US20100179108A1 - Synthesis of Sodium Narcistatin and Related Compounds - Google Patents
Synthesis of Sodium Narcistatin and Related Compounds Download PDFInfo
- Publication number
- US20100179108A1 US20100179108A1 US12/723,912 US72391210A US2010179108A1 US 20100179108 A1 US20100179108 A1 US 20100179108A1 US 72391210 A US72391210 A US 72391210A US 2010179108 A1 US2010179108 A1 US 2010179108A1
- Authority
- US
- United States
- Prior art keywords
- trans
- narciclasine
- deoxy
- cancer cell
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- PDHVRYDRIJXVHV-WAJBGZTRSA-M sodium narcistatin Chemical compound [Na+].C1=C2C3=C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 PDHVRYDRIJXVHV-WAJBGZTRSA-M 0.000 title abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title description 20
- 238000003786 synthesis reaction Methods 0.000 title description 20
- 238000000034 method Methods 0.000 claims description 23
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 17
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 208000032839 leukemia Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims 3
- 208000026310 Breast neoplasm Diseases 0.000 claims 3
- 206010009944 Colon cancer Diseases 0.000 claims 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 3
- 206010060862 Prostate cancer Diseases 0.000 claims 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 3
- 201000007455 central nervous system cancer Diseases 0.000 claims 3
- 208000029742 colonic neoplasm Diseases 0.000 claims 3
- 201000005202 lung cancer Diseases 0.000 claims 3
- 208000020816 lung neoplasm Diseases 0.000 claims 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 3
- 201000002528 pancreatic cancer Diseases 0.000 claims 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 3
- LZAZURSABQIKGB-AEKGRLRDSA-N Narciclasine Chemical compound C1=C2C3=C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 LZAZURSABQIKGB-AEKGRLRDSA-N 0.000 abstract description 37
- VSEJCXBFXFEXPW-UHFFFAOYSA-N narciclasine Natural products OC1CC2=C(C(O)C1O)c3cc4OCOc4c(O)c3C(=O)N2 VSEJCXBFXFEXPW-UHFFFAOYSA-N 0.000 abstract description 28
- SBTGHBALOCEVOR-PUZXQUAOSA-N (2s,3r,4s,4ar,11br)-2,3,4,7-tetrahydroxy-2,3,4,4a,5,11b-hexahydro-1h-[1,3]dioxolo[4,5-j]phenanthridin-6-one Chemical compound C1=C2[C@H]3C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 SBTGHBALOCEVOR-PUZXQUAOSA-N 0.000 abstract description 19
- KKAHUDOWKGIGAA-IAWGOJCDSA-N (2s,3r,4s,4ar,11br)-2,3,4-trihydroxy-2,3,4,4a,5,11b-hexahydro-1h-[1,3]dioxolo[4,5-j]phenanthridin-6-one Chemical compound C1=C2[C@H]3C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=CC2=C1OCO2 KKAHUDOWKGIGAA-IAWGOJCDSA-N 0.000 abstract description 18
- 229910019142 PO4 Inorganic materials 0.000 abstract description 16
- YYDLFVZOIDOGSO-KKBFJBPOSA-N Lycoricidine Chemical compound C1=C2C3=C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=CC2=C1OCO2 YYDLFVZOIDOGSO-KKBFJBPOSA-N 0.000 abstract description 15
- KKAHUDOWKGIGAA-UHFFFAOYSA-N dihydrolycoricidine Natural products C1=C2C3CC(O)C(O)C(O)C3NC(=O)C2=CC2=C1OCO2 KKAHUDOWKGIGAA-UHFFFAOYSA-N 0.000 abstract description 13
- LZAZURSABQIKGB-UHFFFAOYSA-N Narciclasine Tetraacetat Natural products C1=C2C3=CC(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 LZAZURSABQIKGB-UHFFFAOYSA-N 0.000 abstract description 12
- 239000010452 phosphate Substances 0.000 abstract description 11
- SBTGHBALOCEVOR-UHFFFAOYSA-N 10balpha-Dihydro-Narciclasine Natural products C1=C2C3CC(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 SBTGHBALOCEVOR-UHFFFAOYSA-N 0.000 abstract description 10
- ZYIGYGVYWJYYHP-PXRHWMLOSA-M chembl497270 Chemical compound [Na+].C1=C2[C@H]3C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=CC2=C1OCO2 ZYIGYGVYWJYYHP-PXRHWMLOSA-M 0.000 abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 10
- SLCOIDLNVICCQI-MLKYSBHOSA-M sodium trans-dihydronarcistatin Chemical compound [Na+].C1=C2[C@H]3C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 SLCOIDLNVICCQI-MLKYSBHOSA-M 0.000 abstract description 9
- 229940002612 prodrug Drugs 0.000 abstract description 7
- 239000000651 prodrug Substances 0.000 abstract description 7
- XCKKHOCUQNSJOR-KCCDOBPASA-M sodium 7-deoxynarcistatin Chemical compound [Na+].C1=C2C3=C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=CC2=C1OCO2 XCKKHOCUQNSJOR-KCCDOBPASA-M 0.000 abstract description 7
- 241000234270 Amaryllidaceae Species 0.000 abstract description 6
- 241000234479 Narcissus Species 0.000 abstract description 4
- 238000002955 isolation Methods 0.000 abstract description 4
- 239000002243 precursor Substances 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 241000196324 Embryophyta Species 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 23
- 239000007787 solid Substances 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 238000005984 hydrogenation reaction Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- 235000021317 phosphate Nutrition 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 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 10
- 239000002904 solvent Substances 0.000 description 10
- ACQYZSFXPXXIHL-UHFFFAOYSA-N 2-phenylmethoxycarbonyl-3,4-dihydro-1h-isoquinoline-1-carboxylic acid Chemical compound C1CC2=CC=CC=C2C(C(=O)O)N1C(=O)OCC1=CC=CC=C1 ACQYZSFXPXXIHL-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 description 6
- MJOQJPYNENPSSS-XQHKEYJVSA-N [(3r,4s,5r,6s)-4,5,6-triacetyloxyoxan-3-yl] acetate Chemical compound CC(=O)O[C@@H]1CO[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O MJOQJPYNENPSSS-XQHKEYJVSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 230000010261 cell growth Effects 0.000 description 6
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 229940093499 ethyl acetate Drugs 0.000 description 6
- 238000005342 ion exchange Methods 0.000 description 6
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000118 anti-neoplastic effect Effects 0.000 description 4
- 239000012223 aqueous fraction Substances 0.000 description 4
- 150000001768 cations Chemical group 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- YZQLZWYKYCWFGR-HPKWNKRYSA-N narcistatin Chemical class C1=C2C3=C[C@H](O)[C@H]4OP(O)(=O)O[C@H]4[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 YZQLZWYKYCWFGR-HPKWNKRYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000605510 Hymenocallis Species 0.000 description 3
- 240000005062 Hymenocallis littoralis Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 244000015069 Zephyranthes candida Species 0.000 description 3
