZJKSGMX-UHFFFAOYSA-N 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- DXZVZAJBYRSLRX-UHFFFAOYSA-N tert-butyl-[3-[tert-butyl(dimethyl)silyl]oxy-5-[2-(4-methoxyphenyl)ethenyl]phenoxy]-dimethylsilane Chemical compound C1=CC(OC)=CC=C1C=CC1=CC(O[Si](C)(C)C(C)(C)C)=CC(O[Si](C)(C)C(C)(C)C)=C1 DXZVZAJBYRSLRX-UHFFFAOYSA-N 0.000 description 1
- KFZCUPRUJWBWHW-UHFFFAOYSA-N tert-butyl-[3-methoxy-5-[2-(4-methoxyphenyl)ethenyl]phenoxy]-dimethylsilane Chemical compound C1=CC(OC)=CC=C1C=CC1=CC(OC)=CC(O[Si](C)(C)C(C)(C)C)=C1 KFZCUPRUJWBWHW-UHFFFAOYSA-N 0.000 description 1
- PDINJZXKDVUBFQ-UHFFFAOYSA-N tert-butyl-[4-[2-(3,5-dimethoxyphenyl)ethenyl]phenoxy]-dimethylsilane Chemical compound COC1=CC(OC)=CC(C=CC=2C=CC(O[Si](C)(C)C(C)(C)C)=CC=2)=C1 PDINJZXKDVUBFQ-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 235000014101 wine Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
Definitions
- the present invention relates generally to antineoplastic compositions. More particularly this invention relates to derivatives of resveratrol, combretastatin A-4, and methods of synthesis thereof.
- Resveratrol (1) 3,4',5-trihydroxy-t « ⁇ -stilbene, is a phytoalexin found in grapes and certain other plants.
- Orsini, F., et al. Isolation, Synthesis, and Antiplatelet Aggregation of Resveratrol 3-O- ⁇ -D-glucopyranoside and Related Compounds, J. Nat. Prod. 1997, 60, 1082- 1087; Siemann, E. H., et al., Concentration of the Phytoalexin Resveratrol in Wine, Amer. J. of Enology and Viticulture 1992, 43, 49-52; Goldberg, D., et al., A Global Survey of Trans- resveratrol Concentrations in Commercial Wines, Clin.
- the compound exhibits a variety of useful biological properties including antileukemic, antibacterial, antifungal, antiplatelet aggregation, and coronary vasodilator activities.
- useful biological properties including antileukemic, antibacterial, antifungal, antiplatelet aggregation, and coronary vasodilator activities.
- This triphenolic stilbene (1) also has strong antioxidative and anti-inflammatory activities associated with chemopreventive properties. (Pattichis, K., et al., Inhibition of Human LDL Oxidation by Resveratrol, Lancet 1993, 1103-1108; Goldberg, D., More on Antioxidant Activity of Resveratrol in Red Wine, Clin. Chem.
- Resveratrol (1) has been suggested as a possible cancer chemopreventive agent based on inhibitory effects on tumor initiation, promotion, and progression. (Jang, M., et al., Cancer
- resveratrol (1) has displayed cancer cell growth inhibition in vitro.
- Choanvitayapongs, S., et al. Amelioration of Oxidative Stress by Antioxidants and Resveratrol in PC12 cells, NeuroReport 1997, 8, 1499-1502; Mgbonyebi, O., et al., Antiproliferative Effect of Synthetic Resveratrol on Human Breast Epithelial Cells, Int. J. Oncol.
- resveratrol (1) has recently been shown to induce apoptosis and decrease expression of Bcl-2 in the human leukemia HL-60 cell line.
- Resveratrol an Antioxidant Present in Red Wine, Induces Apoptosis in Human Promyelocytic Leukemia (HL-60) cells, Cancer Lett.
- resveratrol Tetramers from Vatica Diospyoides. J. Org. Chem. 1999, 64, 6976-6983; Ohyama, M., et al., Antitumor Agents 200. Cytotoxicity of Naturally Occurring Resveratrol Oligomers and their Acetate Derivatives, Bioorg. Med. Chem. Lett. 1999, 9, 3057-3060.
- Other biological properties of resveratrol (1) include activities targeting cyclooxygenase, tyrosine kinase (PTK), and protein kinase C (PKC), as well as selective human cytochrome P450 1 Al
- Resveratrol is a Selective Human Cytochrome P450 1 Al Inhibitor, Biochem. Biophys. Res. 1999, 262, 20-24; Cichewicz R. H., et al., Biotransformation of resveratrol to piceid by Bacillus cereus, J. Nat. Prod. 1998, 61, 1313-1314.
- the prime object of the present invention was to discover pharmaceutically active derivatives of resveratrol.
- Another object of the present invention was to discover pharmaceutically active derivatives of combretastatin A-4.
- a starting material in stilbene synthesis is 4-methoxybenzyltriphenylphosphonium bromide (3) that was obtained as follows: To a solution of 4-methoxybenzyl bromide (22.4 g) in toluene (200 ml) was added triphenylphosphine (29.2 g). The solution was heated at reflux for 12 hours under argon. The resulting precipitate was collected and recrystallized from ethanol as colorless crystals (44.0 g, 85.3%) mp 235-237°C, (lit 19 mp 234°C).
- the oil was separated by flash column chromatography (49:1 hexane:ethyl acetate).
- Resveratrol (1) was obtained from a stilbene in the following manner. To stilbene 4b (3.1 g) in anhydrous dichloromethane (150 ml) at -78°C was added (dropwise) boron tribromide (1.0 M, 34.5 ml), and the resulting red solution was stined under argon for 30 minutes. The solution was poured into water and extracted with dichloromethane.
- the compound 4-(tert-butyldiphenylsilyloxy)-benzaldehyde (5a) was obtained in the following manner. To a solution of 4-hydroxybenzaldehyde (3.2 g) in dimethylformamide (50 ml) was added imidazole (1.9 g, 1.1 equiv.). The solution was stined for 15 minutes, tert- butyldiphenylsilyl chloride (7.4 ml, 1.1 equiv.) was added, and the light brown solution was stined for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Removal of the solvent in vacuo from the organic phase provided a brown oil. The oil was
- the compound 4-(tert-butyldiphenylsilyloxy)-benzyl alcohol (6) was obtained in the following manner. To a solution of aldehyde 5a (4.7 g) in methanol (100 ml) at 0°C was slowly added sodium borohydride (0.59 g, 1.2 eq.). After stirring for 2 hours the reaction mixture was
- the compound 4-(tert-butyldiphenylsilyloxy)-benzyltriphenylphosphonium bromide (8) was obtained in the following manner. To a solution of bromide (7) (4.3 g) in toluene (100 ml) was added triphenylphosphine (13.2 g).
- the compound 3,5-di(tert-butyldimethylsilyloxy)-benzaldehyde (9a) was obtained in the following manner.
- DIEA (7.7 ml, 2 equiv.) was added to a solution of 3,5- dihydroxybenzaldehyde (3.0 g) in dimethylformamide (30 ml), and the solution was stined for 15 minutes.
- the silyl chloride (7.5g) was added and the light brown solution stined for 16 hours. The mixture was poured into water and extracted with dichloromethane.
- the compound identified as cw-Resveratrol (10) was obtained as follows: the Wittig reaction was performed as summarized above using 5 mmol of phosphonium salt, and the TBDPS-protected stilbene isomers were isolated as a mixture. The mixture was dissolved in tetrahydrofuran and treated with TBAF (3.0 eq), being stined for 1 hour. The product was purified by gravity column chromatography (3:2 hexane:ethyl acetate) and yielded 0.21 g of the cw-isomer as a colorless solid and 0.24 g of a mixture of isomers (95.1%): mp 172-174°C (lit 12c mp 170-174°C).
- Hunig's base (10.2 ml, 2 eq) was added to a solution of 4-hydroxybenzaldehyde (6.0 g) in dimethylformamide (50 ml) to obtain 4-(tert)-butyldimethylsilyloxy-benzaldehyde (5b).
- the solution was stined for 15 minutes, tert-butyldimethylsilyl chloride (8.9 g) was added, and the clear light brown solution was stined for 15 hours.
- the reaction mixture was poured into water,
- the mixture was stined at -10°C for 30 minutes under argon, dibenzylphosphite (5.0 ml, 1.5 equiv.) was added, .and the solution was stined for 12 hours and then poured into 0.5 M monobasic potassium phosphate. The mixture was extracted with ethyl acetate and removal of solvent in vacuo from the organic phase yielded a tan oil.
- bromophenol (4.15 g) was dissolved in anhydrous dichloromethane (40 ml), then imidazole (1.63 g) and tert-butyldimethylsilyl chloride (3.61 g) were added.
- the cream suspension was stined under argon for 12 hours and the reaction was terminated with addition of water.
- the mixture was extracted with ethyl acetate.
- Alcohol 15b (0.12g) was deprotected with TBAF as for the stilbenes above to provide 4'- Hydroxy-3,5-dimethoxybenzhydrol 15c as a colorless oil (0.03 g, 42%): EIMS m/z 260 (M + ),
- Alcohol 15b (0.58 g) led to 4'-(ter/-butyldimethylsilyloxy)-3,5-dimethoxybenzophenone 16b as a colorless oil (0.46 g, 80%): EIMS m/z 372 (M + ), 315, 165, 157, 137, 28; IR (KBr, cm "1 )
- Alcohol 15d (0.72 g) provided 3,5-di-(tert-butyldimethylsilyloxy)-4'- methoxybenzophenone 16d as a colorless oil (0.64 g, 90%): EIMS m/z 472 (M + ), 457, 415, 359,
- the cytotoxicity data from the resveratrol stilbenes was determined.
- the c ⁇ s-isomer of resveratrol (lb) exhibited slightly less inhibitory effects on the cancer cell lines tested than did the tranj-isomer.
- the trimethoxy stilbenes 4a,b are between 10-100 fold more active against tumor cell lines than the parent compound resveratrol (1), with compound 4a (the ⁇ ' s-stilbene) far more active than 4b.
- the synthesized prodrug 14n was essentially identical to 14c in its effects on the growth of cancer cells. From the known antimitotic activity of combretastatin A-4 (2a) and phenstatin (2c) and their potent interactions with tubulin, it seemed possible that the most cytotoxic compounds prepared in the cunent series would also inhibit this important cellular protein.
- Combretastatin A-4 (2a) binds in the colchicine site of tubulin and is exceptionally potent as an inhibitor of the binding of radiolabeled colchicine to tubulin.
- Combretastatin A-4 (2a) displayed its usual potency, inhibiting colchicine binding by 98% when the two drugs were present in equimolar (5 ⁇ M) concentrations and by 91% when 2a was present at 2 ⁇ M (the tubulin
- Resveratrol (1) contained in the roots of Polygonum cuspidatum has apparently been used in Chinese and Japanese traditional medicine as a treatment for gononhea.
- its activity against the etiologic agent of gononhea, Neisseria gonorrhoeae was demonstrated in broth microdilution assays (Table IV).
- Stilbene production has been conelated with the resistance of grape leaves to fungal infection.
- the tubulin polymerization assay was performed as previously described. 24 The tubulin concentration was 10 ⁇ M, with varying drug concentrations, as required, to obtain IC 5 o values. Extent of assembly after 20 min at 30°C was the parameter measured. The colchicine binding assay was performed as earlier reported. 27 The tubulin concentration was 1.0 ⁇ M, the [3H] colchicine concentration was 5.0 ⁇ M, and the potential inhibitor concentrations were as indicated. Binding of colchicine was measured following a 10 min incubation at 37°C.
- Microorganism 1 4a 14c 14h 14k 14u 15c 16a 16c 16e I6g 16! 16k
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Described herein are novel compounds having antineoplastic and antimicrobial activity, obtained via structural modifications of resveratrol and combretastatin A-4, methods for synthesis of these compounds, and their use in pharmaceutical composition and for use in the treatment of mammals having cancer. Examples of the novel compounds are: (Z)- and (E)- 3,4',5-trimethoxystilbene (4a, 4b); (Z)- and (E)-3,5-dimethoxy-4'-hydroxystilbene (14c, 14d); (Z)-and (E)-3-hydroxy-4',5-dimethoxystilbene (14g, 14h); (Z)-and (E)-3,5-dihydroxy-4'-methoxy-stilbene (14k, 14l); sodium resverastatin dibenzyl phosphate ((Z)-3,5-dimethoxy-4-[O-bis(benzyl)phosphoryl]-stilbene) (14m); and sodium resverastatin phosphate (14n).
Description
TITLE OF THE INVENTION Structural Modification of Resveratrol: Sodium Resverastatin Phosphate RELATED APPLICATION DATA This application is based on and claims the benefit of U.S. Provisional Patent Application No. 60/371,782 filed on April 10, 2002.
GOVERNMENT INTEREST Financial assistance for this invention was provided by the United States Government, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Department of Health
and Human Services Outstanding Investigator Grant Numbers CA44344-05-12 and RO1 CA90441-01. Thus, the United States Government has certain rights in this invention.