- PFRIIIIZSBDKMP-QKPHTXKDSA-N [(2s,3r,4s,4ar,11br)-3,4-diacetyloxy-6-oxo-2,3,4,4a,5,11b-hexahydro-1h-[1,3]dioxolo[4,5-j]phenanthridin-2-yl] acetate Chemical compound C1=C2[C@H]3C[C@H](OC(=O)C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]3NC(=O)C2=CC2=C1OCO2 PFRIIIIZSBDKMP-QKPHTXKDSA-N 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 229940034982 antineoplastic agent Drugs 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 239000011995 wilkinson's catalyst Substances 0.000 description 3
- JIMDZZQKKBUKLO-QDWQASTRSA-N (2s,3r,4s)-2,3,4,7-tetrahydroxy-2,3,4,5-tetrahydro-1h-[1,3]dioxolo[4,5-j]phenanthridin-6-one Chemical compound C1=C2C(C[C@@H]([C@H]([C@H]3O)O)O)=C3NC(=O)C2=C(O)C2=C1OCO2 JIMDZZQKKBUKLO-QDWQASTRSA-N 0.000 description 2
- PEOASDPEDCJOME-UHFFFAOYSA-N 4,7-dihydroxy-5h-[1,3]dioxolo[4,5-j]phenanthridin-6-one Chemical compound N1C(=O)C2=C(O)C=3OCOC=3C=C2C2=C1C(O)=CC=C2 PEOASDPEDCJOME-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- -1 carbomethoxy Chemical group 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 208000003747 lymphoid leukemia Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- SBTGHBALOCEVOR-GUHAZCHASA-N (2s,3r,4s,4ar,11bs)-2,3,4,7-tetrahydroxy-2,3,4,4a,5,11b-hexahydro-1h-[1,3]dioxolo[4,5-j]phenanthridin-6-one Chemical compound C1=C2[C@@H]3C[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 SBTGHBALOCEVOR-GUHAZCHASA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 0 C[C@]([C@]([C@@]([C@](C1)O)O2)OP2(*)=O)([C@]1c(c1c2O)cc3c2OCO3)NC1=O Chemical compound C[C@]([C@]([C@@]([C@](C1)O)O2)OP2(*)=O)([C@]1c(c1c2O)cc3c2OCO3)NC1=O 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000319062 Lycoris radiata Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 241001633596 Zephyranthes Species 0.000 description 1
- IGLXRTDMBRBLEF-NOMZHJQSSA-N [H][C@@]12NC(=O)C3=C(C=C4OCOC4=C3)C1=C[C@H](O)[C@H]1OP(C)(=O)O[C@H]12 Chemical compound [H][C@@]12NC(=O)C3=C(C=C4OCOC4=C3)C1=C[C@H](O)[C@H]1OP(C)(=O)O[C@H]12 IGLXRTDMBRBLEF-NOMZHJQSSA-N 0.000 description 1
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- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
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- 150000002148 esters Chemical group 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- OAMZXMDZZWGPMH-UHFFFAOYSA-N ethyl acetate;toluene Chemical compound CCOC(C)=O.CC1=CC=CC=C1 OAMZXMDZZWGPMH-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
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- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
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- GBRZTUJCDFSIHM-UHFFFAOYSA-N licorisoflavan B Natural products C1C=2C(OC)=C(CC=C(C)C)C(O)=CC=2OCC1C1=CC=C(O)C(CC=C(C)C)=C1O GBRZTUJCDFSIHM-UHFFFAOYSA-N 0.000 description 1
- WKTDZPBXTQLYQG-KCCDOBPASA-M lithium 7-deoxynarcistatin Chemical compound [Li+].C1=C2C3=C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=CC2=C1OCO2 WKTDZPBXTQLYQG-KCCDOBPASA-M 0.000 description 1
- JTAWIFDITPSXMM-WAJBGZTRSA-M lithium narcistatin Chemical compound [Li+].C1=C2C3=C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 JTAWIFDITPSXMM-WAJBGZTRSA-M 0.000 description 1
- WWLXQEBJUAUISM-MLKYSBHOSA-M lithium trans-dihydronarcistatin Chemical compound [Li+].C1=C2[C@H]3C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 WWLXQEBJUAUISM-MLKYSBHOSA-M 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- LHMQYKBAVHMNBG-KCCDOBPASA-M potassium 7-deoxynarcistatin Chemical compound [K+].C1=C2C3=C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=CC2=C1OCO2 LHMQYKBAVHMNBG-KCCDOBPASA-M 0.000 description 1
- IIELAIDLKQCQKF-WAJBGZTRSA-M potassium narcistatin Chemical compound [K+].C1=C2C3=C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 IIELAIDLKQCQKF-WAJBGZTRSA-M 0.000 description 1
- ZTXALMONYDPRND-MLKYSBHOSA-M potassium trans-dihydronarcistatin Chemical compound [K+].C1=C2[C@H]3C[C@H](O)[C@H]4OP([O-])(=O)O[C@H]4[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 ZTXALMONYDPRND-MLKYSBHOSA-M 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
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- 238000010898 silica gel chromatography Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
Definitions
- the present invention relates certain compounds, and methods for synthesis of certain compounds, wherein the compounds have shown anti-neoplastic activity against cancerous cell lines, and therefore are anticipated to be useful in the treatment of various forms of cancer in animals and humans.
- the present invention involves use of the compounds narciclasine (2a) and 7-deoxy-narciclasine (2c), which are obtained via isolation from the medicinal plant species Narcissus (Amaryllidaceae), as precursors in a novel synthesis method in which each of these compounds are selectively hydrogenated to produce trans-dihydronarciclasine (1a) and 7-deoxy-trans-dihydronarciclasine (1c). Also described herein is a novel synthesis method for producing sodium narcistatin (11) from narciclasine (2a).
- the present invention involves use of the compounds narciclasine (2a) and 7-deoxy-narciclasine (2c) which are obtained via isolation from certain Narcissus (Amaryllidaceae) as precursors in a novel and unobvious process by which each of these compounds may be selectively hydrogenated to produce trans-dihydronarciclasine (1a) and 7-deoxy-trans-dihydronarciclasine (1c).
- FIG. 1 shows structural formulas for the compounds described herein
- FIG. 2 shows reaction schemes for synthesizing some of the compounds of the present invention.
- Narciclasine (2a) was isolated from the bulbs of Narcissus imcomparabilus
- 7-deoxynarciclasine (2c) and 7-deoxy-transdihydronarciclasine (1c) were isolated from the bulbs of Hymenocallis littoralis grown by the ASU-CRI research group in Tempe, Ariz., now part of the Arizona Biodesign Institute.
- the cation forms of the resin were prepared by eluting with a 1N solution of the appropriate base followed by deionized water. All reaction products were colorless solids unless otherwise noted. All melting points were determined with an Electrothermal digital melting point apparatus model IA9200 and are uncorrected.
- 2,3,4,7-O-Tetraacetoxy-narciclasine (2b) Compound 2b is produced as follows. To a stirred solution of narciclasine (1.00 g, 3.25 mmol) in pyridine (3 ml under nitrogen), add acetic anhydride (6 ml). Stir for 16 hours at room temperature, add ice (50 ml) to the mixture, and extract with dichloromethane (3 ⁇ 20 ml). The combined extract is dried over MgSO 4 , filtered and evaporated in vacuo to afford 2,3,4,7-O-Tetraacetoxy-narciclasine (2b) as a light brown powder (1.4 g, 90% yield).
- Trans-Dihydronarciclasine (1a) Dissolve 2,3,4,7-O-tetraacetoxy-trans-dihydronarciclasine (1b) (0.512 g, 1.07 mmol) in methanol:water (9:1) (20 ml), and add dichloromethane (12 ml) to aid in solubility. Add Potassium carbonate (0.009 g, 0.06 mmol) and stir the reaction at room temperature for three days. TLC(CH 2 Cl 2 :CH 3 OH 4%) shows complete conversion to the product.
- the third minor component isolated was 2-[tert-Butyl-1,1-dimethylsilyl]oxy-3,4-isopropylidene-7-deoxy-iso-dihydro-narciclasine (4c) as a solid (0.005 g, 10%): m.p. 246.5-248.0° C.
- the trans:cis:iso ratios were determined by 1 H-NMR and were based on a 100% conversion of starting material to product. The best ratio observed was 51:47:2 respectively with acetic acid as the solvent and the reaction carried out on a small scale (approx. 0.020 g of narciclasine peracetate). Scaleup of this reaction showed a wide variation in results. When 5 g of narciclasine was hydrogenated in acetic acid in the presence of 5% Pd/C (8 mol %) for 20 hr only starting material was recovered.
- the synthetic trans-isomer (1d) was obtained by deprotection of the acetonide using formic acid (60%) followed by deprotection of the silyl ether with TBAF to yield 1c which was found to be identical with an authentic sample of 7-deoxy-trans-dihydronarciclasine (1d).
- RNA Antiviral activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances. J. Nat. Prod. 55:1569-1581; 1992.
- sodium narcistatin (11) was improved (88% overall yield) and the modified reaction sequence was utilized to synthesize sodium 7-deoxy-narcistatin (8), sodium 7-deoxy-trans-dihydronarcistatin (9) and sodium trans-dihydro-narcistatin (10).
- the human cancer cell line inhibitory isocarbostyril precursors were isolated from the bulbs of Hymenocallis littoralis obtained by horticultural production or reduction of narciclasine (2a) from the same source. Solvents were distilled prior to use and pyridine was dried over potassium hydroxide and distilled.
- the three new 3,4-cyclic phosphate prodrugs (8, 9, and 10), whose synthesis is discussed in further detail below, are being evaluated for further development as anticancer drugs.
- the reaction is stirred for about 96 hours, cooled and filtered to remove precipitated dicyclohexylurea (DCU). Water (100 ml) is added and the mixture refiltered to remove any residual DCU. The mother liquor is concentrated to minimum volume. The aqueous fraction is eluted through an ion exchange column (sodium form). The UV active fractions are combined and lypholized to yield the phosphate 11 as a cream solid (88% yield). Rather than eluting the aqueous fraction via a sodium form of an ion exchange column, another suitable salt form (such as potassium or lithium) could be used to produce a compound such as potassium narcistatin or lithium narcistatin.
- DCU precipitated dicyclohexylurea
- the 7-deoxynarciclasine (2c) and 7-deoxy-trans-dihydronarciclasine (1c) mixture separated from H. littoralis was acetylated by dissolving in pyridine (20 mL) and adding acetic anhydride (20 mL, 2.4 equiv.) The mixture slowly becomes a solution with stirring overnight at room temperature, and TLC(CH 2 Cl 2 —CH 3 OH, 2%) showed no starting material. Ice water (200 ml) is added to the reaction mixture with vigorous stirring. A cream colored precipitate develops and is collected following being stirred for two hours to provide 13.7 g.
- the peracetate mixture (acetylation product) is separated by elution using 7:3 toluene-ethyl acetate, via silica gel column chromatography, to yield the following isocarbostyrils 12 (60% recovery) and 13 (19% recovery).
- Both 2, 3, 4-triacetoxy-7-deoxynarciclasine (12) and 2,3,4-triacetoxy-7-deoxy-trans-dihydronarciclasine (13) were then deprotected with potassium carbonate in aqueous methanol to afford the corresponding triols 14 and 15 in 72% yields.
- the 3,4-cyclic phosphates 8, 9 and 10 were synthesized employing an improvement in the procedure we developed for synthesis of sodium narcistatin (11) using tetrabutylammonium dihydrogen phosphate and an excess of dicyclocarbodiimide in dry pyridine under argon at 80° C. for 48 hours.
- Mondon, A., et al., Chem. Ber. 1975, 94, 617 (Pettit, G. R., et al., J. Nat. Prod. 1986, 49, 995-1002), (Pettit, G. R., et al., J. Nat. Prod. 2003, 66, 92-96.)
- the UV responsive fractions were combined and lyophilized to afford the new 3,4-cyclic phosphates designated sodium 7-deoxy-narcistatin (8, 88% yield), sodium 7-deoxy-trans-dihydro-narcistatin (9, 65% yield) and sodium trans-dihydro-narcistatin (10, 94% yield).
- deletion of the p-toluene sulfonic acid component increased the yield of phosphate 11 to 88% versus the original 50%. That was one of the major improvements that allowed new phosphates 8, 9 and 10 to be obtained in very good yields.
- the cyclic phosphate prodrugs, along with the parent compounds were evaluated against a minipanel of human cancer cell lines and murine P388 lymphocytic leukemia. See Table 2.
- 7-Deoxy-narciclasine (2c) 7-Deoxy-narciclasine (2c).
- a solution of 2,3,4-triacetoxy-7-deoxy-narciclasine (12, 4.36 g) in CH 3 OH-(99 ml) H 2 O-(1 ml) CH 3 OH (30 ml) is added potassium carbonate (0.124 g), with stirring continued for 16 hours at room temperature while a white precipitate separated.
- the mixture is neutralized with acetic acid (2 ml), stirred for 15 minutes and concentrated to minimum volume.
- the colorless product is collected (2.18 g, 72%), recrystallization from acetic acid-methanol afforded fine needles: mp 205-210° C. (dec).
- Tetrabutylammonium dihydrogen phosphate (0.15 g) was added followed by DCCl (0.8 g) and the reaction continued for a further 24 hours. At this point, 1 H NMR analysis of a sample from the reaction mixture showed reaction was complete.
- the reaction mixture was cooled and water (100 ml) was added.
- the precipitated dicyclohexylurea (DCU) was collected and the pyridine-water mother liquor was concentrated to minimum volume.
- the aqueous fraction was then passed through an ion exchange column (DOWER 50W8-400) in the sodium form.
- the UV responsive fractions were combined and lypholized to yield phosphate 8 as a colorless solid: 227 mg (88%); mp 255° C. (dec.).
- Lithium 7-Deoxy-narcistatin (10a) 34 mg, mp 250° C. (dec).
- aqueous extract of product is subjected to ion exchange column of Dowex 50WX8-400 (sodium form) and the UV fluorescing fractions combined and lyophilized as noted above (cf, 8).
- a solution of the sodium salt is prepared in methanol (15 ml with heating), the insoluble material is collected, and the filtrate concentrated to yield (0.124 g, 65%); mp 297° C. (dec.)