FIELD OF THE INVENTION The present invention relates generally to antineoplastic compositions. More particularly this invention relates to derivatives of resveratrol, combretastatin A-4, and methods of synthesis thereof.
BACKGROUND OF THE INVENTION The antitumor properties of a series of structurally simple compounds derived from tropical and subtropical trees of the family Combretaceae are under ongoing investigation. The genus Combretum contains 25 species used in the traditional medical practices of Africa and India. The South African bush willow Combretum caffrum was used by the Zulu and other Southern African people as a charm to ward off enemies and in traditional medical practices.
Combretum caffrum (Eckl. Zehy.) Kuntze collected in 1973 and recollected in 1979 afforded extracts that showed activity in the astrocyte reversal (9 ASK) and murine lymphocytic leukemia screening assays of the National Cancer Institute of the U.S.A. Historically, this
1398874.1/12504.012 9
extract was the first to be successfully fractionated by means of the 9ASK system. In 1982 the isolation of the first member of the combretastatin series was disclosed. Also disclosed was its structure and later synthesis. (Pettit, G. R., et al., Isolation and Structure of Combretastatin, CAn. J. Chem. 1982, 60, 1374-1376; Pettit, G. R., et al., Synthesis of Natural (-) - combretastatin, J. Org. Chem. 1985, 50, 3404-3406.) Subsequently, a number of additional cancer cell line active constituents were isolated. These investigations eventually led to applicant's isolation, structure and synthesis of the -stilbene combretastatin A-4 (2a) and its phosphate prodrug (2b). (Pettit, G.R., et al., Isolation and Structure of the Strong Cell Growth and Tubulin Inhibitor Combretastatin A-4, Experentia, 1989, 45, 209-211; Pettit, G. R, et al., Antineoplastic agents 291. Isolation and Synthesis of Combretastatin A-4, A-5, and A-6, J. Med. Chem. 1995, 38, 1666-1672; Ndayikcngu kiyc, II., ct al., Alkoxylalcd p- phenylenevinylene Oligomers: Synthesis and Spectroscopic and Electrochemical Properties, Tetrahedron 1997, 53, 13811-13828.) The latter has been shown to selectively damage tumor neovasculature with induction of extensive blood flow shutdown in the metastatic tumor compared to normal tissues.
For example, six hours following treatment using the murine CaNT adenocarcinoma and a single i.p. injection of combretastatin A-4 prodrug (100 mg/kg), vascular function shutdown in the tumor was rapid, ineversible and extensive (8). (Ndayikengurukiye, H., et al., Alkoxylated p-phenylenevinylene Oligomers: Synthesis and Spectroscopic and Electrochemical Properties. Tetrahedron 1997, 53, 13811-13828.) In November, 1998 four Phase I human cancer trials were initiated, two in the United States and two in England. Cunent clinical trials (9) have been encouraging and Phase II human cancer clinical trials have been or will be initiated soon. (Cushman, M., et al., Synthesis and Evaluation of Analogues of (Z) - 1 - (4-methoxyphenyl) -2-
1398874.1/12504.012 7
(3, 4, 5-trimethoxyphenyl) ethane as Potential Cytotoxic and Antimitotic Agents, J. Med. Chem- 1992, 35, 2293-2306.)
The need for such compounds is both critical and ongoing. The isolation of such valuable compounds is the purpose of the present invention.
BRIEF SUMMARY OF THE INVENTION
Resveratrol (1), 3,4',5-trihydroxy-t «^-stilbene, is a phytoalexin found in grapes and certain other plants. (Orsini, F., et al., Isolation, Synthesis, and Antiplatelet Aggregation of Resveratrol 3-O-β-D-glucopyranoside and Related Compounds, J. Nat. Prod. 1997, 60, 1082- 1087; Siemann, E. H., et al., Concentration of the Phytoalexin Resveratrol in Wine, Amer. J. of Enology and Viticulture 1992, 43, 49-52; Goldberg, D., et al., A Global Survey of Trans- resveratrol Concentrations in Commercial Wines, Clin. Chem. 1995, 46, 159-1665; Adesanya, S.A., et al., Stilbene Derivatives from Cissus quandrangularis. J. Nat. Prod. 1999, 62, 1694- 1695; Arichi, H., et al., Effects of Stilbene Components of the Root of Polygonum cuspidatum Sieb. Et Zucc. On Lipid Metabolism, Chem. andPharm. Bull. 1982, 30, 1766-1770; Ingham, J., 3,5,4' - trihydroxystilbene as a Phytoalexin from Groundnuts (Arachis hypogaea). Phytochem. 1976, 15, 1791-T793.)
The compound exhibits a variety of useful biological properties including antileukemic, antibacterial, antifungal, antiplatelet aggregation, and coronary vasodilator activities. (Jeandet, P., et al., The Production of Resveratrol by Grape Berries in Different Developmental Stages, Am J. ofEnology and Viticulture 1991, 42, 41-46; Manila, E., et al., Anti-leukaemic compounds Derived from Stilbenes in Picea abies Bark, Phytochem. 1993, 33, 813-816; Kubo, M., et al., Shoyayugaku Zasshi 1981, 35, 58; Creasy, L., et al., Phytoalexin Production Potential of Grape Berries, J. of the Am. Soc. of Horticultural Science 1988, 113, 230-234; Langcake, C, et al.,
1398874.1/12504.012
Identification of Pterostilbene as a Phytoalexin from Vitis vinifera Leaves, Phytochemistry 1979, 18, 1025-1027; Langcake, R., et al., The Relationship of Resveratrol Production to Infection of Grapevine Leaves by Botrytis cenerea, Vitis 1979 18:244-253; Chung, M., et al., An Antiplatelet Principle of Veratrum formosanum, Planta Medica 1992, 58, 274-276; Inamori, Y., et al., The Ichthyotoxicity and Coronary Vasodilator Action of 3,3' - dihydroxy-α, β- diethylstilbene, Chem. Pharm. Bull. 1987, 35, 887-890.) This triphenolic stilbene (1) also has strong antioxidative and anti-inflammatory activities associated with chemopreventive properties. (Pattichis, K., et al., Inhibition of Human LDL Oxidation by Resveratrol, Lancet 1993, 1103-1108; Goldberg, D., More on Antioxidant Activity of Resveratrol in Red Wine, Clin. Chem. 1996, 42, 113-114; Pace-Asciak, C, et al., The Red Wine Phenolics Trans-resveratrol and Quercetin Block Human Platelet-Aggregation and Eicosanoid Synthesis-implications for Protection Against Coronary Heart-Disease, Clinical Chemica Acta 1995, 235, 207=219.) Resveratrol (1) has been suggested as a possible cancer chemopreventive agent based on inhibitory effects on tumor initiation, promotion, and progression. (Jang, M., et al., Cancer
Chemopreventive Activity of Resveratrol. A natural product Derived from Grapes, Science 1997, 275, 218-220; Uenobe, F., Antimutagenic Effects of Resveratrol Against Trp-P-1, Mutation Res. 1997, 373, 197-200.)
In addition to antitumor promoting activity, resveratrol (1) has displayed cancer cell growth inhibition in vitro. (Chanvitayapongs, S., et al., Amelioration of Oxidative Stress by Antioxidants and Resveratrol in PC12 cells, NeuroReport 1997, 8, 1499-1502; Mgbonyebi, O., et al., Antiproliferative Effect of Synthetic Resveratrol on Human Breast Epithelial Cells, Int. J. Oncol. 1998, 12, 865-869; Jayatilake, G., et al., Kinase Inhibition From polygonum cuspidatum 1993, 56, 1805-1810; Chun, Y., et al., Resveratrol is a Selective Human Cytochrome P450 1A1
1398874.1/12504.012 *s
inhibitor, Biochem. Biophys. Res. 1999, 262, 20-24.) Importantly, resveratrol (1) has recently been shown to induce apoptosis and decrease expression of Bcl-2 in the human leukemia HL-60 cell line. (Surh, Y. J., et al., Resveratrol, an Antioxidant Present in Red Wine, Induces Apoptosis in Human Promyelocytic Leukemia (HL-60) cells, Cancer Lett. 1999, 140, 1-10.) Furthermore, the resveratrol tetramers vatdiospyridol and resveratrol oligomers recently isolated from Asian plants have shown significant inhibition of the growth of several cancer cell lines. (Seo, H., et
al., Resveratrol Tetramers from Vatica Diospyoides. J. Org. Chem. 1999, 64, 6976-6983; Ohyama, M., et al., Antitumor Agents 200. Cytotoxicity of Naturally Occurring Resveratrol Oligomers and their Acetate Derivatives, Bioorg. Med. Chem. Lett. 1999, 9, 3057-3060.) Other biological properties of resveratrol (1) include activities targeting cyclooxygenase, tyrosine kinase (PTK), and protein kinase C (PKC), as well as selective human cytochrome P450 1 Al
inhibition and microbiological transformation to resveratrol 3-O-β-D-glucoside. (Jang, M., et al.,
Cancer Chemopreventive Activity of Resveratrol. A Natural Product Derived from Grapes, Science 1997, 275, 218-220; Jayatilake, G., et al., Kinase Inhibition from Polygonum cuspidatum, J. Nat. Prod. 1993, 56, 1805-1810; Chun, Y., et al., Resveratrol is a Selective Human Cytochrome P450 1 Al Inhibitor, Biochem. Biophys. Res. 1999, 262, 20-24; Cichewicz R. H., et al., Biotransformation of resveratrol to piceid by Bacillus cereus, J. Nat. Prod. 1998, 61, 1313-1314.)
The compounds in question were isolated/synthesized in the manner generally described below. These compounds were discovered to have the properties noted.
Accordingly the prime object of the present invention was to discover pharmaceutically active derivatives of resveratrol.
1398874.1/12504.012
Another object of the present invention was to discover pharmaceutically active derivatives of combretastatin A-4.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds discovered were obtained in the following manner, using the following lexicon that should be familiar to one of ordinary skill in the art.
All solvents were redistilled. Hunig's base and proton sponge refer respectively to N,N,- diisopropylcthylaminc and l,8-b-_.-(dimethylamino)-naphthalcnc. Both the course and products from reactions were monitored by thin-layer chromatography using Analtech silica gel GHLF uniplates. All reactions were carried out under an inert atmosphere. Solvent extracts of aqueous solutions were dried over anhydrous sodium sulfate unless otherwise noted. Flash column chromatography was performed using silica gel (230-400 mesh ASTM).
Melting points were recorded employing an Electrothermal 9100 digital melting point apparatus and are unconected. The IR spectra were obtained using a Mattson FTIR model 2020 instrument. Low-resolution mass spectral data were collected using a Varian MAT 312 instrument (EIMS). The high-resolution FAB spectra were obtained employing a Kratos MS-50 spectrometer. All H and C-ΝMR spectra were determined using a Varian Gemini 300 MHz instrument with CDC13 (TMS internal reference) as solvent unless otherwise noted. The 31P- ΝMR spectra were measured in CDC13 with 85% H3PO4 as an external standard employing a Varian Unity 500 MHz instrument.
1398874.1/12504.012
The following schemes and structural formulae of identified compounds, set forth at the end of this application, were used. Where practical general procedures for certain classes of compounds are also set forth below.
A starting material in stilbene synthesis is 4-methoxybenzyltriphenylphosphonium bromide (3) that was obtained as follows: To a solution of 4-methoxybenzyl bromide (22.4 g) in toluene (200 ml) was added triphenylphosphine (29.2 g). The solution was heated at reflux for 12 hours under argon. The resulting precipitate was collected and recrystallized from ethanol as colorless crystals (44.0 g, 85.3%) mp 235-237°C, (lit19 mp 234°C).
The general procedure for the stilbene syntheses was as follows. To the phosphonium bromide (1-35 mmol) in anhydrous tetrahydrofuran (5-200 ml) at -78°C was added w-butyl lithium (2.44 M, 1.0 equiv.), and the resulting red solution was stined under argon for 2-4 hours. A solution of the aldehyde (1.0 equiv.) in tetrahydrofuran was added dropwise over 30 minutes and the mixture stined for 6-15 hours. The resulting cream suspension was poured into water and extracted with dichloromethane. The organic phase was washed with water and removal of the solvent in vacuo afforded a tan oil. The oil was separated by flash column chromatography (49:1 hexane:ethyl acetate). The cis stilbene eluted first as a clear oil followed by the trans isomer as a colorless sold or oil (TBDMS protected).
By following the above general procedure, 3,4',5-trimethoxystilbene (4a,b) was obtained in the following manner. Reaction of phosphonium bromide (12.5 g) (3) and 3,5- dimethoxybenzaldehyde (4.5 g) led to cis stilbene (4a) as a clear oil (3.56 g) and the trans isomer (4b) as a colorless sold (3.08 g), 91% total yield: (Z) isomer (4a) IR neat, cm"1 vmax 3449, 2957,
2836, 1591, 1250, 1065, 640; 1H-NMR δ 6.22 (2H, dd, J= 2.4, 8.7 Hz), 6.77 (2H, dd, J= 2.4, 8.7 Hz), 6.53 (1H, d, J= 12.0 Hz), 6.45 (1H, d, J= 12.0 Hz), 6.44 (2H, d, J= 2.1 Hz), 6.32 (1H,
1398874.1/12504.012
t, J= 2.1 Hz), 3.78 (3H, s, OCH3), 3.67 (6H, s, OCH3 x 2); (E) isomer (4b) mp 57-58°C, (lit20 mp 55-56°C).