- trans-dihydro-narcistatin (10, 0.010 g) was dissolved in water (1 ml) and the solution passed through a column of Dowex 50WX8-200, bearing the respective cation. The UV-active fractions are then combined and freeze-dried to give the corresponding trans-dihydro-narcistatin salt as a white solid.
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Abstract
Description
- This application is based on and claims the priority to U.S. Provisional Patent Application No. 60/644,397 filed on Jan. 14, 2005, the disclosure of which is incorporated herein in its entirety.
- 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 CA-44344-01A1-01-12; CA 44344-01-12 and CA 90441-01-03; the Arizona Disease Control Research Commission; and private contributions. Thus, the United States Government has certain rights in this invention.
- The present invention relates certain compounds, and methods for synthesis of certain compounds, wherein the compounds have shown anti-neoplastic activity against cancerous cell lines, and therefore are anticipated to be useful in the treatment of various forms of cancer in animals and humans.
- The present invention involves use of the compounds narciclasine (2a) and 7-deoxy-narciclasine (2c), which are obtained via isolation from the medicinal plant species Narcissus (Amaryllidaceae), as precursors in a novel synthesis method in which each of these compounds are selectively hydrogenated to produce trans-dihydronarciclasine (1a) and 7-deoxy-trans-dihydronarciclasine (1c). Also described herein is a novel synthesis method for producing sodium narcistatin (11) from narciclasine (2a). Further described herein are
certain novel 3,4-cyclic phosphate prodrugs, including sodium-7-deoxynarcistatin (8), sodium-7-deoxy-trans-dihydronarcistatin (9), and sodium transdihydronarcistatin (10). - The present invention involves use of the compounds narciclasine (2a) and 7-deoxy-narciclasine (2c) which are obtained via isolation from certain Narcissus (Amaryllidaceae) as precursors in a novel and unobvious process by which each of these compounds may be selectively hydrogenated to produce trans-dihydronarciclasine (1a) and 7-deoxy-trans-dihydronarciclasine (1c).
-
FIG. 1 shows structural formulas for the compounds described herein -
FIG. 2 shows reaction schemes for synthesizing some of the compounds of the present invention. - The isolation of new compounds from substances found in nature, such as plants, and the creation of derivatives of these compounds, is an active area of research for compounds having pharmaceutical utility. Described herein are methods for the synthesis of, and for the use of such “natural” compounds in the synthesis of other compounds, many of which show promise as anti-neoplastic drugs.
- From a 1982 collection (bulbs) of the Chinese medicinal plant Zephyranthes candido (Amaryllidaceae) was isolated the strong (ED50 0.0032 μg/ml) P388 lymphocytic leukemia cell growth inhibitor trans-dihydronarciclasine (1a). (Pettit G. R., et al., Antineoplastic 162. Zephyranthes candida. J. Nat. Prod. 53:176-178; 1990.) The structure was established by detailed spectral analyses of its peracetate derivative (1b) and confirmed by comparison with the product from catalytic hydrogenation of narciclasine (2a). (Mondon, A., et al., Zur Kenntnis des Narciclasins. Chem. Ber. 108:445-463; 1975.) Hydrogenation afforded as the major product the expected cis-dihydronarciclasine (3a), accompanied by the trans isomer (1a) and iso-narciclasine (4a). More recently, trans-dihydronarciclasine (1a) was found to exhibit strong cancer cell growth inhibition (mean panel GI50 12.6 nM) against the U.S. National Cancer Institute (NCl) panel of cancer cell lines, whereas its cis isomer (3a) was only very weakly active (mean panel GI50 3800 nM). (Pettit, G. R., et al., Antineoplastic agents 256. Cell growth inhibitory isocarbostyrils from Hymenocallis. J. Nat. Prod. 56: 1682-1687; 1993.) Importantly, the trans isomer (1a) gave an active Compare correlation coefficient of 0.92 in respect to (+)-pancratistatin (5) equals 1.00. (Pettit, G. R., et al., Antineoplastic agents 256. Cell growth inhibitory isocarbostyrils from Hymenocallis. J. Nat. Prod. 56: 1682-1687; 1993.) The trans isomer (1a) also showed strong activity against a range of RNA viruses while the synthetic cis isomer (3a) was completely inactive. (Gabrielsen, B., et al., Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances. J. Nat. Prod. 55:1569-1581; 1992.)
- Narciclasine (2a) was isolated from the bulbs of Narcissus imcomparabilus, and 7-deoxynarciclasine (2c) and 7-deoxy-transdihydronarciclasine (1c) were isolated from the bulbs of Hymenocallis littoralis grown by the ASU-CRI research group in Tempe, Ariz., now part of the Arizona Biodesign Institute. (Piozzi, F., et al., Narciclasine and Narciprimine. Tetrahedron. 24:1119-1131; 1968), (Pettit, G. R., et al., Antineoplastic agents 256. Cell growth inhibitory isocarbostyrils from Hymenocallis. J. Nat. Prod. 56: 1682-1687; 1993). All solvents were redistilled, and reagents were purchased from Lancaster, Sigma-Aldrich Co. and Aeros Chemical Co. Reaction progress was ascertained by thin-layer chromatography using Analtech silica gel GHLF Uniplates visualized under long- and short-wave UV irradiation and developed in an ethanolic solution of phosphomolybdic acid reagent (Sigma-Aldrich Co.). Column chromatography was performed with silica gel 60 (230-400 mesh) from E. Merck. Dowex 50WX8-400 cation exchange resin (H+) form) was first eluted with methanol, 1N hydrochloric acid and deionized water. The cation forms of the resin were prepared by eluting with a 1N solution of the appropriate base followed by deionized water. All reaction products were colorless solids unless otherwise noted. All melting points were determined with an Electrothermal digital melting point apparatus model IA9200 and are uncorrected.
- Methods for Synthesis of trans-dihydronarciclasine (1a)
- 2,3,4,7-O-Tetraacetoxy-narciclasine (2b)—Compound 2b is produced as follows. To a stirred solution of narciclasine (1.00 g, 3.25 mmol) in pyridine (3 ml under nitrogen), add acetic anhydride (6 ml). Stir for 16 hours at room temperature, add ice (50 ml) to the mixture, and extract with dichloromethane (3×20 ml). The combined extract is dried over MgSO4, filtered and evaporated in vacuo to afford 2,3,4,7-O-Tetraacetoxy-narciclasine (2b) as a light brown powder (1.4 g, 90% yield).
- 2,3,4,7-Tetraacetoxy-trans-dihydronarciciasine (1b).