Resveratrol (1) was obtained from a stilbene in the following manner. To stilbene 4b (3.1 g) in anhydrous dichloromethane (150 ml) at -78°C was added (dropwise) boron tribromide (1.0 M, 34.5 ml), and the resulting red solution was stined under argon for 30 minutes. The solution was poured into water and extracted with dichloromethane. The organic phase was washed with water and removal of the solvent in vacuo afforded a tan oil, which was separated by flash column chromatography (l:l/hexane: ethyl acetate) to afford a colorless sold (2.26 g, 86%): mp 260°C (lit12c mp 260°C).
The compound 4-(tert-butyldiphenylsilyloxy)-benzaldehyde (5a) was obtained in the following manner. To a solution of 4-hydroxybenzaldehyde (3.2 g) in dimethylformamide (50 ml) was added imidazole (1.9 g, 1.1 equiv.). The solution was stined for 15 minutes, tert- butyldiphenylsilyl chloride (7.4 ml, 1.1 equiv.) was added, and the light brown solution was stined for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Removal of the solvent in vacuo from the organic phase provided a brown oil. The oil was
separated by flash column chromatography (1:0 — 19:1 hexane:ethyl acetate) to afford the aldehyde (5a) as a colorless solid (6.4 g, 68%):mp 103-105°C IR (neat, cm"1) vmax 3399, 2932,
2859, 1699, 1599, 1506, 1273, 1157, 910; 1H-NMR δ 9.80 (1H, s, CHO), 7.69 (4H, m, Ar-H),
7.64 (2H, d, J= 8.7 Hz), 7.40 (6H, m, Ar-H), 6.86 (2H, d, J=8.7 Hz), 1,11 (9Hm sm C(CH3)3), Anal. (C23H24O2Si) C, H.
The compound 4-(tert-butyldiphenylsilyloxy)-benzyl alcohol (6) was obtained in the following manner. To a solution of aldehyde 5a (4.7 g) in methanol (100 ml) at 0°C was slowly added sodium borohydride (0.59 g, 1.2 eq.). After stirring for 2 hours the reaction mixture was
1398874.1/12504.012
poured into water, solvent reduced to a minimum, extracted with ethyl acetate and the solvent
removed in vacuo to give 4.1 g of a clear oil (88%); IR (neat, cm"1) vmax 3346, 2932, 2859, 1609,
1510, 1427, 1256, 1113, 918; 1H-NMR δ 7.72 (4H, m, Ar-H), 7.39 (6H, m, Ar-H), 7.10 (2H, d, J = 8.7 Hz), 6.76 (2H, d, J= 8.7 Hz), 4.55 (2H, s, CH2), 1.11 (9H, s, C(CH3)3). Anal.
(C23H26O2Si) C, H.
The following procedure was used to obtain 4-(tert-butyldiphenylsilyloxy)-benzyl bromide (7). Phosphorus tribromide (0.5 ml) was slowly added to a solution of the alcohol 6 (4.0 g) in dichloromethane (75 ml) at 0°C, and stirring was continued for 12 hours. The reaction
mixture was poured into aqueous sodium bicarbonate, extracted with dichloromethane and the
solvent removed in vacuo to afford 4.3 g of a colorless solid (89%): EIMS m/z 426 (M+, 81Br),
424 (M+ 79Br), 390, 369, 367, 345, 289, 135: IR (neat.cm"1) vmax 3397, 3073, 2932, 2859, 1607,
1510, 1427, 1263, 1113, 918; ]H-NMR δ 7.72 (4H, m, Ar-H), 7.39 (6H, m, Ar-H), 7.13 (2H, d, J
= 8.4 Hz) 6.72 (2H, d, J= 8.4 Hz), 4.42 (2H, s, CH2), 1.11 (9H, s, C(CH3)3). 13C-NMR (75.5
MHz) δ 155.6, 135.4, 132.4, 130.1, 129.9, 127.7, 119.9, 34.0, 26.5, 19.5. Anal. (C23H25BrOSi) C, H.
The compound 4-(tert-butyldiphenylsilyloxy)-benzyltriphenylphosphonium bromide (8) was obtained in the following manner. To a solution of bromide (7) (4.3 g) in toluene (100 ml) was added triphenylphosphine (13.2 g). After heating at 100°C for 2 hours, the reaction mixture was cooled to room temperature, and the product was collected and recrystallized from ethanol to yield 6.1 g of a colorless solid (89%) mp 233°C; FABMS m/z 607.2583 (M+-Br), IR (neat, cm"1) vmax 3385, 3054, 2934, 2859, 2787, 1607, 1512, 1437, 1273, 1111, 924; 1H-NMR δ 7.61
(19H, m, Ar-H), 7.30 (6H, m, Ar-H), 6.76 (2H, dd, J= 2.4, 8.7 Hz) 6.51 (2H, d, J= 8.7 Hz), 5.18
(2H, s, CH2), 1.04 (9H, s, C(CH3)3). 13C-NMR (75.5 MHz) δ 155.7, 135.3, 134.7, 134.7, 134.3,
1398874.1/12504.012 J Q
132.3, 132.3, 130.0, 129.8, 127.6, 120.2, 120.1, 118.9, 118.9, 118.1, 117.3, 30.5, 30.1, 26.5, 19.4.
Anal. (C4ιH40BrOSi) C, H.
The compound 3,5-di(tert-butyldimethylsilyloxy)-benzaldehyde (9a) was obtained in the following manner. DIEA (7.7 ml, 2 equiv.) was added to a solution of 3,5- dihydroxybenzaldehyde (3.0 g) in dimethylformamide (30 ml), and the solution was stined for 15 minutes. The silyl chloride (7.5g) was added and the light brown solution stined for 16 hours. The mixture was poured into water and extracted with dichloromethane. Removal of the solvent in vacuo yielded a brown oil that was separated by flash column chromatography (9:1 hexane:ethyl acetate) to yield the disilylether as a tan oil (7.6 g, 94%): EIMS m/z 366 (M+), 309,
267, 239, 133,73; IR (KBr, cm"1) vmax 2957, 2861, 2805, 2710, 1705, 1385, 831; 1H-NMR δ 9.85
(1H, s, CHO), 6.95 (2H, d, J= 2.1 Hz), 6.58 (1H, t, J= 2.1 Hz), 0.99 (18H, s, C(CH3)3 x 2), 0.22 (12H, s, Si(CH3)2 x 2).
The compound identified as cw-Resveratrol (10) was obtained as follows: the Wittig reaction was performed as summarized above using 5 mmol of phosphonium salt, and the TBDPS-protected stilbene isomers were isolated as a mixture. The mixture was dissolved in tetrahydrofuran and treated with TBAF (3.0 eq), being stined for 1 hour. The product was purified by gravity column chromatography (3:2 hexane:ethyl acetate) and yielded 0.21 g of the cw-isomer as a colorless solid and 0.24 g of a mixture of isomers (95.1%): mp 172-174°C (lit12c mp 170-174°C).
Hunig's base (10.2 ml, 2 eq) was added to a solution of 4-hydroxybenzaldehyde (6.0 g) in dimethylformamide (50 ml) to obtain 4-(tert)-butyldimethylsilyloxy-benzaldehyde (5b). The solution was stined for 15 minutes, tert-butyldimethylsilyl chloride (8.9 g) was added, and the clear light brown solution was stined for 15 hours. The reaction mixture was poured into water,
1398874.1/12504.012 \ \
extracted with dichloromethane and the solvent removed in vacuo to afford a brown oil. The oil was separated by vacuum distillation to yield aldehyde 5b as a colorless oil (8.4 g, 73%): IR
(neat, cm"1) vmax 3385, 2932, 2859, 1699, 1599, 1508, 1273, 1155, 909; 1H-NMR δ 9.88 (IH, s,
CHO), 7.79 (2H, d, J= 8.4 Hz), 6.94 (2H, d, J= 8.4 Hz), 0.98 (9H, s, C(CH3)3), 0.25 (6H, s, Si(CH3)2). Anal. (C,3H20O2Si) C, H.
To obtain 3,5-dimethoxybenzyltriphenylphosphonium bromide (13) 3,5 - dimethoxybenzaldehyde (10 g) in methanol was reduced with sodium borohydride, the oily product 11, (9.6 g, 93% yield) was treated (0°, 12 hours) with phosphorous tribromide (2.7 ml), and to its resulting bromide 12 (11.6 g, 89%) in toluene (200 ml) was added triphenylphosphine (13.2 g). After heating at reflux for 12 hours the mixture was cooled to room temperature. The product was collected and recrystallized from ethanol to yield 22.8 g of a colorless solid (92%)
mp 275°C, lit12c mp 266-268°C; Η-NMR δ 7.70 (15H, m), 6.33 (2H, d, J= 2.1 Hz), 6.30 (IH, t,
J= 2.1 Hz), 5.30 (2H, d, J= 14.4 Hz), 3.53 (6H, s, OCH3 x 2).
To obtain 4'-(tert-butyldimethylsilyloxy)-3,5-dimethoxy-stilbene (14a,b), phosphonium bromide 13 (6.9 g) in anhydrous tetrahydrofuran (40 ml) at 78°C was treated with «-butyl lithium 2.5 M, 5.6 ml) and aldehyde 5b (3.3 g) in tetrahydrofuran (10 ml) according to the general Wittig-stilbene procedure (see above). (Z)-isomer (14a): EIMS m/z 370 (M+), 355, 313,
298,157; IR (KBr, cm"1) vmax 2932, 2857, 1591, 1508, 1262, 1155, 914; 1H-NMR δ 7.14 (2H, d,
J= 8.5 Hz), 6.70 (2H, d, J= 8.5 Hz), 6.51 (IH, d, J= 12.0 Hz), 6.43 (IH, d, J= 12.0 Hz), 6.42 (2H, d, J= 2.0 Hz), 6.31 (1 H, t, J= 2.0 Hz), 3.65 (6H, s, OCH3 x 2), 0.96 (9H, s, C(CH3)3), 0.17
(6H, s Si(CH3)2); 13C-NMR (75.5 MHz) δ 160.51, 154.87, 139.40, 130.27, 130.21, 128.76,
119.77, 106.57, 99.81, 55.17, 25.65, 18.22, -4.45. Anal. (C22H30O3Si) C,H. (E) isomer (14b): EIMS m/z 370 M+), 355, 313, 255 165 73; IR (KBr, cm"1) vmax 2955, 2859, 1595, 1508, 1263,
1398874,1/12504.012 12
1154, 914, 839; 1H-NMR δ 7.40 (2H, d, J= 8.5 Hz). 7.05 (IH, d, J= 16.0 Hz), 6.92 (IH, d, J= 16.0 Hz), 6.85 (2H, d, J= 8.5 Hz), 6.66 (2H, d, J= 2.5 Hz), 6.39 (IH, t, J= 2.5 Hz), 3.84 (6H, s, OCH3 x 2), 1.01 (9H, s, C(CH3)3), 0.23 (6H, s, Si(CH3)2); 13C-NMR (75.5 MHz) δ 160.9, 155.7, 139.7, 130.5 128.8, 127.7, 126.7, 120.3, 104.3, 99.6, 55.3, 25.7, 18.2, -4.4. Anal. (C22H30O3Si) C, H.
(Z) and (E)-3,5-dimethoxy-4'-hydroxy-stilbene (14c and d) and General Silyloxy Deportation Procedure were performed as follows. To a solution of the silyloxy protected (Z)- stilbene (14a, 1.2 g) in anhydrous tetrahydrofuran (20 ml) was added tetrabutylammonium fluoride (1 M, 3.4 ml). The clear light yellow solution was stined for 45 minutes, poured into water, extracted with dichloromethane and the solvent removed in vacuo to provide a tan oil. The oil was separated by gravity column chromatography (4: 1 hexane-ethyl acetate) to afford cis stilbene 14c as a yellow oil (88%): IR (neat, cm1) vmax 3385, 3005, 2940, 2837, 1591, 1512, 1456, 1152 1065, 679; 1H-NMR δ 8.01 (IH, s, OH), 7.15 (2H, d, J= 8.7 Hz), 6.71 (2H, d, J=
8.7 Hz). 6.51 (IH, d, J= 12.6 Hz), 6.43 (2H, d, J= 2.5 Hz), 6.42 (IH, d, J= 12.6 Hz), 6.31 (2H, d, J= 2.5 Hz), 3.66 (6H s, OCH3 x 2). Anal. (Cι6Hι6O3) C, C, H. (E)-3,5-dimethoxy-4'- hydroxy-stilbene (14d) was similarly prepared from stilbene 14b (0.5 g) and tetrabutylammonium fluoride (1M, 1.3 ml) in anhydrous tetrahydrofuran (10 ml) was added to yield 0.8 g of yellow oil (90%): IR (neat, cm"1) vmax 3385, 3005, 2940, 2837, 1591, 1512, 1456, 1152, 1065,
961; Η-NMR δ 8.01 (IH, s, OH), 7.44 (2H, d, J= 8.7 Hz), 7.18 (IH, d, J= 16.5 Hz), 6.98 (IH, d, J= 16.5 Hz), 6.85 (2H, d, J= 8.7 Hz), 6.73 (2H, d, J= 2.1 Hz), 6.38 (IH, t, J= 2.1 Hz), 5.25 (IH, bs, OH), 3.81 (6H, s, OCH3 x 2).
Unless otherwise noted the following intermediates and stilbene objectives were prepared by the preceding general methods for silyloxy protection, Wittig reaction and deprotection. The
1398874.1/12504.012 1 3
following procedure was followed to obtain 3-(tert-butyldimethylsilyloxy)-5- hydroxybenzaldehyde (9b). 3,5-dihydroxybenzaldehyde (1.1 g) in dimethylformamide (10 ml) was monosilylated using DIEA (1.9 ml, 1.4 equiv.) and the silyl chloride (1.2 g) with stirring for 3 hours. The oily product was separated by flash column chromatography (9:1 hexane:ethyl acetate) afford some disilylated product (0.7 g) and the desired monosilylated product as a colorless oil (0.8 g, 38.5%) that crystallized from ethanol: mp = 79.6-80°C; EIMS m/z 252 (M+), 195, 167, 58, 45; IR (KBr, cm"1) vmax 3211, 2930, 2859, 1672, 1591, 1332, 841; 1H-NMR δ 9.84
(IH, s, CHO), 6.99 (IH, dd, J= 2.0, 1.0 Hz), 6.91 (IH, dd, J= 2.0, 1.0 Hz), 6.64 (IH, t, J= 2.0
Hz), 6.00 (IH, bs, OH), 0.97 (9H, s, C(CH3)3), 0.21 (6H, s, Si(CH3)2); 13C-NMR (75.5 MHz) δ
192.4, 157.6, 157.4, 138.3, 114.4, 114.0, 109.1, 25.6, 18.2, -4.47. Anal. (Cι3H20O3Si) C, H
Also, 3-(tert-butyldimethylsilyloxy)-5-methoxybenzaldehyde (9c) was obtained in a like manner. To a solution of phenol 9b (0.7 g) in dichloromethane (10 ml) was added molecular sieves (4 A, 0.8 g), proton sponge (1.6 g, 2.5 eq.), and trimethyloxonium tetrafluoroborate (1.1 g, 2.5 eq), and the solution was stined for 15 hours. The solution was filtered, the sieves were rinsed with ethyl acetate and the solvent was removed from the combined filtrate in vacuo to yield a yellow oil. The oil was purified by flash column chromatography (10:1 hexane:ethyl acetate), yielding a colorless oil (0.6 g, 79%): EIMS m/z 266 (M+), 209, 181, 166, 89, 58, IR
(KBr, cm"1) vmax 2932, 2859, 1703, 1593, 1468, 1337, 1059, 839; Η-NMR δ 9.86 (IH, s, CHO), 7.00 (IH, d, J= 2.0 Hz), 6.92 (IH, d, J= 2.0 Hz), 6.63 (IH, t, J= 2.0 Hz), 3.81 (3H, s, OCH3),
0.97 (9H, s, C(CH3)3), 0.21 , (6H, Si(CH3)2); 13C-NMR (75.5 MHz) δ 191.8, 161.2, 157.3,
138.4, 114.5, 113.0, 106.6, 55.5, 25.6, 18.2, -4.5. Anal. (CHH22O3Si) C,H.
In addition, 3-(tert-butyldimethylsilyloxy)-5,4'-dimethoxy-stilbene (14e and 14f) was obtained in a similar fashion. Reacting phosphonium bromide 8 (1.71 g) with aldehyde 9c (1.0
1398874.1/12504.012 \_\
g) led to stilbenes 14e and 14f (0.75 g, 55% total yield). (Z)-isomer (14e): EIMS m/z 370 (M+),
313, 298, 156, 89; IR (KBr, cm"1) vmax 2955, 2859, 1588, 1510, 1433, 1252, 1159, 1034, 839,
679; 1H-NMR δ 7.21 (2H, d, J= 9.0 Hz), 6.77 (2H, d, J= 9.0 Hz), 6.52 (IH, d, J= 12.0 Hz),
6.45 (IH, s) 6.43 (IH d, J= 12.0 Hz), 6.36 (IH, d, J= 2.1 Hz), 6.27 (IH, t, J= 2.1 Hz), 3.78 (3H, s, OCH3), 3.67 (3H, s, OCH3), 0.95 (9H, s, C(CH3)3), 0.11 (6H, s, Si(CH3)2); 13C-NMR
(75.5 MHz) (75.5 MHz) δ 160.6, 158.8, 156.7, 139.4, 130.3, 128.8, 127.5, 126.3, 113.6,110.9,
105.4, 55.2, 25.3, 14.1, -4.5. Anal. (C22H30O3Si) C,H. (E)-isomer (14f): EIMS m/z 370 (M+),
313, 298, 156, 89; IR (KBr, cm"1) vmax 2955, 2859, 1588, 1510, 1433, 1252, 1159, 1034, 941,
839; 1H-NMR δ 7.45 (2H, d, J= 8.7 Hz), 7.01 (IH, d, J= 15.9 Hz), 6.90 (2H, d, J= 8.7 Hz),
6.87 (IH, d, J= 15.9 Hz), 6.66 (IH, s), 6.58 (IH, s), 6.31 (IH, t, J= 2.1 Hz), 3.83 (3H, s, OCH3),
3.81 (3H, s, OCH3), 1.00 (9H, s, C(CH3)3), 0.23 (6H, s, Si(CH3)2); 13C-NMR (75.5 MHz) δ 160.8, 159.4, 156.9, 139.6, 130.0, 128.5, 127.8, 126.6, 114.1, 110.9, 104.8, 55.3, 25.7, 14.1, - 4.4. Anal. (C22H30O3Si) C, H.
A similar process was followed to obtain 3-hydroxy-4',5-dimethoxystilbene (14g and 14h). The preceding stilbene (0.75 g) isomeric mixture was deprotected and the products separated by gravity column chromatography (9:1 hexane:ethyl acetate). As usual the cis- stilbene (0.25 g) eluted first followed by the trans-isomer (0.26 g, 99% total yield): (_Z)-isomer
(14g): EIMS m/z 256 (M+), 225, 181, 152, 115; IR (KBr, cm"1) vmax 3407, 3005, 2938, 2837,
1607, 1511, 1456, 1300, 1254, 1154 1057, ' H-NMR δ 7.20 (2H, d, J= 9.0 Hz), 6.77 (2H, d, J=
9.0 Hz), 6.52 (IH, d, J= 12.0 Hz), 6.42 (IH, s), 6.40 (IH d, J= 12.0 Hz), 6.33 (IH, d, J= 2.1 Hz), 6.27 (IH, t, J= 2.1 Hz), 3.79 (3H, s, OCH3), 3.67 (3H, s, OCH3). Anal. (Cι6Hι6O3) C,H.
(EHsomer (14h): EIMS m/z 256 (M+), 225, 181, 152, 115; IR (KBr, cm"1) vmax 3405, 2936,
2837, 1593, 1510, 1456, 1252, 1150,1057; and 1H-NMR δ 7.44 (2H, d, J= 8.7 Hz), 7.02 (IH, d,
1398874.1/12504.012 15
J= 15.9 Hz), 6.90 (2H, d, J= 8.7 Hz), 6.86 (IH, d, J= 15.9 Hz), 6.63 (1 H, t, J= 2.1 Hz), 6.58 (1 H, t, J= 2.1 Hz), 6.31 (1 H, t, J= 2.1 Hz), 3.83 (3H, s, OCH3) 3.82 (3H, s, OCH3).
In a like manner 3,5-di(tert-butyldimethylsilyloxy)-4'-methoxy-stilbene (14i and 14j) was obtained. Intermediate 9a and 3 served as starting material for preparing stilbene 14i (1.73 g)
and 14j (0.19 g). (Z)-isomer (14i); EIMS m/z 470 (M+), 455, 413, 147, 73; IR (KBr, cm"1) vmax
2955, 2859, 1582, 1510, 1437, 1331, 1254, 1165, 1031, 678; 1H-NMR δ 7.17 (2H, d, J= 8.1
Hz), 6.75 (2H, d, J= 8.1 Hz), 6.49 (1 H, d, J= 12.0 Hz), 6.39 (IH, d, J= 12.0 Hz), 6.35 (2H, d, J = 2.4 Hz), 6.19 (IH, t, J= 2.4 Hz), 3.77 (3H, s, OCH3), 0.93 (18H, s, C(CH3)3 x 2), 0.10 (12H, s, Si(CH3)2 x 2). Anal. (C25H42O3Si2) C.H. (E)-isomer (14j); EIMS m/z 470 (M+), 455, 413, 147, 73; IR (KBr, cm"1) vmax 2955, 2859, 1582, 1510, 1437, 1331, 1254, 1165, 1031, 980; Η-NMR δ 7.44 (2H, d, -7= 8.1 Hz), 6.97 (IH, d, J= 16.2 Hz), 6.89 (2H, d, J= 8.1 Hz), 6.83 (1 H, d, J= 16.2 Hz), 6.59 (2H, d, J= 2.1 Hz), 6.24 (114, t, J= 2.1 Hz), 3.83 (3H, s, OCH3), 1.00 (18H, s, C(CH3)3 x 2), 0.22 (12H, s, Si(CH3)3 x 2).
The preceding silyloxy protected stilbene isomers (14i and j) were deprotected to yield 3,5-dihydroxy-4'-methoxy-stilbene (14k and 1) 0.60 g and 0.05 g respectively. (Z)-isomer (14k);
EIMS m/z 242 (M+), 226, 211, 194, 181, 152, 137, IR (KBr, cm"1) vmax 3356, 3009, 2971, 2837,
1605, 1510, 1254, 1154, 1005, 677; Η-NMR δ 7.20 (2H, d, J= 8.7), 6.77 (2H, d, J= 8.7 Hz),
6.50 (IH, d, J= 12.0 Hz) 6.36 (IH, d, J= 12.0 Hz), 6.32 (2H, d, J= 2.1 Hz), 6.22 (IH, t, J= 2.1 Hz), 4.89 (2H, bs, OH x2), 3.77 (3H, s, OCH3). Anal. (Cι5Hι4O3) C,H. E-Isomer (141); EIMS
m/z 242, (M+), 226, 211, 194, 181, 152,137; IR (KBr, cm"1) vmax 3356, 3009, 2971, 2837, 1605,
1510, 1254, 1154, 1005, 974; Η-NMR δ 7.43 (2H, d, J= 8.1 Hz), 7.01, (IH, d, J = 15.9 Hz),
6.90 (2H, d, J= 8.1 Hz), 6.83 (IH, d, J= 15.9 Hz), 6.56 (2H, d, J= 2.4 Hz), 6.25 (IH, t, J= 2.4 Hz), 4.70 (2H, bs, OH x 2), 3.83 (3H, s, OCH3).
1398874.1/12504.012 tfj
Then (Z)-3,5-dimethoxy-4 -[O-bis(benzyl)phosphoryl]-stilbene (14m) was obtained as follows. A mixture of phenol 14c (3.9 g) and N,N-dimcthyla inopyridinc (0.2 g) in anhydrous acetonitrile (30 ml) was cooled to -10°C, and carbon tetrachloride (7.3 ml, 5 equiv.) and DIEA (5.5 ml, 2.1 equiv.) were added. The mixture was stined at -10°C for 30 minutes under argon, dibenzylphosphite (5.0 ml, 1.5 equiv.) was added, .and the solution was stined for 12 hours and then poured into 0.5 M monobasic potassium phosphate. The mixture was extracted with ethyl acetate and removal of solvent in vacuo from the organic phase yielded a tan oil. This was subjected to column chromatography (4:1 hexane:ethyl acetate), and the phosphate ester was recovered as a tan oil (6.6 g, 85%): EIMS m/z 516 (M+), 425, 334, 319, 255, 227, 91; IR (KBr, cm"1) vmax 3443, 3007, 2959, 2837, 1591, 1505, 1456, 1289, 1208, 1155, 1015, 953: 1H-ΝMR δ 7.32 (10H, m, AR-H), 7.19 (2H d, J= 8.4 Hz), 7.01 (2H, d, J= 8.4 Hz), 6.52 (2H, s, H,a>,.a), 6.36 (2H, d, J= 2.0 Hz), 6.31 (IH, t, J= 2.0 Hz), 5.11 (2H, s, Bn), 5.08 (2H, s, Bn), 3.62 (6H, s, OCH3 x 2); 13C-NMR (75.5 MHz) δ 160.6, 149.5, 149.5, 138.8,135.4, 135.4, 134.2, 130.4, 130.3, 129.4, 128.6, 128.6, 128.0, 127.0, 119.8, 119.7, 106.6, 99.8, 70.0, 69.9, 55.2. Anal. (C30H29O6P) C, H, P.