-
Method 1 for producing 1b. To a solution of narciclasine tetraacetate (2b) (0.97 g, 20.42 mmol) in glacial acetic acid (120 ml), add 5% Pd/C catalyst (0.56 g, 26 mol %). Stir the mixture under an atmosphere of hydrogen at room temperature for 3 hours and then filter the solution, such as through fluted filter paper. Dry the filtrate over MgSO4, again filter and evaporate in vacuo. Purify the residue by column chromatography on silica gel eluting with 0.5% methanol in dichloromethane to afford the product (1b) as a powder (0.290 g, 30%) along with the cis-dihydro-peracetate (3b) as a solid (0.60 g, 62%). Analysis of 1b by comparison of NMR data found it to be identical with an authentic sample. (Pettit G. R., et al., Antineoplastic 162. Zephyranthes candida. J. Nat. Prod. 53:176-178; 1990.) -
Method 2 for producing 1b. To a solution of narciclasine tetracetate (2b) (0.200 g, 0.42 mmol) in a 1:1 mixture of ethanol/dichloromethane was added 10% Pd/C catalyst (0.004 g, 0.042 mmol). The mixture was stirred under 1 atm. of hydrogen at room temperature for 4 hours. The reaction mixture was then filtered through a pad of silica and the solvent removed in vacuo. The residue was then purified by column chromatography (flash silica; eluant 45:55 n-hexane-EtOAc) to afford the trans-dihydro-peracetate (1b) as a solid (0.131 g, 65%), along with the cis-dihydro-peracetate (3b) as a solid (0.050 g, 25%). - Trans-Dihydronarciclasine (1a). Dissolve 2,3,4,7-O-tetraacetoxy-trans-dihydronarciclasine (1b) (0.512 g, 1.07 mmol) in methanol:water (9:1) (20 ml), and add dichloromethane (12 ml) to aid in solubility. Add Potassium carbonate (0.009 g, 0.06 mmol) and stir the reaction at room temperature for three days. TLC(CH2Cl2:CH3OH 4%) shows complete conversion to the product.
- The reaction mixture is concentrated and the residue purified by column chromatography on silica gel to give (CH2Cl2:CH3OH 4%) (1a) as an amorphous solid (0.134 g, 40%); mp 260° C. (dec), 285° C. (melts).
- 3,4-isopropylidene-7-deoxynarciclasine (2e)—Initially, 7-deoxynarciclasine (2c) (0.205 g, 0.704 mmol) and TsOH (0.133 g, 0.704 mmol) are dissolved in DMF (10 ml) and 2′,2′-dimethoxypropane (0.864 ml, 7.04 mmol) is added. The resulting solution is stirred for 16 hours and then poured into water (50 ml) and extracted with ethyl acetate (4×30 ml). The combined organic phase is dried (MgSO4), filtered and concentrated in vacuo to yield a pale yellow solid which is separated by column chromatography (flash silica; eluant 3:7 n-hexane-EtOAc) to afford the product 2e as a solid (0.215 g, 92%); Recrystallized from methanol as needles.
- 2-[Cert-Butyl-1,1-dimethylsilyl]oxy-3,4-isopropylidene-7-deoxy-narciclasine (2f)—To 3,4-isopropylidene-7-deoxy-narciclasine (2e, 0.024 g, 0.0725 mmol) in DMF (3 ml) is added TBDMSCI (0.016 g, 0.109 mmol) and imidazole (0.007 g, 0.109 mmol). Stir the resulting solution for 5 hours and remove the DMF in vacuo to afford a pale yellow oil. The residue is separated by column chromatography (flash silica; eluant 3:2/n-hexane-EtOAc) to afford the silyl ether as a solid (0.028 g, 87%): m.p. 269° C.
- 2-[tert-Butyl-1,1-dimethylsilyl]oxy-3,4-isopropylidene-7-deoxy-trans-dihydro-narciclasine (Id)—To a solution of 2-(tert-Butyl-1,1-dimethylsilyl]oxy-3,4-isopropylidene-7-deoxy-narciclasine (2f, 0.050 g, 0.112 mmol), in a 1:1 mixture of ethanol and dichloromethane (8 ml) add 10% Pd/C (1.2 mg, 0.0112 mmol). Stir the resulting mixture was stirred under 1 atm. of hydrogen for 4 hours and then pass through a short column of silica gel, eluting with ethyl acetate. Remove solvent in vacuo to afford a solid. Separate the residue by column chromatography (gravity, silica gel; eluant 7:3/n-hexane EtOAc) to yield a solid (0.028 g, 56%): m.p. 181.5-182.5° C.
- Also isolated was 2-[tert-Butyl-1,1-dimethylsilyl]oxy-3,4-isopropylidene-7-deoxy-cis-dihydro-narciclasine (3c) as a solid (0.013 g, 26%): m.p. 237.5-238.5° C.
- The third minor component isolated was 2-[tert-Butyl-1,1-dimethylsilyl]oxy-3,4-isopropylidene-7-deoxy-iso-dihydro-narciclasine (4c) as a solid (0.005 g, 10%): m.p. 246.5-248.0° C.
- 7-deoxy-trans-dihydronarciclasine (1c). 2-[tert-Butyl-1,1-dimethylsilyl]oxy-3,4-isopropylidene-7-deoxy-trans-dihydro-narciclasine (0.02 g, 0.045 mmol) is dissolved in tetrahydrofuran (2 ml) and formic acid (60%) (2 ml) is added at room temperature. The reaction mixture is heated to 60° C. for three hours. TLC (
ethylacetate 15%:hexane) shows complete conversion to a slower moving product. The reaction is concentrated to a white residue which is purified by silica gel flash column chromatography (CH2Cl2:CH3OH 10%) to yield a white solid (13.1 mg, 71.4%) mp 230° C. 1H NMR (300 MHz, DMSO-d6) showed the silyl ether still present, which was confirmed by HRMS, APCI+calcd. for C20H30NO6Si (M+H)+=408.1842, found m/z=408.1845. This material is taken without further purification to the silyl ether deprotection step. - 2-[tert-Butyl-1,1-dimethylsilyl]oxy-7-deoxy-trans-dihydronarciclasine (0.037 g, 0.09 mmol) is dissolved in tetrahydrofuran (5 ml), and tetrabutylammoniumfloride (TBAF) (0.01 ml, 0.01 mmol) is added and the reaction stirred at room temperature under argon. TLC(CH33OH 10%; CH2Cl2) after 6 hours shows incomplete conversion starting material to product, and therefore TBAF (0.1 ml, 0.1 mmol) is added and the reaction continued for 24 hours. Additional TBAF (0.1 ml, 0.1 mmol) was added after 24 hours. The reaction is stirred for 5 days. Ethyl acetate (35 ml) is added and the organic phase washed with brine (25 ml), dried MgSO4, filtered and concentrated in vacuo to a yellow oil. The oil is taken up in tetrahydrofuran and eluted on a column of silica gel with a gradient elution using CH2Cl2:CH3OH 10%-CH2Cl2:CH3OH 30%. The product is isolated as a white solid, 13.4 mg, 50% and was identical by 1H NMR with a natural sample of 7-deoxy-trans-dihydronarciclasine. (Gabrielsen, B., et al., Antiviral (RNA) activity of selected Ammyllidaceae isoquinoline constituents and synthesis of related substances. J. Nat. Prod. 55:1569-1581; 1992.)