Sodium Resverastatin Phosphate (14n) was obtained as described below. To a solution of the dibenzyl phosphate (14m, 2.62 g) in anhydrous dichloromethane (15 ml) at 0°C was added bromotrimethylsilane (1.40 ml, 2.1 equiv.), and the mixture was stined for 2 hours. Water (10 ml) was added, the solution was stined for 1 hour and then washed with ethyl acetate, and the aqueous phase was freeze-dried to a white solid. To a solution of the solid in ethanol (30 ml) was added sodium methoxide (0.57 g), and the suspension was stined for 12 hours. Solvent was removed in vacuo and the resulting tan oil was dissolved in water. The solution was washed with ethyl acetate and then freeze-dried to afford 1.88 g of colorless solid (98%): HRFAB m/z;
1398874.1/12504.012 17
IR (KBr, cm"1) vmax 3385, 2999, 2938, 2834, 1601, 1508, 1366, 1155, 1063, 683; 1H-NMR δ
6.93 (2H, d, J= 8.4 Hz), 6.85 (2H, d, J= 8.4 Hz), 6.29 (1 H, d, J= 12.4 Hz), 6.17 (2H, s, H2>6),
6.15 (IH, d, J= 12.4 Hz), 6.09 (IH, s, H4),3.34 (6H, s, OCH3 x 2); 13C-NMR (75.5 MHz) δ
171.1, 160.1, 139.9, 131.8, 130.8, 130.0, 129.0, 120.3, 107.3, 99.7, 55.6.
The following general procedure was used for benzhydrol formation. To the bromide (1- 10 mmol) in anhydrous tetrahydrofuran (5-35 ml) at -78°C was added n-butyllithium (2.5 M, 1.1 equiv.) and the resulting solution stined under argon for 15 minutes. A solution of aldehyde (1.0 equiv.) in tetrahydrofuran was added dropwise over 30 minutes and the mixture stined for 6 hours. The solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water and removal of the solvent in vacuo afforded an oil that was purified by flash column chromatography (9:1 hexane-ethyl acetate).
Reacting 4-bromoanisole (2.3 g) and 3,5-dimethoxybenzaldehyde (2.1 g) led to 15a (2.7 g, 80.9%) as a colorless oil: EIMS m/z 274 (M+) 257, 243, 227, 165, 139, 135, 109, 77; IR
(KBr, cm"1) vmax 3451, 3001, 2940, 2837, 1597, 1248, 1172, 1034; 1H-NMR δ 7.28 (2H, d, J=
8.8 Hz), 6.85 (2H, d, J= 8.8 Hz), 6.53 (2H, d, J= 2.0 Hz), 6.35 (IH, t, J= 2.0 Hz), 5.72 (IH, d, J
= 2.8 Hz), 3.78 (3H, s, OCH3), 3.76 (3H, s, OCH3); 13C-NMR (75.5 MHz) δ 160.9, 159.1, 146.5,
135.9, 127.9, 113.9, 104.4, 99.3, 75.8, 55.3, 55.3. Anal. (C.6Hι8O4) C, H.
The following general procedure was followed for benzophenone formation. To a solution of the benzhydrol (1-10 mmol) in dichloromethane (5-35 ml) was added pyridinium dichromate (2.0 equiv.) and molecular sieves (4 A activated powder, same weight as PDC), and the resulting suspension was stined under argon for 24 hours. The reaction mixture was filtered through celite and the solvent removed in vacuo to yield a brown oil. The oil was subjected to
1398874.1/12504.012 l g
gravity column chromatography (4:1 hexane-ethyl acetate) to yield the desired product in 75-
90% yield.
Further, 3,4',5-trimethoxybenzophenone (16a) was obtained. Alcohol 15a (1.1 g) provided a solid (0.8 g, 77.7%) that recrystallized from methanol in colorless needles: m.p. = 90.3-91.6°C (lit.21 m.p. = 97-98°C); EIMS m/z 272 (M+), 257, 241, 229, 165, 135, 92, 77; IR (KBr.cm"1) vmax 3071, 2967, 2841, 1645, 1588, 1263, 1065; 1H-NMR δ 7.84 (2H, d, J= 9.0 Hz),
6.95 (2H, d, J= 9.0 Hz), 6.87 (2H, d, J= 2.0 Hz), 6.65 (IH, t, J= 2.0 Hz), 3.88 (3H, s, OCH3),
3.82 (3H, s, OCH3); 13C-NMR (75.5 MHz) δ 195.2, 163.3, 160.5, 140.2, 132.6, 130.1, 113.6,
107.6, 104.2, 55.6, Anal. (Cι6Hι6O4) C, H.
Then l-bromo-4-O-(/ert-butyldimethylsilyloxy)benzene (17) was obtained. First, 4-
bromophenol (4.15 g) was dissolved in anhydrous dichloromethane (40 ml), then imidazole (1.63 g) and tert-butyldimethylsilyl chloride (3.61 g) were added. The cream suspension was stined under argon for 12 hours and the reaction was terminated with addition of water. The mixture was extracted with ethyl acetate. The organic phase was washed with water and the solvent was removed in vacuo to afford a yellow oil that was subjected to flash column chromatography (9:1 hexane:ethyl acetate) to yield a colorless oil (87%, 6.0g): EIMS m/z 274 (M+), 257, 243, 227,
165, 139, 135, 109, 77; IR (KBr, cm"1) vmax 2957, 2859, 1588, 1487, 1458, 910, 839; 1H-NMR δ
7.32 (2H, d, J= 8.7 Hz), 6.71 (2H, d, J=8.7 Hz), 0.97 (9H, s, C(CH3)3), 0.18 (6H, s, Si(CH3)2). Anal (Cι2H]9BrOSi) C, H.
Protected bromophenol 17 (3.2 g) and 3,5-dimethoxybenzaldehyde (1.8 g) afforded 15b as a colorless oil (3.4 g, 83%): EIMS m/z 374 (M+), 317, 167, 151, 139; IR (KBr, cm"1 vmax
3420, 2957, 2859, 1607, 1260, 1155, 1063, 839; 1H-NMR δ 7.21 (2H, d, J= 8.4 Hz), 6.80 (2H, d, J= 8.4 Hz), 6.53 (2H, d, J= 2.0 Hz), 6.36 (IH, t, J= 2.0 Hz), 5.67 (IH, s), 3.75 (6H, s, OCH3
1398874.1/12504.012 19
x 2), 0.99 (9H, s, C(CH3)3), 0.20 (6H, s, Si(CH3)2); 13C-NMR (75.5 MHz) δ 160.7, 155.0, 146.5,
136.4, 127.8, 119.9, 104.4, 99.2, 75.7, 55.2, 25.6, 18.1, -4.5. Anal. (C2ιH30O4Si) C, H.
Alcohol 15b (0.12g) was deprotected with TBAF as for the stilbenes above to provide 4'- Hydroxy-3,5-dimethoxybenzhydrol 15c as a colorless oil (0.03 g, 42%): EIMS m/z 260 (M+),
243, 165, 139, 121, 95; IR (KBr, cm"1) vmax 3362, 2932, 2859, 1599, 1256, 1155, 1067; 1H-NMR
δ 7.16 (2H, d, J= 8.4 Hz), 6.72 (2H, d, J= 8.4 Hz), 6.52 (2H, d, J= 2.4 Hz), 6.34 (IH, t, J= 2.4
Hz), 5.66 (IH, s), 3.73 (6H, s, OCH3 x 2); 13C-NMR (75.5 MHz) δ 160.6, 155.4, 146.3, 135.3, 128.0, 115.3, 104.4, 99.2, 75.8, 55.3. Anal. (Cι5H,6O4) C, H.
Alcohol 15b (0.58 g) led to 4'-(ter/-butyldimethylsilyloxy)-3,5-dimethoxybenzophenone 16b as a colorless oil (0.46 g, 80%): EIMS m/z 372 (M+), 315, 165, 157, 137, 28; IR (KBr, cm"1)
vmax 2957, 2859, 1657, 1260, 1067, 910, 841; Η-NMR δ 7.78 (2H, d, J= 9.2 Hz), 6.89 (2H, d, J
= 9.2 Hz), 6.87 (2H, t, J= 2.0 Hz), 6.63 (IH, t, J= 2.0 Hz), 3.80 (6H, s, OCH3 x 2), 0.98 (9H, s,
C(CH3)3), 0.23 (6H, s, Si(CH3)2); 13C-NMR (75.5 MHz) δ 195.0, 160.3, 159.8, 140.0, 132.3,
130.5, 119.6, 107.5, 104.1, 55.5, 25.6, 18.3, -4.3. Anal. (C2.H28O4Si) C;H.
The general procedure for benzophenone deprotection with TBAF is set forth below. To a solution of the protected phenol (0.3-3.5 mmol) in anhydrous tetrahydrofuran (5-25 ml) was added tetrabutylammonium fluoride (1 M, 1.0 equiv. per TBDMS), and the pale yellow solution was stined for 45 minutes. The mixture was poured into water and extracted with ethyl acetate. Removal of the solvent in vacuo from the organic phase afforded a tan oil that was subjected to gravity column chromatography (9:1 hexane:ethyl acetate) to afford the product (70-93% yield).
Protected benzophenone 16b (0.71 g) led to 16c as a white solid (0.35 g, 72%): EIMS
m/z 258 (M+), 243, 227, 199, 165, 121, 45; IR (KBr, cm"1) vmax 3424, 2940, 1640, 1591, 1454,
1206, 1157, 1065; 1H-NMR δ 7.68 (2H, d, J= 8.8 Hz), 6.80 (2H, d, J= 8.8 Hz), 6.75 (2H, d, J=
1398874.1/12504.012 20
2.0 Hz), 6.53 (IH, t, J= 2.0 Hz), 3.70 (6H, s, OCH3 x 2);13C-NMR (75.5 MHz) δ 196.0, 162.3,
160.4, 140.2,133.1, 128.6, 115.6, 107.5, 104.2, 55.5. Anal. (Cι5H,4O4) C, H.
Combining 4-bromoanisole (0.43 g) and aldehyde 9a (0.76 g) provided 3,5-di-(tert- butyldimethylsilyloxy)-4'-methoxybenzhydrol 15d as a faint yellow oil (0.80 g, 82%): EIMS
m/z 474 (M+), 459, 417, 361, 343, 73; IR (KBr, cm"1) vmax 3420, 2932, 2859, 2361, 1591, 1451,
1252, 1163, 1026, 833; 1H-NMR δ 7.29 (2H, d, J= 9.04 Hz), 6.89 (2H, d, J= 9.0 Hz), 6.52 (2H,
d, J= 2.0 Hz), 6.28 (IH, t, J= 2.0 Hz), 5.70 (IH, s), 3.83 (3H, s, OCH3), 1.00 (18H, s, C(CH3)3 x
2), 0.20 (12H s, Si(CH3)2 x 2); 13C-NMR (75.5 MHz) δ 159.0, 156.5, 146.1, 136.0, 127.9, 113.7,
111.5, 111.0, 75.5, 55.3, 25.7, 18.2, -4.4. Anal. (C26H_,2O4Si2) C, H.
Alcohol 15d (0.72 g) provided 3,5-di-(tert-butyldimethylsilyloxy)-4'- methoxybenzophenone 16d as a colorless oil (0.64 g, 90%): EIMS m/z 472 (M+), 457, 415, 359,
135, 73, IR (KBr, cm"1) vmax 2957, 2932, 2859, 1657, 1586, 1437, 1339, 1254, 1169, 831; Η-
NMR δ 7.82 (2H, d, J= 9.0 Hz), 6.94 (2H, d, J= 9.0 Hz), 6.80 (2H, d, J= 1.5 Hz), 6.52 (IH, t, J
= 1.5 Hz), 3.88 (3H, s, OCH3), 0.97 (18H, s, C(CH3)3 x 2), 0.19 (12H, s, Si(CH3)2 x 2); 13C-
NMR (75.5 MHz) δ 195.0, 163.2, 156.3, 140.1, 132.5, 130.2, 115.6, 114.7, 113.5, 55.5, 25.7,
18.2, -4.4. Anal. (C26H40O4Si2) C, H.
Protected benzophenone 16d (0.54 g) led to 16e as a white solid (0.36 g, 93%): EIMS
m/z 244 (M+), 227, 135, 107, 92; IR (KBr, cm"1) vmax 3300, 2972, 2841, 2361, 1692, 1591, 1451,
1350, 1263,1171,1030; 1H-NMR δ 8.60 (2H, bs, OH x 2), 7.80 (2H, d, J= 9.0 Hz), 7.06 (2H, d, J
= 9.0 Hz), 6.69 (2H, d, J= 2.5 Hz), 6.59 (IH, t, J= 2.5 Hz), 3.91 (3H, s, OCH3); 13C-NMR (75.5
MHz) δ 195.4, 164.6, 159.7, 141.8, 133.4, 131.5, 114.8, 109.3, 107.2, 56.4. Anal. (C!4HI2O ) C, H.