- Functional groups such as hydroxyl, ester and amide often direct the stereochemistry of hydrogenation. Homogenous hydrogenation of allylic alcohols usually occurs with high stereoselectivity. Catalysts used in such hydroxy-directed hydrogenation often include Wilkinson's catalyst (6) [RhCI(PPh3)3] and Crabtree's catalyst (7) [Ir(COD)(Pcy3)(py)]PF6 (8). Consequently, narciclasine, protected as its acetonide (2d), was treated with Crabtree's catalyst (7) in dichloromethane, but failed to yield any hydrogenation product. (Mondon, A., et al., Zur Kenntnis des Narciclasins. Chem. Ber. 108:445-463; 1975.) The reaction was also attempted with Wilkinson's catalyst (6) in toluene and again narciclasine acetonide (2d) resisted hydrogenation. With a related trisubstituted styrene that proved unreactive towards hydrogenation with Wilkinson's catalyst (6) even under forcing conditions, it was successfully hydrogenated when first converted to its alkoxide. That led exclusively to the cis isomer. (Thompson, H. W., et al., Stereochemical control of reductions. IV. Control of hydrogenation stereochemistry by intramolecular anionic coordination to homogeneous catalysts. J. Amer. Chem. Soc. 96:6232-6233; 1974.) This approach was unsuccessful when using narciclasine acetonide (2d). Without intending to be bound by this theory, because this reaction is believed to be associated with the olefin's ability to donate unshared electron pairs to unfilled surface orbitals of the catalyst metal, the double bond in narciclasine is probably too hindered to allow this type of hydroxy-directed hydrogenation. (Thompson, H. W. Stereochemical control of reductions. The directive effect of carbomethoxy vs. hydroxymethyl groups in catalytic hydrogenation. J. Org. Chem. 36:2577-2581; 1971.) So, attention was next directed to ionic hydrogenation. Interestingly, in our experiments narciclasine (2a) and derivatives (2b) and (2d) resisted hydrogenation with triethylsilane/trifluoroacetic acid in dichloromethane at −75° C. and at 25° C.
- Hydrogentation of narciclasine (2a) using Adam's catalyst in ethanol results in the following: 28% of the trans isomer (1a) was usually obtained, along with 58% of the
cis isomer 3a and 13% of iso-narciclasine (4a). (Mondon, A., et al., Zur Kenntnis des Narciclasins. Chem. Ber. 108:445-463; 1975.) The hydrogenation of narciclasine peracetate (2b) was conducted in the presence of 5% Pd/C (20 mol %) at 1 atm and a variety of solvents: ethyl acetate, ethanol, acetic acid, hexane, tetrahydrofuran, pyridine and dimethylformamide. (Thompson, H. W., et al., Stereochemical control of reductions. 5. Effects of electron density and solvent on group haptophilicity. J. Org. Chem. 41:2903-2906; 1976), (Okamoto, T., et al., Lycoricidinol and lycoricidine. New plant growth regulators in the bulbs of Lycoris radiata Herb. Chem. Pharm. Bull. 16:1860-1864; 1968), (Immirzi, A., et al., The crystal and molecular structure of narciclasine tetra-acetate. J. Amer. Chem. Soc. 240-240; 1972.) The results are shown in Table I. -
TABLE I Effect of solvent on hydrogenation of narciclasine acetate (2b) with 5% Pd/C (20 mol %) at 1 atm., 25° C. for 2 hours. Products Wt. g Sm % Sma % transa % cisa % isoa Solvent 2b 2b 1b 3b 4b hexane 0.026 100 — — — pyridine 0.022 100 — — — tetrahydrofuran 0.025 70 15 15 — ethyl acetate 0.025 — 47 40 13 ethanol 0.219 — 36 54 10 ethanol:DCM (1:1) 0.025 22 25 53 — ethanol:DCM (1:1)* 0.200 — 65 25 — acetic acid 0.024 — 51b 47 2 Dimethylformamide 0.019 — 38 42 20 aValues determined by 1H NMR; bIncreased to 57% with 55 mol % of Pd/C, but dropped to 49% with 100 mol % of Pd/C. *Isolated yield from reaction with 10% Pd/C (10% mol). - The trans:cis:iso ratios were determined by 1H-NMR and were based on a 100% conversion of starting material to product. The best ratio observed was 51:47:2 respectively with acetic acid as the solvent and the reaction carried out on a small scale (approx. 0.020 g of narciclasine peracetate). Scaleup of this reaction showed a wide variation in results. When 5 g of narciclasine was hydrogenated in acetic acid in the presence of 5% Pd/C (8 mol %) for 20 hr only starting material was recovered. When the hydrogenation was carried out on narciclasine peracetate 1 g using 10% Pd/C (25.8 mol %) the trans and cis products were isolated in 30% and 62% yield respectively following chromatography on silica gel. The solvent system dichloromethane:ethanol (1:1) gave good results when narciclasine tetraacetate (2b) (200 mg) was hydrogenated in the presence of 10% Pd/C (10 mol %). The yield of trans was 65% following chromatography. The peracetylated isomers (1b), (3b), and (4b) were separated by column chromatography on silica gel. The structure of the synthetic trans isomer (1b) was established by detailed spectral data comparison with an authentic sample. (Pettit G. R., et al., Antineoplastic 162. Zephyranthes candida. J. Nat. Prod. 53:176-178; 1990.)
- Method for Synthesis of 7-deoxy-trans-dihydronarciclasine (1c)
- Having developed a method for the hydrogenation of 2b to 1b, a similar method was sought for the interconversion of 7-deoxynarciclasine (2c) to 7-deoxy-trans-dihydronarciclasine (1c). This was achieved by initially protecting the cis diol unit as its acetonide (2d) in good yield (92%). The remaining hydroxyl group was protected as its silyl ether (2f) to avoid the potential problems which had already been encountered when attempting the hydrogenation of narciclasine acetonide (2d). With the silyl ether in hand, the hydrogenation of the olefin was attempted using the conditions which had been most successful in the reduction of
peracetate 2b to the trans-dihydroperacetate (1b). Hydrogenation with 10% Pd/C (10 mol %) at 1 atm in ethanol/dichloromethane (1:1) of (2f)(0.05 g) gave a separable mixture of trans:cis:iso in 56%:26%:10% yields, respectively. However, this reaction suffered upon scaleup and yields of trans were reduced to 27% when the reaction was carried out on a 2 g scale. The synthetic trans-isomer (1d) was obtained by deprotection of the acetonide using formic acid (60%) followed by deprotection of the silyl ether with TBAF to yield 1c which was found to be identical with an authentic sample of 7-deoxy-trans-dihydronarciclasine (1d). (Gabrielsen, B., et al., Antiviral (RNA) activity of selected Amaryllidaceae isoquinoline constituents and synthesis of related substances. J. Nat. Prod. 55:1569-1581; 1992.) - As described below, the synthesis of sodium narcistatin (11) was improved (88% overall yield) and the modified reaction sequence was utilized to synthesize sodium 7-deoxy-narcistatin (8), sodium 7-deoxy-trans-dihydronarcistatin (9) and sodium trans-dihydro-narcistatin (10). The human cancer cell line inhibitory isocarbostyril precursors were isolated from the bulbs of Hymenocallis littoralis obtained by horticultural production or reduction of narciclasine (2a) from the same source. Solvents were distilled prior to use and pyridine was dried over potassium hydroxide and distilled. The three new 3,4-cyclic phosphate prodrugs (8, 9, and 10), whose synthesis is discussed in further detail below, are being evaluated for further development as anticancer drugs.
- Method for Synthesis of Sodium Narcistatin (11). Synthesis of 3,4-
cyclic phosphate 11 from narciclasine (2a) (0.113 g, 0.368 mmol) was carried out in pyridine (4 ml) using tetrabutylammonium dihydrogen phosphate (0.075 g, 0.22 mmol) and dicyclohexylcarbodiimide (0.4 g, 1.94 mmol), with additional amounts of tetrabutylammonium dihydrogen phosphate (0.185 g) and dicyclohexylcarbodiimide (0.4 g) added after about the first 24 hours stirring at about 80° C. The reaction is stirred for about 96 hours, cooled and filtered to remove precipitated dicyclohexylurea (DCU). Water (100 ml) is added and the mixture refiltered to remove any residual DCU. The mother liquor is concentrated to minimum volume. The aqueous fraction is eluted through an ion exchange column (sodium form). The UV active fractions are combined and lypholized to yield thephosphate 11 as a cream solid (88% yield). Rather than eluting the aqueous fraction via a sodium form of an ion exchange column, another suitable salt form (such as potassium or lithium) could be used to produce a compound such as potassium narcistatin or lithium narcistatin. - Method for Synthesis of 3,4-cyclic phosphates sodium 7-deoxynarcistatin (8), sodium 7-deoxy-trans-dihydronarcistatin (9) and sodium trans-dihydronarcistatin (10).
- The 7-deoxynarciclasine (2c) and 7-deoxy-trans-dihydronarciclasine (1c) mixture separated from H. littoralis was acetylated by dissolving in pyridine (20 mL) and adding acetic anhydride (20 mL, 2.4 equiv.) The mixture slowly becomes a solution with stirring overnight at room temperature, and TLC(CH2Cl2—CH3OH, 2%) showed no starting material. Ice water (200 ml) is added to the reaction mixture with vigorous stirring. A cream colored precipitate develops and is collected following being stirred for two hours to provide 13.7 g. Thereafter, the peracetate mixture (acetylation product) is separated by elution using 7:3 toluene-ethyl acetate, via silica gel column chromatography, to yield the following isocarbostyrils 12 (60% recovery) and 13 (19% recovery). Both 2, 3, 4-triacetoxy-7-deoxynarciclasine (12) and 2,3,4-triacetoxy-7-deoxy-trans-dihydronarciclasine (13) were then deprotected with potassium carbonate in aqueous methanol to afford the corresponding triols 14 and 15 in 72% yields.
- The 3,4-
cyclic phosphates - In each case, 1H-NMR of the crude product showed the reaction to be only 50% complete following a 24 hour period. Additional reagents were added at this stage and the reaction allowed to proceed to completion (a further 24 hours). Increasing the amount of tetrabutylammonium dihydrogen phosphate from 0.65 equivalents to 1 equivalent in the first 24 hours did not increase the reaction rate. Water was added to the reaction mixture to precipitate the dicyclohexylurea (DCU) and the pyridine/water filtrate was concentrated to remove the pyridine. An aqueous extract of the residue was passed through a Dowex 50WX8-400 ion exchange column (sodium form). The UV responsive fractions were combined and lyophilized to afford the new 3,4-cyclic phosphates designated sodium 7-deoxy-narcistatin (8, 88% yield), sodium 7-deoxy-trans-dihydro-narcistatin (9, 65% yield) and sodium trans-dihydro-narcistatin (10, 94% yield).
- In a more preferred embodiment, deletion of the p-toluene sulfonic acid component increased the yield of
phosphate 11 to 88% versus the original 50%. That was one of the major improvements that allowednew phosphates - The cyclic phosphate prodrugs, along with the parent compounds were evaluated against a minipanel of human cancer cell lines and murine P388 lymphocytic leukemia. See Table 2.
-
TABLE 2 Aqueous Solubility, Human Cancer Cell Line and Murine P-388 Lymphocytic Inhibitory Activities GI50 (μg/ml) Aqueous ED50 Lung- Solubility (μg/ml) NSC 25° C. Leukemia Pancreasa Breast CNS NCI- Colon Prostate Isocarbostyril (mg/ml) P388 BXPC-3 MCF-7 SF268 H460 KM20L2 DU-145 2c <1 0.019 0.070 0.046 0.120 0.053 0.084 0.051 1c <1 0.029 0.046 0.034 0.059 0.043 0.051 0.040 1a <1 0.0024 0.012 0.0053 0.020 0.0092 0.015 0.0066 10 >190 1.7 5.3 4.0 6.3 4.7 5.6 3.9 10a >10 0.42 >1 >1 >1 >1 >1 >1 10b >10 1.4 >1 >1 >1 >1 >1 >1 11 >10 1.6 >10 7.2 >10 >10 >10 >10 11a >5 0.39 >1 >1 >1 >1 >1 >1 11b >5 1.7 >1 >1 >1 >1 >1 >1 12 >10 0.88 5.6 4.6 8.8 7.8 9.6 5.2 12a >1 0.26 >1 >1 >1 >1 >1 >1 12b >1 0.35 >1 0.64 >1 >1 >1 0.54 - Results of the cancer cell line evaluations reconfirmed the strong cancer cell growth inhibitory activity of 7-deoxy-trans-dihydronarciclasine (1c) and trans-dihydronarciclasine (1a). The corresponding 3,5-cyclic phosphates were less inhibitory under the experimental conditions employed. However, cleavage of the phosphate groups is expected to be very effective in vivo and such anticancer evaluations are now underway as part of the further preclinical development of these new anticancer drug candidates. (Pettit, G. R., et al., J. Nat. Prod. 2003, 66, 92-96), (Dowlati, A., et al., Cancer Research 2002, 62, 3408-3416), (Dziba, J. M., et al.,
Thyroid 2002, 12, 1063-1070), (Eikesdal, H. P., et al., Cancer Lett. 2002, 178, 209-217), (Prise, V., et al., Int. J. Oncology 2002, 21, 717-726), (Hill, S. A., et al., Int. J. Cancer 2002, 102, 70-74.) - 7-Deoxy-narciclasine (2c). To obtain 7-deoxy-narciclasine (2c), a solution of 2,3,4-triacetoxy-7-deoxy-narciclasine (12, 4.36 g) in CH3OH-(99 ml) H2O-(1 ml) CH3OH (30 ml) is added potassium carbonate (0.124 g), with stirring continued for 16 hours at room temperature while a white precipitate separated. The mixture is neutralized with acetic acid (2 ml), stirred for 15 minutes and concentrated to minimum volume. The colorless product is collected (2.18 g, 72%), recrystallization from acetic acid-methanol afforded fine needles: mp 205-210° C. (dec).