1398874.1/12504.012 21
Protected bromophenol 17 (0.49 g) and aldehyde 9a (0.62 g) afforded 15e as a faint
yellow oil (0.76 g, 78%): EIMS m/z 574 (M+), 559, 517, 461, 443, 73; IR (KBr, cm"1) vmax 3420,
2932, 2859, 2361, 1591, 1451, 1252, 1163, 1026, 833; 1H-NMR δ 7.18 (2H, d, J= 8.5 Hz), 6.79
(2H, d, J= 8.5 Hz), 6.48 (2H, d, J= 2.0 Hz), 6.25 (IH, t, J= 2.0 Hz), 5.63 (IH, s, CH), 0.99 (9H, s, C(CH3)3), 0.97 (18H, s, C(CH3)3 x 2), 0.19 (6H, s, Si(CH3)2 x 2), 0.17 (12H, s, Si(CH3)2 x2);
13C-NMR (75.5 MHz) δ 156.4, 155.0, 146.2, 136.7, 127.9, 119.9, 111.6, 111.0, 75.4, 25.7, 18.2, -
4.4, -4.5. Anal. (C3ιH54O4Si3) C, H.
Alcohol 15e (0.50 g) led to 16f as a colorless oil (0.44 g, 89%): EIMS m/z 572 (M+),
515, 459, 323, 193, 73; IR (KBr, cm"1) vmax 2932, 2861, 1661, 1589, 1437, 1339, 1256, 1167,
831; lH-NMR δ 7.74 (2H, d, J= 8.5 Hz), 6.88 (2H, d, J= 8.5 Hz), 6.80 (2H, d, J= 2.5 Hz), 6.52
(IH, t, J= 2.5 Hz), 0.99 (9H, s, C(CH3)3), 0.97 (18H, s, C(CH3)3 x 2), 0.24 (6H, s, Si(CH3)2),
0.19 (12H, s, Si(CH3)2 x 2); 13C-NMR (75.5 MHz) δ 195.2, 159.9, 156.3, 140.0, 132.4, 130.7,
119.7, 115.7, 114.7, 25.7, 25.6, 18.3, 18.2, -4.4. Anal. (C3ιH52O4Si3) C,H.
Protected benzophenone 16f (0.42 g) led to 3,4',5-trihydroxybenzophenone 16g as a
white solid (0.12 g, 73%): EIMS m/z 230 (M+, 137, 121, 93, 65, 28; IR (KBr, cm"1) vmax 3300,
2974, 1692, 1593, 1346, 1260, 1167; 1H-NMR δ 7.73 (2H, d, J= 8.5 Hz), 6.95 (2H, d,.J= 8.5
Hz), 6.68 (2H, d, J= 2.0 Hz), 6.57 (IH, t, J= 2.0 Hz); 13C-NMR (75.5 MHz) δ 195.0, 162.4,
159.2, 141.6, 133.3, 130.2, 115.9, 108.8, 106.7. Anal. (Cι3Hι0O4) C, H.
Protected bromophenol 17 (1.07 g) and aldehyde 9c (0.99 g) provided 15f as a faint
yellow oil (1.19 g, 67%): EIMS m/z 474 (M+), 459, 417, 361, 343, 73; IR (KBr, cm"1) vmax 3397,
2932, 2859, 1595, 1508, 1256, 1159, 839; Η-NMR δ 7.19 (2H, d, J= 8.4 Hz), 6.78 (2H, d, J= 8.4 Hz), 6.55 (IH, s), 6.42 (IH, s), 6.29 (IH, s), 5.67 (IH, s, CH), 3.74 (3H, s, OCH3), 0.96 (9H, s, C(CH3)3), 0.95 (9H, s, C(CH3)3), 0.17 (6H, s, Si(CH3)2), 0.15 (6H, s, Si(CH3)2); 13C-NMR
1398874.1/12504.012 22
(75.5 MHz) δ 160.5, 156.6, 155.0, 146.2, 136.4, 127.8, 119.9, 110.8, 105.1, 105.0, 75.7, 55.3,
25.7,18.3), -4.3. Anal. (C26H42O Si2) C, H.
Alcohol 15f (0.91 g) led to 16h as a colorless oil (0.71 g, 78%): EIMS m/z 472 (M+),
415, 223, 193, 179, 73; IR (KBr, cm"1) vmax 2932, 2859, 1659, 1595, 1507, 1258, 1163, 839; 1H-
NMR δ 7.76 (2H, d, J= 8.8 Hz), 6.90 (IH, t, J= 2.4 Hz), 6.88 (2H, d, J= 8.8 Hz), 6.77 (IH, t, J
= 2.4 Hz), 6.58 (IH, t, J= 2.4 Hz), 3.80 (3H, s, OCH3), 0.99 (9H, s, C(CH3)3), 0.97 (9H, s,
C(CH3)3), 0.24 (6H, s, Si(CH3)2), 0.20 (6H, s, Si(CH3)2); 13C-NMR (75.5 MHz) δ 195.0, 160.3,
159.8, 156.3, 140.0, 132.3, 130.6, 119.6, 114.2, 110.1, 107.6, 55.5, 25.7, 25.7, 18.3, 18.3, -4.3.
Anal. (C26H4oO4Si2) C, H.
Protected benzophenone 16h (0.61 g) led to 3,4'-dihydroxy-5-methoxybenzophenone 16i as a white solid (0.26 g, 82%): mp 179-180°C; EIMS m/z 244 (M+), 229, 213, 151, 121, 93; IR (KBr, cm"1) vmax 3333, 2961, 2841, 1690, 1589, 1435, 1346, 1165, 1059, 849; Η-NMR δ 9.21 IH bs, OH), 8.66 (IH, bs, OH), 7.75 (2H, d, J= 9.0 Hz), 6.96 (2H, d, J= 9.0 Hz), 6.77 (2H, t, J = 2.0 Hz), 6.74 (IH, t, J= 2.0 Hz), 6.63 (IH, t, J= 2.0 Hz), 3.80 (3H, s, OCH3); 13C-NMR (75.5 MHz) δ 195.0, 162.6, 161.8, 159.2, 141.6, 133.4, 130.1, 116.0, 109.9, 107.0, 105.50, 55.8. Anal.
(Cι4H]2O4) C, H.
Combining 4-bromoanisole (0.59 g) and aldehyde 9c (0.82 g) provided compound 15g as a faint yellow oil (0,59 g, 52%): EIMS m/z 374 (M+), 359, 317, 299, 243, 75; IR (KBr, cm"1)
vmax 3418, 2932, 2859, 1595, 1462, 1250, 1157, 1036, 837; 1H-NMR δ 7.30 (2H, d, J= 8.4 Hz), 6.89 (2H, d, J= 8.4 Hz), 6.58 (IH, s), 6.49 (IH, s), 6.32 (IH, s), 5.72 (IH, s, CH), 3.82 (3H, s, OCH3), 3.77 (3H, s OCH3), 0.99 (9H, s, C(CH3)3), 0.20 (6H, s, Si(CH3)2); 13C-NMR (75.5 MHz)
δ 160.5, 158.9, 156.6, 146.2, 135.9, 127.8, 113.8, 110.7, 105.1, 104.9, 75.6, 55.3, 25.8, 18.3, - 4.3. Anal. (C2ιH30O4Si) C,H.
1398874.1/12504.012 23
Alcohol 15g (0.54 g) led to colorless oil 3'-(tert-butyldimethylsilyloxy)-4',5- dimethoxybenzophenone 16j (0.41 g, 76%): EIMS m/z 372 (M+), 315, 272, 135; IR (KBr, cm"1) vmax 2932, 2859, 1657, 1593, 1454, 1429, 1339, 1254, 1161, 1034, 839; Η-NMR δ 7.83 (2H, d, J= 8.8 Hz), 6.95 (2H, d, J= 8.8 Hz), 6.89 (IH, t, J= 1.2 Hz), 6.77 (IH, t, J= 1.6 Hz), 6.58 (IH, t, J= 2.2 Hz), 3.88 (3H, s, OCH3), 3.80 (3H, s, OCH3), 0.97 (9H, s, C(CH3)3), 0.20 (6H, s,
Si(CH3)2); 13C-NMR (75.5 MHz) δ 194.9, 163.1, 160.4, 156.3, 140.1, 132.5, 130.0, 114.2, 113.4,
110.1, 107.6, 55.6, 55.5, 25.7, 18.1, -4.3. Anal. (C2ιH28O4Si) C,H.
Protected benzophenone 16j (0.37 g) led to 4',5-dimethoxy-3-hydroxybenzophenone 16k
as a colorless solid (0.18 g, 70%): EIMS m/z 258 (M+), 227, 135, 92, 77; IR (KBr, cm"1) vmax
3354, 3005, 2938, 2841, 1692, 1636, 1593, 1433, 1346, 1256, 1171, 1030; Η-NMR δ 8.67 (IH,
bs, OH), 7.80 (2H, dd, J= 6.8, 2.0 Hz), 7.05 (2H, dd, J= 6.8, 2.0 Hz), 6.77 (IH, dd, J= 2.0, 1.6 Hz), 6.74 (IH, dd, J= 2.4, 1.2 Hz), 6.64 (IH, t, J= 2.4 Hz), 3.90 (3H, s, OCH3), 3.80 (3H, s,
OCH3); 13C-NMR (75.5 MHz) δ 194.6, 164.0, 161.5, 159.0, 141.1, 132.8, 130.8, 114.3, 109.7,
106.9, 105.4, 55.9, 55.7. Anal. (C15Hι4O4) C, H.
The following results lead to some observations. Because of the interesting biological properties of resveratrol (1), combined with the remarkable in vivo anticancer activity of combretastatin A-4 (2a) and its sodium phosphate prodrug (2b), a series of resveratrol structural modifications were investigated as an extension of applicant's combretastatin and phenstatin (2c) SAR research. (Ndayikengurukiye, H., et al., Alkoxylated p-phenylenevinylene Oligomers: Synthesis and Spectroscopic and Electrochemical Properties, Tetrahedron 1997, 53, 13811- 13828.) Suitable application of the experimental procedures already developed for synthesis of combretastatin A-4 and its prodrug derivatives was extended to obtaining the cis and trans stilbenes as well as the benzophenones. (Pettit, G. R., et al., Antineoplastic agents 291. Isolation
1398874.1/12504.012 24
and synthesis of Combretastatin A04, A-5, and A-6, J. Med. Chem. 1995, 38, 1666-1672; Pettit, G. R., et al., Antineoplastic agents 443. Synthesis of the Cancer Cell Growth Inhibitor Hydocyphenstatin and its Sodium Diphosphate Prodrug, J. Med. Chem. 2000, 43, 2731-2727.)
The cytotoxicity data from the resveratrol stilbenes was determined. The cΛs-isomer of resveratrol (lb) exhibited slightly less inhibitory effects on the cancer cell lines tested than did the tranj-isomer. The trimethoxy stilbenes 4a,b are between 10-100 fold more active against tumor cell lines than the parent compound resveratrol (1), with compound 4a (the α's-stilbene) far more active than 4b.
Demethylation at any position yielded much less cytotoxic compounds than 4a, but the cw-stilbenes 14c, 14g and 14k all retained anticancer activity comparable to that of resveratrol. The conesponding traws-isomers 14d, 14h and 141 were all slightly less active than their cis counterparts.
Previous work by applicant had found that phenstatin (2c) retained most of the cytotoxic properties of combretastatin A-4 (2a); this suggested that the properties of compound 16a, as well as additional benzophenones might possibly be worthy of further investigation. (Pettit, G. R., et al., Antineoplastic Agents. 379. Synthesis of Phenstatin Phosphate, J. Med. Chem. 1998, 41, 1688-1695.) While the cytotoxic properties of most of these compounds were quite similar to those of the stilbene derivatives of resveratrol the trimethoxy derivative was again the most potent of the series. However, it was 10- 100-fold less active than compound 4a, the analogous cw-stilbene.
General conclusions arising from the structure-activity relationship study of resveratrol based on cytotoxic effects on P-388 and human tumor cell lines can be summarized as: 3,4',5- OCH3»resveratrol,4'-OH,prodrug,3-OH>3,5-OH,3,4'-OH»3,4',5-OH. The trimethoxy
1398874.1/12504.012 25
derivatives (4a,b,16a) were all superior in activity to resveratrol (1) as well as the remaining variations. Resveratrol (1), however, was comparable in activity to several of the other cis- stilbenes described here, including the 4'-hydroxy (14g) and the 3-hydroxy (14c) -derivatives.
For this reason the synthesis of the prodrug of the 4'-hydroxystilbene 14c and the 3- hydroxystilbene 14g was attempted. The synthesized prodrug 14n was essentially identical to 14c in its effects on the growth of cancer cells. From the known antimitotic activity of combretastatin A-4 (2a) and phenstatin (2c) and their potent interactions with tubulin, it seemed possible that the most cytotoxic compounds prepared in the cunent series would also inhibit this important cellular protein.