- Sodium 7-Deoxy-narcistatin (8). A solution of 7-deoxy-narciclasine (2c, 0.2 g, 0.69 mmol) in pyridine (8 ml) was heated to 80° C. and tetrabutylammonium dihydrogen phosphate (0.15 g, 0.45 mmol, 0.65 equiv) followed by dicyclohexylcarbodiimide (0.8 g, 5.6 equiv) were added. The reaction was allowed to proceed at 80° C. for 24 hours. An 1H NMR analysis of the reaction mixture composition indicated a 50:50 mixture of starting material to product. Tetrabutylammonium dihydrogen phosphate (0.15 g) was added followed by DCCl (0.8 g) and the reaction continued for a further 24 hours. At this point, 1H NMR analysis of a sample from the reaction mixture showed reaction was complete. The reaction mixture was cooled and water (100 ml) was added. The precipitated dicyclohexylurea (DCU) was collected and the pyridine-water mother liquor was concentrated to minimum volume. The aqueous fraction was then passed through an ion exchange column (DOWER 50W8-400) in the sodium form. The UV responsive fractions were combined and lypholized to yield
phosphate 8 as a colorless solid: 227 mg (88%); mp 255° C. (dec.). - Methods for Synthesis of 7-Deoxy-
narcistatin prodrugs - Sodium 7-deoxy-narcistatin (8, 52 mg) is dissolved in water (1 ml) and the solution is passed through a column of Dowex 50WX8-400, bearing the respective cation. For example, a column containing lithium or potassium cations, respectfully, may be used. The UV-active fractions are then combined and freeze-dried to give the corresponding narcistatin salt as a white solid, as follows:
- Lithium 7-Deoxy-narcistatin (10a). 34 mg, mp 250° C. (dec).
- Potassium 7-Deoxy-narcistatin (10b). 43 mg, mp 230-235° C. (dec).
- 7-Deoxy-trans-dihydro-narciclasine (1c). This compound is produced as follows. 2,3,4-triacetoxy-7-deoxy-trans-dihydro narciclasine (13, 0.14 g) is saponified in 9:1 aqueous methanol and with potassium carbonate (0.003 g), and is conducted as described above for obtaining
alcohol 2c to yieldtriol 1c as a colorless solid; 89 mg (91% yield); mp>300° C. (dec.). - Sodium 7-Deoxy-trans-dihydro-narcistatin (9). The conversion of 7-deoxy-trans-dihydro-narciclasine (1c, 0.15 g, 0.51 mmol) to
narcistatin 9 in pyridine (6 ml) with tetrabutylammonium dihydrogen phosphate (0.21 g, 0.62 mmol, 1.2 equiv), and dicyclohexylcarbodiimide (0.54 g, 2.62 mmol, 5.13 equiv) is conducted and the phosphate isolated as summarized for synthesis of narcistatin 8 (cf, above) including the additional tetrabutylammonium dihydrogen phosphate (0.21 g, 1.2 equiv) and DCCl (0.54 g). The aqueous extract of product is subjected to ion exchange column of Dowex 50WX8-400 (sodium form) and the UV fluorescing fractions combined and lyophilized as noted above (cf, 8). A solution of the sodium salt is prepared in methanol (15 ml with heating), the insoluble material is collected, and the filtrate concentrated to yield (0.124 g, 65%); mp 297° C. (dec.) - Method for Synthesis of 7-Deoxy-trans-dihydro-narcistatin prodrugs 11a and 11b. Sodium 7-deoxy-trans-dihydro-narcistatin (9, 30 mg) was dissolved in water (1 ml) and the solution passed through a column of Dowex 50WX8-400, bearing the respective cation. The UV-active fractions were combined and freeze-dried to give the corresponding narcistatin salt as a white solid.
- Lithium 7-deoxy-trans-dihydro-narcistatin (9a). 25.4 mg, mp 253° C. (dec).
- Potassium 7-deoxy-trans-dihydro-narcistatin (9b). 23.2 mg, mp 287° C. (dec).
- Sodium trans-dihydro-narcistatin (10). Synthesis of 3,4-cyclic-
phosphate 10 from trans-dihydronarciclasine (1a, 57 mg, 0.184 mmol) is accomplished in pyridine (2 ml) employing tetrabutylammonium dihydrogen phosphate (60 mg, 0.176 mmol) and 60 mg for the delayed addition) and dicyclohexylcarbodiimide (0.18 g, 0.87 mmol) and 0.18 g for the second addition as described for preparation of phosphate 9 (refer above). (Trans-dihydro-narciclasine was synthesized by our group in 1992 from narciclasine according to procedures described by Mondon and Krohn.19), (Mondon, A., et al., Chem. Ber., 1975, 108, 445-463.) The aqueous fraction eluted from the ion exchange column (Dowex 50WX8-400, sodium form) provided sodium trans-dihydro narcistatin (10) as a colorless solid (86 mg, 94% yield), mp>300° C. - Method for Synthesis of Trans-dihydro-
narcistatin Prodrugs - Sodium trans-dihydro-narcistatin (10, 0.010 g) was dissolved in water (1 ml) and the solution passed through a column of Dowex 50WX8-200, bearing the respective cation. The UV-active fractions are then combined and freeze-dried to give the corresponding trans-dihydro-narcistatin salt as a white solid.
- Lithium trans-dihydro-narcistatin (10a). 8 mg, mp 275° C. (dec).
- Potassium trans-dihydro-narcistatin (10b). 7.1 mg, mp 230-235° C. (dec).
Claims (7)
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PCT/US2006/001658 WO2006076726A1 (en) | 2005-01-14 | 2006-01-17 | Synthesis of sodium narcistatin and related compounds |
US81365709A | 2009-01-21 | 2009-01-21 | |
US12/723,912 US20100179108A1 (en) | 2005-01-14 | 2010-03-15 | Synthesis of Sodium Narcistatin and Related Compounds |
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US11174291B2 (en) | 2015-02-13 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Silstatin compounds |
US11629167B2 (en) | 2017-11-09 | 2023-04-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Betulastatin compounds |
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JP2008527010A (en) * | 2005-01-14 | 2008-07-24 | アリゾナ・ボード・オブ・リージェンツ・ア・ボディ・コーポレート・オブ・ザ・ステート・オブ・アリゾナ・アクティング・フォー・アンド・オン・ビハーフ・オブ・アリゾナ・ステート・ユニバーシティ | Synthesis of narcystatin sodium and related compounds |
CA2665605A1 (en) * | 2006-10-13 | 2008-04-17 | Unibioscreen Sa | New isocarbostyril alkaloid derivatives |
FR2934266B1 (en) * | 2008-07-28 | 2010-09-17 | Pf Medicament | NITROGEN DERIVATIVES OF PANCRATISTATIN |
CN107501282B (en) * | 2017-08-22 | 2019-10-18 | 华南理工大学 | The preparation method of isoquinolone Alkaloid compound in a kind of short-tube lycoris |
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DE60324196D1 (en) * | 2002-12-09 | 2008-11-27 | Univ Arizona | NARCISTATIN PRODRUGS |
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Cited By (2)
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US11174291B2 (en) | 2015-02-13 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Silstatin compounds |
US11629167B2 (en) | 2017-11-09 | 2023-04-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Betulastatin compounds |
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US7709643B2 (en) | 2010-05-04 |
CN101102769A (en) | 2008-01-09 |
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WO2006076726A1 (en) | 2006-07-20 |
WO2006076726A9 (en) | 2008-01-24 |
RU2007130942A (en) | 2009-02-20 |
AU2006204672A1 (en) | 2006-07-20 |
JP2008527010A (en) | 2008-07-24 |
CA2594569A1 (en) | 2006-07-20 |
EP1845981A4 (en) | 2008-02-06 |
EP1845981A1 (en) | 2007-10-24 |
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