Several of the newly synthesized compounds were therefore examined for inhibitory effects on tubulin assembly, in a direct comparison with 2a and 2c. Compound 4a proved to be more inhibitory than 2a, while, in contrast, 16a was somewhat less potent than 2c. Resveratrol (1) was inactive as an inhibitor of tubulin assembly. Compound 14c, representing demethylation at position 3 of 4a, was 16-fold less active than 4a.
Combretastatin A-4 (2a) binds in the colchicine site of tubulin and is exceptionally potent as an inhibitor of the binding of radiolabeled colchicine to tubulin. (Lin, C. M., et al., Antimitotic natural products Combretastatin A-4 and Combretastatin A-2: Studies on the Mechanism of Their Inhibition of the Binding of Colchicine to Tubulin, Biochem. 1989, 28, 6984-6991.) The two new active compounds, 4a and 4c, were compared to 2a and phenstatin (2c) for their effects on colchicine binding to tubulin. Combretastatin A-4 (2a) displayed its usual potency, inhibiting colchicine binding by 98% when the two drugs were present in equimolar (5 μM) concentrations and by 91% when 2a was present at 2 μM (the tubulin
concentration in these experiments was 1.0 μM).
1398874.1/12504.012 26
Compound 4a was essentially equivalent to 2a as an inhibitor of colchicine binding. Phenstatin (2c), despite its greater inhibition of polymerization, was less potent than combretastatin A-4 (2a) as an inhibitor of colchicine binding, while 16a had the least activity in both assays. The reasons for these discrepancies are at present unknown but do not appear to derive from salt or temperature differences in the reaction condition.
There is also some indication that Resveratrol (1) contained in the roots of Polygonum cuspidatum has apparently been used in Chinese and Japanese traditional medicine as a treatment for gononhea. (Kubo, M., et al., Shoyayugaku Zasshi 1981, 35, 58.) In the present study, its activity against the etiologic agent of gononhea, Neisseria gonorrhoeae, was demonstrated in broth microdilution assays (Table IV). Stilbene production has been conelated with the resistance of grape leaves to fungal infection. (Langcake, R., et al., The Relationship of Resveratrol Production to Infection of Grapevine Leaves by Botrytis cenerea, Vitis 1979 18:244- 253.) Most of the stilbenes evaluated for antimicrobial action had antifungal activity (Table IV). The dimethyl derivative of cw-resveratrol (14c), with both antibacterial and antifungal activities, was the most active of the stilbenes and benzophenones tested (Table IV). Further biological evaluation of such resveratrol structural modifications should include chemopreventive potential targets such as COX-1 and COX-2.
1398874.1/12504.012 27
Table I. Cytotoxicity Data of Resveralrol (1), Combrclastalin A-4 (2a), Resvcraslalin (14c), the Oisodium Resverastatin Prodnig (14n) and Related Stilbenes.
Leukemia I'uncrcas-a Drcust CNS lung-NSC Colon I'loslalc
Compound P388 UXl'C-3 MCF-7 SF-268 NCI-11460 KM20L2 DU-145
EDjoμg/mL GIjoμg/mL
4.49 j .3 3. 9 4.1 3 . - TTT — I7T-
TT 24.4 1S . S 14.8 5.0 13.2 22.0 10.2
Ta 3.0x10'* 0.39 - -1.0x10"'' 6.0X10-' 0.34 8.0x10'
Ta 2.62xl0'i 3.4xl0"3 - 4.4X10"1 2.8xl0"J 5.4x10'
TIT 2.77 3 .5X10'1 - 5.6x10-' 6.2x10'' 1.5
ΈΓ 2.95 12.6 3 . 0 2.2 2.8 11.9 2.3
T?Γ 4.87 6.5 2.3 4.3 2.7 3.4 2.7
-149- 3.82 3.3 - 1.5 7.2x10" 2.6 2.5 lAh.
31.5 12.7 - 10.3 11.2 13.1 6.0
______
2.75 14.1 12.7 15.6 6.4 17.7 10.6
______
28.9 6.3 3 .4 3.1 6 .8 3 .8 2.7
______
4.45 5.4 9.0 38.5 10.7 24.7 35.6
1 1"
2.81 6.6 7.3X10'1 1.9 3 .6 11.8 3.7
1398874.1/12504.012 28
Table II. Cytoloxicily Data ot Resveratrol (1), Phenstatin (2c) and Relaled Benzophenones and Benzhydrols.
Compound Leukemia Pαiicreas-a Breast CNS Lung-NSC Colon Pros
P388 BXPC-3 MCF-7 SH-268 NCI-H460 KM20L2 DU- l-D_0μg/nιL GIjoμg/mL
4.49 3.3 3.9 4.1 3.6 13.1
2C 3.3xl0'J - - 5.2x10"' 5.7xlO'J 4.0X10"1
Tϊn .
20.2 16.1 - 23.3 21.7 21.0 2
1.23 4.2X10'1 - 8.6x10"' 5.3x10" 4.2X10'1
_L5c_
>10 1.3 2.0 6.5x10" 2.3 5.3
.fir
24.8 4.0 2.2 3.8 3.0 3.6
______
17.8 21.2 21.7 24.5 16.6 24.5 1
>100 20.5 30.6 22.3 25.0 24.5 1
■ fit
26.2 21.7 26.8 26.4 12.1 31.6 ]
_!£--_
13.4 15.0 14.2 13.9 10.3 16.2 ]
1398874.1/12504.012 29
Table III. Interactions of stilbenes .and benzophenones with tubulin. Compound Inhibition of tubulin Inhibition of colchicine
Polymerization binding
IC50 (μM) ±SD % Inhibition
2μM inhibitor 5μM inhibitor
Resveratrol (1) >40
Combretastatin A-4 (2a) 2.0 ± 0.2 91 ± 3 98 ± 1
Phenstatin (2c) 1.1 ± 0.1 73 ± 1 85 ± 2
4a 1.8 ± 0.3 88 ± 1 95 ± 1
Resverastatin (14c) 29 ± 9
16a 2.6 ± 0.3 47 ± 5 69 ± 0.3
The tubulin polymerization assay was performed as previously described.24 The tubulin concentration was 10 μM, with varying drug concentrations, as required, to obtain IC5o values. Extent of assembly after 20 min at 30°C was the parameter measured. The colchicine binding assay was performed as earlier reported.27 The tubulin concentration was 1.0 μM, the [3H] colchicine concentration was 5.0 μM, and the potential inhibitor concentrations were as indicated. Binding of colchicine was measured following a 10 min incubation at 37°C.
04.012 30
Table IV. Antimicrobial activities of resveratrol (1) and related stilbenes and benzophenones
Minimum inhibitory concentration (μg/ml)
Microorganism 1 4a 14c 14h 14k 14u 15c 16a 16c 16e I6g 16! 16k
Cryptocaccus neofonnaiis * * 16 16 * 64 * * * * * * 64
Candida albicans * * 64 ♦ * * * * * * * * *
Staphylocυccus aureus * * 32 * * * * * * * * * *
Streptococcus pneumoniae * * 16 * * * 16 * 64 * 64 64 32-64
Enterococcus faecalis * * 32-64 * * * * * * * *
Microcυccus luteus * * 8 16-64 • 32-64 + * * *
Escherichla coll * * * * * * * + * * * *
Enterococcus faecalis * « * * * * * * ♦ * ♦ * *
Enterobacter cloacae * * * * * + • * •*• * * *
Slenυtrυphυmonas * * * * * + * * * * * * * nialtophilia
Neisseria gonorrhoeae 16-32 * 8 8 16 8-32 2-4 32 32-64 * * 32 16-32
\ no inhibition at 64 μg/ml
4.1/12504.012 31
Claims
What is claimed is: 1. A resveratrol derivative having the formula:
2. A resveratrol derivative having the formula:
wherein R4 = R5 = -OCH3 and R^ = -OH.
3. A resveratrol derivative having the formula:
R*. wherein R7 = R8 = -OH and R9 = -OCH3.
1398874.1/12504.012 32
4. A resveratrol derivative having the formula:
selected from the group consisting of compounds wherein: a) Rio = Ri i = -OCH3 and Ri2 = -O(PO)(OBn)2; and b) R10 = Rn = -OCH3 and Ri2 = -O(PO)(ONa)2.
5. A method for synthesizing the resveratrol derivative of claim 1 wherein Ri = R2 = R3 -OCH , comprising reacting phosphonium bromide and 3,5-dimethylbenzaldehyde.
6. A method for synthesizing the resveratrol derivative of claim 1 wherein Ri = -OH and R2 = R3 = -OCH3, comprising the following steps:
5a 6
14b -*■ 14d (£)
90%
14e,f 14g,
34
7. A method for synthesizing the resveratrol derivative of claim 2 comprising the following steps:
4a (Z),4b(£)
9a
1398874.1/12504.012 35
8. A method for synthesizing the resveratrol derivative of claim 3 comprising the following steps:
9a
5b
14b - 14d (E)
90%
37
9. A method for synthesizing the resveratrol derivative of claim 4 wherein Rio = Ri ι = -OCH3 and Rι2 = -O(PO)(OBn)2, comprising the following steps:
14b * 14d (£)
90%
14e,f 14g,h
10. A method for synthesizing the resveratrol derivative of claim 4 wherein Rio = Ri 1 -OCH3 and -O(PO)(ONa)2, comprising the following steps:
Λa (Z),4b(-=)
9a
14b „»B ' 4 (E) 90%
11. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising the compound of claim 2, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising the compound of claim 3, or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising the compound of claim 4, or a pharmaceutically acceptable salt thereof.
15. A method for treating humans and mammals afflicted with cancer, comprising administering a physiologically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.
1398874.1/12504.012 42
16. A method for treating humans and mammals afflicted with cancer, comprising administering a physiologically effective amount of the compound of claim 2, or a pharmaceutically acceptable salt thereof.
17. A method for treating humans and mammals afflicted with cancer, comprising administering a physiologically effective amount of the compound of claim 3, or a pharmaceutically acceptable salt thereof.
18. A method for treating humans and mammals afflicted with cancer, comprising administering a physiologically effective amount of the compound of claim 4, or a pharmaceutically acceptable salt thereof.
1398874.1/12504.012 43
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/510,675 US7705188B2 (en) | 2002-04-10 | 2003-04-10 | Structural modification of resveratrol: sodium resverastatin phosphate |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US37178202P | 2002-04-10 | 2002-04-10 | |
US60/371,782 | 2002-04-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003086414A1 true WO2003086414A1 (en) | 2003-10-23 |
Family
ID=29250742
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2003/011008 WO2003086414A1 (en) | 2002-04-10 | 2003-04-10 | Structural modification of resveratrol: sodium resverastatin phosphate |
Country Status (2)
Country | Link |
---|---|
US (1) | US7705188B2 (en) |
WO (1) | WO2003086414A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006029484A1 (en) * | 2004-09-14 | 2006-03-23 | Ajinomoto Omnichem S.A. | Topical compositions containing phosphorylated polyphenols |
WO2006029483A1 (en) * | 2004-09-14 | 2006-03-23 | Ajinomoto Omnichem S.A. | Phosphorylated polyphenols as colour-stable agents |
EP1748767A1 (en) * | 2004-05-28 | 2007-02-07 | Unigen Pharmaceuticals, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
WO2008012321A1 (en) * | 2006-07-28 | 2008-01-31 | Clariant Specialty Fine Chemicals (France) | Novel process for the synthesis of (e)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol |
CN100567309C (en) * | 2007-06-15 | 2009-12-09 | 中国科学院广州化学研究所 | (E) 3, 5-dimethoxystilbene-4'-0-phosphate and its preparation, pharmaceutical composition and use |
US8362305B2 (en) | 2008-07-21 | 2013-01-29 | Unigen, Inc. | Series of skin whitening (lightening) compounds |
US8399714B2 (en) | 2007-10-03 | 2013-03-19 | Clariant Speciality Fine Chemicals (France) | Process for the synthesis of polyhydroxystilbene compounds |
US8586799B2 (en) | 2011-03-24 | 2013-11-19 | Unigen, Inc. | Compounds and methods for preparation of diarylpropanes |
CN103992212A (en) * | 2014-05-29 | 2014-08-20 | 河北科技大学 | Synthesis method for cis-benvitimod, and applications of cis-benvitimod |
CN104844517A (en) * | 2015-04-15 | 2015-08-19 | 上海应用技术学院 | (E)-3-hydroxy-5-(hydroxystyryl)imidazole phenol acetate and preparation method and application thereof |
CN104844505A (en) * | 2015-04-15 | 2015-08-19 | 上海应用技术学院 | (E)-3-hydroxy-5-(hydroxystyryl)pyridine-2-phenol formate and preparation method and application thereof |
CN108689805A (en) * | 2018-05-22 | 2018-10-23 | 荆楚理工学院 | A kind of preparation method of resveratrol |
JP2020514249A (en) * | 2016-11-30 | 2020-05-21 | コンセホ・スペリオール・デ・インベスティガシオネス・シエンティフィカスConsejo Superior De Investigaciones Cientificas | Silylated derivatives of resveratrol and their use in neurodegenerative, neurological or inflammatory diseases |
US11174291B2 (en) | 2015-02-13 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Silstatin compounds |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070292545A1 (en) * | 2005-10-18 | 2007-12-20 | Aaron Monte | Anti-infective agents and methods of use |
US8426369B2 (en) | 2006-12-07 | 2013-04-23 | Rutgers, The State University Of New Jersey | Prevention and treatment of colon cancer |
WO2009038731A2 (en) * | 2007-09-17 | 2009-03-26 | The Trustees Of Columbia University In The City Of New York | Synthesis of resveratrol-based natural products |
WO2010141107A1 (en) * | 2009-06-01 | 2010-12-09 | Aptuit Laurus Private Limited | Solid forms of pterostilbene |
ITRM20130135A1 (en) | 2013-03-06 | 2014-09-07 | Michele Azzolini | NEW RESVERATROLO DERIVATIVES. |
US10138423B1 (en) | 2017-05-31 | 2018-11-27 | International Business Machines Corporation | Resveratrol-based flame retardant materials |
US11629167B2 (en) | 2017-11-09 | 2023-04-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Betulastatin compounds |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001060774A1 (en) * | 2000-02-16 | 2001-08-23 | Brigham Young University | Synthesis of resveratrol |
US20020028852A1 (en) * | 1999-09-21 | 2002-03-07 | Geetha Ghai | Resveratrol analogs for prevention of disease |
US20030118617A1 (en) * | 2001-12-21 | 2003-06-26 | Avon Products, Inc. | Resveratrol analogues |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6197834B1 (en) * | 1998-09-01 | 2001-03-06 | Northeastern Ohio Universities College Of Medicine | Method of inhibiting formation of infectious herpes virus particles |
WO2002006279A1 (en) * | 2000-07-17 | 2002-01-24 | Oxigene Inc | Efficient method of synthesizing combretastatin a-4 prodrugs |
-
2003
- 2003-04-10 US US10/510,675 patent/US7705188B2/en not_active Expired - Fee Related
- 2003-04-10 WO PCT/US2003/011008 patent/WO2003086414A1/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020028852A1 (en) * | 1999-09-21 | 2002-03-07 | Geetha Ghai | Resveratrol analogs for prevention of disease |
WO2001060774A1 (en) * | 2000-02-16 | 2001-08-23 | Brigham Young University | Synthesis of resveratrol |
US20030118617A1 (en) * | 2001-12-21 | 2003-06-26 | Avon Products, Inc. | Resveratrol analogues |
Non-Patent Citations (7)
Title |
---|
CUSHMAN ET AL.: "Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, no. 12, June 1992 (1992-06-01), pages 2293 - 2306, XP000571677 * |
GRACZA ET AL.: "High-performance liquid chromatographic separation and quantitative determination of plant stilbene derivatives", JOURNAL OF CHROMATOGRAPHY, vol. 287, no. 2, April 1984 (1984-04-01), pages 462 - 465 * |
PETTIT ET AL.: "Antineoplastic agents. 465. Structural modification of resveratrol: Sodium resverastatin phosphate", JOURNAL OF MEDICINAL CHEMISTRY, vol. 45, no. 12, May 2002 (2002-05-01), pages 2534 - 2542, XP002968964 * |
RIMANDO ET AL.: "Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occuring analogue of resveratrol", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, vol. 50, no. 12, June 2002 (2002-06-01), pages 3453 - 3457, XP002968963 * |
RYU ET AL.: "Antitumor activity of some phenolic components in plants", ARCH. PHARM. RES., vol. 17, no. 1, January 1994 (1994-01-01), pages 42 - 44, XP002968965 * |
SPATH ET AL.: "Constituents of red sandalwood. III. Synthesis of pterostilbene", BER., vol. 74B, February 1941 (1941-02-01), pages 189 - 192, XP002968966 * |
TAKAOKA MICHIO: "The synthesis of resveratrol and its derivatives", PROCEEDINGS OF THE IMPERIAL ACADEMY, vol. 16, October 1940 (1940-10-01), TOKYO, pages 405 - 407, XP002968962 * |
Cited By (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7767661B2 (en) | 2004-05-28 | 2010-08-03 | Unigen Pharmaceuticals, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
US9126913B2 (en) | 2004-05-28 | 2015-09-08 | Unigen, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
EP1748767A1 (en) * | 2004-05-28 | 2007-02-07 | Unigen Pharmaceuticals, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
US10548825B2 (en) | 2004-05-28 | 2020-02-04 | Unigen, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
US8729136B2 (en) | 2004-05-28 | 2014-05-20 | Unigen, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
US8592488B2 (en) | 2004-05-28 | 2013-11-26 | Unigen, Inc. | Diarylalkanes as potent inhibitors of binuclear enzymes |
EP1748767A4 (en) * | 2004-05-28 | 2008-12-24 | Unigen Pharmaceuticals Inc | Diarylalkanes as potent inhibitors of binuclear enzymes |
CN101018554B (en) * | 2004-09-14 | 2010-10-27 | 味之素欧姆尼凯姆股份有限公司 | Topical compositions containing phosphorylated polyphenols |
AU2004323347B2 (en) * | 2004-09-14 | 2011-02-24 | Ajinomoto Omnichem S.A. | Topical compositions containing phosphorylated polyphenols |
JP2008513378A (en) * | 2004-09-14 | 2008-05-01 | アジノモト オムニケム エッス.アー. | Topical composition containing phosphorylated polyphenols |
WO2006029484A1 (en) * | 2004-09-14 | 2006-03-23 | Ajinomoto Omnichem S.A. | Topical compositions containing phosphorylated polyphenols |
US8465973B2 (en) | 2004-09-14 | 2013-06-18 | Estee Lauder Coordination Center N.V. | Topical compositions containing phosphorylated polyphenols |
WO2006029483A1 (en) * | 2004-09-14 | 2006-03-23 | Ajinomoto Omnichem S.A. | Phosphorylated polyphenols as colour-stable agents |
EP2202215A3 (en) * | 2006-07-28 | 2010-09-08 | Clariant Specialty Fine Chemicals (France) | Novel process for the synthesis of (E)-Stilbene derivatives which makes it possible to obtain resveratrol and piceatannol |
US8101804B2 (en) | 2006-07-28 | 2012-01-24 | Clariant Specialty Fine Chemicals (France) | Process for the synthesis of (E)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol |
JP2009544663A (en) * | 2006-07-28 | 2009-12-17 | クラリアント スペシャルティー ファイン ケミカルズ(フランス) | Novel process for the synthesis of (E) -stilbene derivatives that makes it possible to obtain resveratrol and piceatannol |
FR2904311A1 (en) * | 2006-07-28 | 2008-02-01 | Clariant Specialty Fine Chem | NEW PROCESS FOR THE SYNTHESIS OF (E) STILBENIC DERIVATIVES PERM TO OBTAIN RESVERATROL AND PICEATANNOL |
EP2202215A2 (en) * | 2006-07-28 | 2010-06-30 | Clariant Specialty Fine Chemicals (France) | Novel process for the synthesis of (E)-Stilbene derivatives which makes it possible to obtain resveratrol and piceatannol |
WO2008012321A1 (en) * | 2006-07-28 | 2008-01-31 | Clariant Specialty Fine Chemicals (France) | Novel process for the synthesis of (e)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol |
CN100567309C (en) * | 2007-06-15 | 2009-12-09 | 中国科学院广州化学研究所 | (E) 3, 5-dimethoxystilbene-4'-0-phosphate and its preparation, pharmaceutical composition and use |
US8399714B2 (en) | 2007-10-03 | 2013-03-19 | Clariant Speciality Fine Chemicals (France) | Process for the synthesis of polyhydroxystilbene compounds |
US9096507B2 (en) | 2008-07-21 | 2015-08-04 | Unigen, Inc. | Series of skin whitening (lightening) compounds |
US8658838B2 (en) | 2008-07-21 | 2014-02-25 | Unigen, Inc. | Series of skin whitening (lightening) compounds |
US8362305B2 (en) | 2008-07-21 | 2013-01-29 | Unigen, Inc. | Series of skin whitening (lightening) compounds |
US8586799B2 (en) | 2011-03-24 | 2013-11-19 | Unigen, Inc. | Compounds and methods for preparation of diarylpropanes |
US9045405B2 (en) | 2011-03-24 | 2015-06-02 | Unigen, Inc. | Compounds and methods for preparation of diarylpropanes |
CN103992212B (en) * | 2014-05-29 | 2015-07-01 | 河北科技大学 | Synthesis method for cis-benvitimod, and applications of cis-benvitimod |
CN103992212A (en) * | 2014-05-29 | 2014-08-20 | 河北科技大学 | Synthesis method for cis-benvitimod, and applications of cis-benvitimod |
US11174291B2 (en) | 2015-02-13 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Silstatin compounds |
CN104844517A (en) * | 2015-04-15 | 2015-08-19 | 上海应用技术学院 | (E)-3-hydroxy-5-(hydroxystyryl)imidazole phenol acetate and preparation method and application thereof |
CN104844505A (en) * | 2015-04-15 | 2015-08-19 | 上海应用技术学院 | (E)-3-hydroxy-5-(hydroxystyryl)pyridine-2-phenol formate and preparation method and application thereof |
JP2020514249A (en) * | 2016-11-30 | 2020-05-21 | コンセホ・スペリオール・デ・インベスティガシオネス・シエンティフィカスConsejo Superior De Investigaciones Cientificas | Silylated derivatives of resveratrol and their use in neurodegenerative, neurological or inflammatory diseases |
JP7082977B2 (en) | 2016-11-30 | 2022-06-09 | コンセホ・スペリオル・デ・インベスティガシオネス・シエンティフィカス(セエセイセ) | Resveratrol silylated derivatives and their use in neurodegenerative, neurological, or inflammatory diseases |
US11365208B2 (en) | 2016-11-30 | 2022-06-21 | Consejo Superior De Investigaciones Cientificas | Silylated derivatives of resveratrol and the use thereof in neurodegenerative, neurological or inflammatory diseases |
CN108689805A (en) * | 2018-05-22 | 2018-10-23 | 荆楚理工学院 | A kind of preparation method of resveratrol |
CN108689805B (en) * | 2018-05-22 | 2021-08-03 | 荆楚理工学院 | Preparation method of resveratrol |
Also Published As
Publication number | Publication date |
---|---|
US7705188B2 (en) | 2010-04-27 |
US20050240062A1 (en) | 2005-10-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7705188B2 (en) | Structural modification of resveratrol: sodium resverastatin phosphate | |
Pettit et al. | Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6 | |
Cirla et al. | Combretastatins: from natural products to drug discovery | |
Mukherjee et al. | Synthetic and biological activity evaluation studies on novel 1, 3-diarylpropenones | |
Onegi et al. | Antiplasmodial activity of naphthoquinones and one anthraquinone from Stereospermum kunthianum | |
AU2005249493B2 (en) | Diarylalkanes as potent inhibitors of binuclear enzymes | |
Flores et al. | Antiparasitic activity of prenylated benzoic acid derivatives from Piper species | |
Wijeratne et al. | A new dihydroxanthenone from a plant-associated strain of the fungus Chaetomium globosum demonstrates anticancer activity | |
Ahmed | Chemistry of natural products | |
Mihigo et al. | Total synthesis, antiprotozoal and cytotoxicity activities of rhuschalcone VI and analogs | |
Abbasi et al. | Curcumin and its derivatives: Moderate inhibitors of acetylcholinesterase, butyrylcholinesterase and trypsin | |
Sarg et al. | Two new polyphenolic compounds from Ficus retusa L." variegata" and the biological activity of the different plant extracts | |
Pettit et al. | E-Combretastatin and E-resveratrol structural modifications: Antimicrobial and cancer cell growth inhibitory β-E-nitrostyrenes | |
Motiur Rahman et al. | Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation, and structure–activity relationship studies | |
Jung et al. | Additional bioactive heptenes from Melodorum fruticosum | |
Tietze et al. | Synthesis of highly functionalized anthraquinones and evaluation of their antitumor activity | |
Al-Rehaily et al. | Bioactive Chemical Constituents of Ononis natrix. | |
Yousaf et al. | A 5-alkylresorcinol and three3, 4-dihydroisocoumarins derived from Ononis natrix | |
Jung et al. | New Synthetic Routes to Biologically Interesting Geranylated Flavanones and Geranylated Chalcones: First Total Synthesis of (±)‐Prostratol F, Xanthoangelol, and (±)‐Lespeol | |
EP2984072B1 (en) | Synthetic analogues of xanthohumol | |
Pettit et al. | Antineoplastic agents 460. Synthesis of combretastatin A‐2 prodrugs | |
Dias et al. | Dihydrobenzofuran neolignans: An overview of their chemistry and biological activities | |
Um et al. | New coumarins from Cedrelopsis grevei | |
Taborga et al. | Antifungal toxicity of linear geranylphenol. Influence of oxigenate substituents | |
US8673971B2 (en) | Derivatives of 4-nerolidylcatechol, pharmaceutical compositions comprising them and process for producing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 10510675 Country of ref document: US |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |