CN114751863A - Terestacin derivative, preparation method thereof and application of Terestacin derivative in preparation of low-oxygen factor inhibitor - Google Patents
Terestacin derivative, preparation method thereof and application of Terestacin derivative in preparation of low-oxygen factor inhibitor Download PDFInfo
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- CN114751863A CN114751863A CN202210427448.6A CN202210427448A CN114751863A CN 114751863 A CN114751863 A CN 114751863A CN 202210427448 A CN202210427448 A CN 202210427448A CN 114751863 A CN114751863 A CN 114751863A
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- Prior art keywords
- terestacin
- nhchrco
- terestacino
- derivative
- methyl ester
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000003112 inhibitor Substances 0.000 title claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 title abstract description 5
- 239000001301 oxygen Substances 0.000 title abstract description 5
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 19
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 201000011510 cancer Diseases 0.000 claims abstract description 12
- 230000007954 hypoxia Effects 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 5
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 150000001875 compounds Chemical class 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- -1 L-amino acid methyl ester Chemical class 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- FDHZZQKBIPRSFU-UHFFFAOYSA-N C(Cl)Cl.ClCC(=O)Cl Chemical compound C(Cl)Cl.ClCC(=O)Cl FDHZZQKBIPRSFU-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 239000003599 detergent Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
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- 230000001093 anti-cancer Effects 0.000 abstract 1
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- VXYFARNRGZWHTJ-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)propanoate;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VXYFARNRGZWHTJ-FVGYRXGTSA-N 0.000 description 16
- 238000001308 synthesis method Methods 0.000 description 15
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
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- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
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- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
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- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- 150000008575 L-amino acids Chemical class 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- VEEIFXWJNCAVEQ-RGMNGODLSA-N methyl (2s)-2-amino-3-(1h-imidazol-5-yl)propanoate;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)CC1=CNC=N1 VEEIFXWJNCAVEQ-RGMNGODLSA-N 0.000 description 2
- HQEIPVHJHZTMDP-JEDNCBNOSA-N methyl (2s)-pyrrolidine-2-carboxylate;hydrochloride Chemical group Cl.COC(=O)[C@@H]1CCCN1 HQEIPVHJHZTMDP-JEDNCBNOSA-N 0.000 description 2
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- SCGWHMHVOQPGLS-DFWYDOINSA-N (3s)-3-amino-4-methoxy-4-oxobutanoic acid;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)CC(O)=O SCGWHMHVOQPGLS-DFWYDOINSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- SEWIYICDCVPBEW-BYPYZUCNSA-N L-glutamate methyl ester Chemical group COC(=O)[C@@H](N)CCC(O)=O SEWIYICDCVPBEW-BYPYZUCNSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
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- GGTBEWGOPAFTTH-GEMLJDPKSA-N [(2s,3s)-1-methoxy-3-methyl-1-oxopentan-2-yl]azanium;chloride Chemical group Cl.CC[C@H](C)[C@H](N)C(=O)OC GGTBEWGOPAFTTH-GEMLJDPKSA-N 0.000 description 1
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- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 1
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- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical group COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 1
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- XWBUDPXCXXQEOU-VKHMYHEASA-N methyl (2s)-2,4-diamino-4-oxobutanoate Chemical group COC(=O)[C@@H](N)CC(N)=O XWBUDPXCXXQEOU-VKHMYHEASA-N 0.000 description 1
- GBDRMPRTNVKBAD-BYPYZUCNSA-N methyl (2s)-2,5-diamino-5-oxopentanoate Chemical group COC(=O)[C@@H](N)CCC(N)=O GBDRMPRTNVKBAD-BYPYZUCNSA-N 0.000 description 1
- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical group Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 description 1
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 1
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 description 1
- MEVUPUNLVKELNV-JEDNCBNOSA-N methyl (2s)-2-amino-4-methylsulfanylbutanoate;hydrochloride Chemical group Cl.COC(=O)[C@@H](N)CCSC MEVUPUNLVKELNV-JEDNCBNOSA-N 0.000 description 1
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical group COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
The invention discloses a Terestacin derivative, a preparation method thereof and application thereof in preparing a low-oxygen factor inhibitor. TerestacinO17‑CH2CO‑NHCHRCO2Me derivatives having the structural formula shown in formula (I): wherein R is H, CH3,CH(CH3)2,CH3CHCH2CH3,CH2CH(CH3)2,CH2CH2SCH3,CH2OH,CHCH2OH,CH2Ph,CH2‑3‑indolyl,CH2Ph‑4‑OH,CH2‑4‑imidazolyl,CH2CH2CO2Me,CH2CH2CONH2,CH2CO2Me,CH2CONH2,CH2CH2CH2. The invention discloses TerestacinO capable of inhibiting expression of hypoxia factor in cancer cells17‑CH2CO‑NHCHRCO2Me derivative, its preparing process, and its preparing process are disclosed. Terestacino of the invention17‑CH2CO‑NHCHRCO2The Me derivative has good activity of inhibiting the hypoxia factor, is expected to be used for researching and preparing a candidate drug with potential anticancer activity, and has great development potential.
Description
The technical field is as follows:
the invention belongs to the field of chemical medicine preparation, and particularly relates to TerestacinO17-CH2CO-NHCHRCO2Me derivatives, preparation method thereof and application thereof as hypoxia factor (HIF-1 alpha) inhibitor in inhibiting cancer cell growth.
Background art:
the rapid growth and proliferation of tumor can easily cause the hypoxia of the microenvironment of tumor tissues, and at the moment, hypoxia inducible factor (HIF-1) is activated and continuously highly expressed so as to regulate the rapid adaptation of tumor cells to the hypoxia environment and promote the tumor cells to continue to proliferate at high speed. HIF-1 is a kind of heterologous protein dimer, mainly composed of two subunits, HIF-1 alpha and HIF-1 beta, in which HIF-1 alpha is the active subunit under its hypoxia condition. Under normoxic conditions, HIF-1 α is degraded by the ubiquitin-proteasome pathway, but under hypoxic conditions, this pathway is blocked and HIF-l α is stably expressed, where its stability is regulated by the level of Reactive Oxygen Species (ROS), a signal molecule. Studies have shown that down-regulation of ROS levels interferes with HIF-1 α aggregation, thereby inhibiting its downstream signaling pathways. HIF-l alpha can regulate more than 70 downstream genes, and is mostly closely related to the occurrence and development of tumors, wherein one main and extremely important pathway is the expression regulation of VEGF by HIF-1 alpha, which can promote VEGF transcription, increase VEGF mRNA stability, and up-regulate VEGF expression, so that the regulation of HIF-1 alpha expression can possibly inhibit the growth of tumors. Just because of the important regulatory role of oxygen in cell function, the nobel physiological or medical prize in 2019 awarded three scientists William g.kaelin Jr, Sir Peter j.ratecliffe and Gregg l.semenza from meiying, who "discovered how cells perceive and adapt to the availability of oxygen". They have revealed the working mechanism of HIF-1 alpha under normoxic and hypoxic conditions, and the important regulatory functions in cancer development and development, and these work provides reliable basis for our treatment of cancer by regulating the HIF-1 alpha pathway. Compared with the direct action of VEGF or VEGFR, the mediated expression of the HIF-1 alpha protein is beneficial to simultaneously regulating and controlling a plurality of cancer signal paths and avoiding the generation of tumor drug resistance, so that the regulation and control of the HI F-1 alpha signal path to inhibit the tumor growth have great advantages. Intervention of a particular target, complex or gene type of the HIF signaling pathway is a common anti-tumor strategy, and development of HIF-1 α inhibitors has attracted considerable attention, and a few molecules are also under preclinical or clinical trial (stage I, II) studies. Therefore, the development and preparation of the protein inhibitor have important significance and development prospect.
The invention content is as follows:
the first purpose of the invention is to provide a class of TerestacinO with the function of inhibiting the activity of the hypoxic factor protein17-CH2CO-NHCHRCO2Me derivatives.
TerestacinO of the invention17-CH2CO-NHCHRCO2Me derivatives or medicinal salts thereof, the structural formula of which is shown in formula (I):
wherein R is a substituent on the side chain of the common L-amino acid and is respectively H and CH3,CH(CH3)2,CH3CHCH2CH3,CH2CH(CH3)2,CH2CH2SCH3,CH2OH,CHCH2OH,CH2Ph,CH2-3-indolyl,CH2Ph-4-OH,CH2-4-imidazolyl,CH2CH2CO2Me,CH2CH2CONH2,CH2CO2Me,CH2CONH2Or CH2CH2CH2。O17Refers to the hydroxyl group on the 17-position C atom of Terestacin.
Preferably, the TerestacinO17-CH2CO-NHCHRCO2The Me derivative or the pharmaceutically acceptable salt thereof is any one of the following compounds:
the second purpose of the invention is to provide the TerestacinO17-CH2CO-NHCHRCO2A process for the preparation of Me derivatives, characterized in that it comprises the following steps:
adding Et3Dissolving N and L-amino acid methyl ester or salt thereof in dichloromethane, slowly dripping chloroacetyl chloride dichloromethane solution into the solution, adding water and dichloromethane for washing, extracting and separating after the reaction is finished, and purifying the extract to obtain an intermediate product
Dissolving the intermediate product and Termescalin in DMF, adding catalytic amount of KI, and adding Cs2CO3Stirring, adding water after the reaction is finished, extracting with ethyl acetate, and separating and purifying the product to obtain the target product
Wherein R is a substituent on the side chain of the common L-amino acid and is respectively H and CH 3,CH(CH3)2,CH3CHCH2CH3,CH2CH(CH3)2,CH2CH2SCH3,CH2OH,CHCH2OH,CH2Ph,CH2-3-indolyl,CH2Ph-4-OH,CH2-4-imidazolyl,CH2CH2CO2Me,CH2CH2CONH2,CH2CO2Me,CH2CONH2,CH2CH2CH2。O17Refers to the hydroxyl group on the 17-position C atom of Terestacin.
Preferably, Et3N, L-amino acid methyl ester and chloroacetyl chloride in a molar ratio (moL) of 3:1: 1.5-3: 1:3, wherein the reaction is preferably carried out at 0 ℃ for 1-3 hours in the presence of dichloromethane as a reaction solvent.
Preferably, the first and second liquid crystal materials are,
Cs2CO3the mass ratio of the Terestacin to the Terestacin is 5:3: 1-3: 3:1, the reaction condition is preferably room temperature reaction for 1-3 hours, and the reaction solvent is N, N-dimethylformamide.
The third purpose of the invention is to provide the TerestacinO17-CH2CO-NHCHRCO2Application of Me derivatives or medicinal salts thereof in preparing cancer cell hypoxia factor (HIF-1 alpha) inhibitors.
It is a fourth object of the present invention to provide a cancer cell hypoxia factor (HIF-1. alpha.) inhibitor containing Terestaci nO17-CH2CO-NHCHRCO2Me derivatives or pharmaceutically acceptable salts thereof as active ingredients.
The invention discloses TerestacinO17-CH2CO-NHCHRCO2Me derivatives, a process for their preparation. The marine natural product Terestacin is obtained by fermentation, and the preparation method of the derivative is simple in process, suitable for large-scale production and reliable and stable in source. Terestacino of the invention17-CH2CO-NHCHRCO2The Me derivative is a novel hypoxia factor inhibitor, can be used for inhibiting cancer cells and anticancer drugs, and has a huge prospect in subsequent development and research.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: synthesis of Compound 1
Reaction of methyl-tyrosine hydrochloride (1mmol, 231mg) with Et at 0 deg.C3N (3mmol, 303mg) was mixed and dissolved in methylene chloride (10ml), and then a mixed solution of chloroacetyl chloride (2 mmol, 226mg, 0.16ml) dissolved in methylene chloride (5ml) was slowly dropped into the above solution, and stirring was continued for 3 hours after completion of the dropping. Adding dichloromethane 50ml and water (20ml × 3), washing, drying dichloromethane layer with anhydrous sodium sulfate, removing dichloromethane, and performing silica gel column chromatography to obtain 217mg intermediate
Yield: 80 percent.
This intermediate (0.037mmol, 10mg, 3 equivalents) and Terestacin (0.01244mmol, 5mg, 1 equivalent) were dissolved in DMF (0.2ml), catalytic amount of KI (0.2mg) was added, then Cs was added2CO3(0.037mmol,12mg, 3 equiv.) and stirred at room temperature until the reaction was complete. After completion of the reaction, 10ml of water was added, and extracted three times with ethyl acetate (3X 3 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate, and the product was purified by HPLC to give the target compound 1 in 52% yield.
The nuclear magnetic data for compound 1 is as follows:
1H NMR(700MHz,MeOD)δ7.03(d,J＝8.5Hz,2H),6.73(d,J＝8.5Hz,2H),5.41(d,J＝5.4Hz,1H),5.33(dd,J＝10.4,5.1Hz,1H),5.21(s,1H),4.81(d,J＝15.1Hz,1H),4.74(dd,J＝7.4,5.7Hz,1H),4.60(d,J＝15.1Hz,1H),4.01(dd,J＝9.9,4.1Hz,1H),3.83(dd,J＝10.6,8.4Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.3Hz,1H),3.10(dd,J＝14.0,5.7Hz,1H),3.02(dd,J＝14.0,7.5Hz,1H),2.81(dd,J＝11.2,2.2Hz,1H),2.78–2.70(m,1H),2.49(d,J＝17.2Hz,1H),2.32(ddd,J＝24.2,11.2,8.3Hz,3H),2.20–1.97(m,4H),1.87–1.75(m,3H),1.67(d,J＝5.6Hz,7H),1.60(s,3H),1.20(d,J＝7.1Hz,3H),1.00(s,3H).13C NMR(176MHz,MeOD)δ210.11,173.17,171.24,163.63,157.53,149.91,138.88,137.53,133.80,131.34,130.08,128.23,125.38,122.88,116.36,77.07,68.93,66.12,54.86,52.79,51.12,50.88,41.33,40.31,39.27,37.56,35.91,30.86,29.69,24.80,16.83,15.65,15.50,15.03,10.47.
example 2: synthesis of Compound 2
Tyrosine methyl ester hydrochloride was replaced with histidine methyl ester hydrochloride, synthesized as in example 1, wherein Et3The mass ratio of N, histidine methyl ester hydrochloride and chloroacetyl chloride is 3:1: 1.5. The target compound 2 was obtained, yield: 33 percent.
The nuclear magnetic data for compound 2 is as follows:
1H NMR(700MHz,MeOD)δ7.59(s,1H),6.90(s,1H),5.38(d,J＝5.2Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.18(s,1H),4.80(d,J＝15.1Hz,1H),4.76(dd,J＝7.3,5.3Hz,1H),4.61(d,J＝14.2Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.83(dd,J＝10.6,8.3Hz,1H),3.72(s,3H),3.67(dd,J＝10.7,6.4Hz,1H),3.15(dd,J＝14.8,5.3Hz,1H),3.10(dd,J＝14.9,7.4Hz,1H),2.79(dd,J＝11.2,2.1Hz,1H),2.75(dd,J＝14.7,7.0Hz,1H),2.46(d,J＝17.1Hz,1H),2.35–2.24(m,3H),2.17–1.95(m,4H),1.85–1.72(m,3H),1.64(d,J＝6.2Hz,7H),1.57(s,3H),1.21(d,J＝7.1Hz,3H),0.96(s,3H).13C NMR(176MHz,MeOD)δ210.12,172.93,171.40,163.49,149.95,138.87,137.52,136.47,133.81,130.07,125.37,122.88,77.06,68.96,66.09,53.61,52.91,51.12,50.79,41.32,40.31,39.26,35.90,30.86,29.72,24.80,16.83,15.65,15.49,14.97,10.46.
example 3: synthesis of Compound 3
Tyrosine methyl ester hydrochloride was replaced with glutamic acid methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 3, with yield: 33 percent.
The nuclear magnetic data for compound 3 are as follows:
1H NMR(700MHz,MeOD)δ5.42–5.36(m,1H),5.31(dd,J＝10.4,5.1Hz,1H),5.21–5.14(m,1H),4.89(d,J＝15.3Hz,1H),4.62(d,J＝15.2Hz,1H),4.57(dd,J＝9.2,4.9Hz,1H),3.98(dd,J＝9.9,4.2Hz,1H),3.88(dd,J＝10.7,8.4Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),3.66(s,3H),2.78(ddd,J＝22.2,12.5,4.6Hz,2H),2.45(dd,J＝21.6,13.3Hz,3H),2.35–2.26(m,3H),2.23(dtd,J＝14.1,7.7,5.0Hz,1H),2.13(t,J＝12.8Hz,1H),2.10–1.94(m,4H),1.84–1.72(m,3H),1.68–1.61(m,7H),1.57(s,3H),1.24(d,J＝7.1Hz,3H),0.96(s,3H).13C NMR(176MHz,MeOD)δ210.09,174.80,173.24,171.89,162.79,149.97,138.87,137.52,133.80,130.07,125.37,122.95,77.06,68.82,66.07,52.92,52.56,52.20,51.16,50.77,41.34,40.39,39.25,35.90,30.87,30.82,29.77,27.70,24.80,16.82,15.65,15.48,14.93,10.45.
example 4: synthesis of Compound 4
Tyrosine methyl ester hydrochloride was replaced with glutamine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 4 with a yield: and 63 percent.
The nuclear magnetic data for compound 4 are as follows:
1H NMR(700MHz,MeOD)δ5.39(d,J＝5.2Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.24–5.13(m,1H),4.84(d,J＝15.2Hz,1H),4.62(d,J＝15.2Hz,1H),4.53(dd,J＝9.1,4.9Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.86(dd,J＝10.7,8.3Hz,1H),3.74(s,3H),3.70(dd,J＝10.7,6.4Hz,1H),2.88–2.71(m,2H),2.47(d,J＝17.0Hz,1H),2.39–2.25(m,5H),2.21(dtd,J＝12.7,7.8,4.9Hz,1H),2.15–2.11(m,1H),2.10–1.97(m,4H),1.84–1.72(m,3H),1.65(t,J＝7.2Hz,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.97(s,3H).13C NMR(176MHz,MeOD)δ210.27,177.58,173.29,171.89,163.28,150.12,138.90,137.54,133.81,130.05,125.36,122.89,77.06,69.04,66.08,52.96,52.89,51.15,50.71,41.33,40.37,39.24,35.90,32.42,30.86,29.76,28.35,24.80,16.84,15.65,15.50,14.93,10.45.
example 5: synthesis of Compound 5
Tyrosine methyl ester hydrochloride was replaced with aspartic acid methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 5, with yield: 50 percent.
The nuclear magnetic data for compound 5 are as follows:
1H NMR(700MHz,MeOD)δ5.38(d,J＝5.3Hz,1H),5.30(dd,J＝10.4,5.2Hz,1H),5.22–5.14(m,1H),4.81(d,J＝15.3Hz,1H),4.64(d,J＝15.3Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.86(dd,J＝10.7,8.3Hz,1H),3.74(s,3H),3.72–3.67(m,4H),2.93(d,J＝5.7Hz,2H),2.79(dd,J＝11.2,2.2Hz,1H),2.75(dt,J＝13.9,6.9Hz,1H),2.47(d,J＝17.1Hz,1H),2.38–2.24(m,3H),2.13(t,J＝13.1Hz,1H),2.10–1.91(m,3H),1.84–1.72(m,3H),1.69–1.60(m,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.96(s,3H).13C NMR(176MHz,MeOD)δ209.97,172.66,172.27,171.42,163.21,149.90,138.87,137.53,133.80,130.08,125.37,122.91,77.06,68.96,66.10,53.18,52.52,51.12,50.83,49.75,49.52,49.51,41.33,40.34,39.29,36.62,35.90,30.87,29.72,24.80,16.83,15.65,15.48,14.96,10.45.
example 6: synthesis of Compound 6
Tyrosine methyl ester hydrochloride was replaced with asparagine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 6, with yield: and 63 percent.
The nuclear magnetic data for compound 6 are as follows:
1H NMR(700MHz,MeOD)δ5.39(d,J＝3.9Hz,1H),5.30(dd,J＝10.3,5.1Hz,1H),5.18(s,1H),4.83(t,J＝5.2Hz,1H),4.76(d,J＝15.2Hz,1H),4.67(d,J＝15.3Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.85(dd,J＝10.6,8.1Hz,1H),3.74(s,3H),3.70(dd,J＝10.7,6.7Hz,1H),2.91(dd,J＝16.2,5.3Hz,1H),2.78(dtd,J＝14.7,10.1,4.7Hz,3H),2.46(d,J＝17.1Hz,1H),2.37–2.23(m,3H),2.13(t,J＝12.7Hz,1H),2.10–1.96(m,3H),1.84–1.73(m,3H),1.67–1.61(m,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.96(s,3H).13C NMR(176MHz,MeOD)δ209.99,174.87,172.71,171.24,163.52,149.84,138.88,137.53,133.81,130.07,125.38,122.89,77.06,69.08,66.08,53.08,51.11,50.76,49.85,41.34,40.31,39.30,37.28,35.91,30.85,29.70,24.80,16.84,15.64,15.49,14.93,10.46.
example 7: synthesis of Compound 7
Tyrosine methyl ester hydrochloride was replaced with proline methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 7, with yield: 46 percent.
The nuclear magnetic data for compound 7 is as follows:
1H NMR(700MHz,MeOD)δ5.38(d,J＝5.4Hz,1H),5.35(d,J＝15.4Hz,1H),5.29(dd,J＝10.2,4.9Hz,1H),5.17(d,J＝5.2Hz,1H),4.77(d,J＝15.4Hz,1H),4.44(dd,J＝8.7,4.1Hz,1H),4.00–3.92(m,2H),3.71(s,3H),3.66–3.61(m,1H),3.61–3.51(m,2H),2.80–2.66(m,2H),2.45(d,J＝17.1Hz,1H),2.36–2.19(m,4H),2.13(t,J＝13.1Hz,1H),2.10–2.01(m,4H),1.96(tdd,J＝12.8,10.6,2.9Hz,2H),1.83–1.71(m,3H),1.67–1.60(m,7H),1.56(s,3H),1.20(d,J＝7.1Hz,3H),0.94(s,3H).13C NMR(176MHz,MeOD)δ210.32,174.15,170.13,161.21,149.48,138.73,137.44,133.79,130.19,125.36,123.03,77.07,67.09,65.75,60.40,52.81,51.40,51.04,47.01,41.32,40.47,39.56,35.90,30.83,29.81,29.75,25.79,24.80,16.86,15.65,15.47,14.78,10.44.
example 8: synthesis of Compound 8
The tyrosine methyl ester hydrochloride is replaced by glycine methyl ester hydrochloride, the synthesis method is the same as that of example 1, and the intermediate and Cs are2CO3The amount of Terestacin was 5:3: 1. The target compound 8 was obtained, yield: 38 percent.
The nuclear magnetic data for compound 8 is as follows:
1H NMR(700MHz,MeOD)δ5.39(d,J＝5.0Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.20–5.15(m,1H),4.81(d,J＝15.2Hz,1H),4.66(d,J＝15.2Hz,1H),4.02(s,2H),3.98(dd,J＝9.9,4.1Hz,1H),3.85(dd,J＝10.6,8.3Hz,1H),3.74(s,3H),3.70(dd,J＝10.6,6.4Hz,1H),2.84–2.75(m,2H),2.47(d,J＝17.0Hz,1H),2.35–2.24(m,3H),2.13(t,J＝12.9Hz,1H),2.10–1.96(m,3H),1.84–1.72(m,3H),1.68–1.61(m,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.97(s,3H).13C NMR(176MHz,MeOD)δ210.08,172.18,171.52,163.53,150.07,138.88,137.53,133.81,130.06,125.37,122.88,77.06,69.07,66.13,52.68,51.10,50.67,41.49,41.34,40.32,39.16,35.90,30.87,29.75,24.80,16.83,15.65,15.48,14.95,10.45.
example 9: synthesis of Compound 9
Tyrosine methyl ester hydrochloride was replaced with alanine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 9 with yield: and 69 percent.
Nuclear magnetic data for compound 9 are as follows:
1H NMR(700MHz,MeOD)δ5.39(d,J＝5.2Hz,1H),5.30(dd,J＝10.4,5.0Hz,1H),5.17(d,J＝9.1Hz,1H),4.85(d,J＝15.2Hz,1H),4.62(d,J＝15.1Hz,1H),4.50(q,J＝7.3Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.86(dd,J＝10.7,8.3Hz,1H),3.73(s,3H),3.70(dt,J＝10.7,5.2Hz,1H),2.78(ddd,J＝21.9,12.7,4.6Hz,2H),2.47(d,J＝17.2Hz,1H),2.37–2.25(m,3H),2.13(t,J＝13.3Hz,1H),2.10–1.95(m,3H),1.86–1.72(m,3H),1.69–1.59(m,7H),1.57(s,3H),1.42(d,J＝7.3Hz,3H),1.24(d,J＝7.1Hz,3H),0.97(s,3H).13C NMR(176MHz,MeOD)δ210.17,174.32,171.39,163.14,150.09,138.86,137.52,133.80,130.07,125.36,122.90,77.06,68.93,66.08,52.86,51.13,50.75,41.33,40.35,39.23,35.90,30.87,29.76,24.80,17.59,16.83,15.65,15.48,14.95,10.45.
example 10: synthesis of Compound 10
Tyrosine methyl ester hydrochloride was replaced with valine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 10 with yield: 71 percent.
The nuclear magnetic data for compound 10 is as follows:
1H NMR(700MHz,MeOD)δ5.45–5.35(m,1H),5.30(dd,J＝10.5,5.0Hz,1H),5.21–5.13(m,1H),4.92(d,J＝15.1Hz,1H),4.67(d,J＝15.1Hz,1H),4.43(d,J＝5.7Hz,1H),3.98(dd,J＝9.9,4.2Hz,1H),3.88(dd,J＝10.7,8.4Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),2.78(ddd,J＝21.9,13.1,4.6Hz,2H),2.47(d,J＝17.2Hz,1H),2.38–2.23(m,3H),2.20(tt,J＝13.7,6.8Hz,1H),2.16–1.93(m,4H),1.86–1.71(m,3H),1.70–1.59(m,7H),1.57(s,3H),1.24(d,J＝7.1Hz,3H),1.03–0.82(m,9H).13C NMR(176MHz,MeOD)δ210.15,173.27,171.69,162.84,150.00,138.82,137.52,133.80,130.09,125.36,122.92,77.07,68.83,66.06,58.66,52.62,51.16,50.87,41.33,40.41,39.31,35.90,32.10,30.86,29.76,24.80,19.49,18.37,16.81,15.65,15.47,14.96,10.45.
example 11: synthesis of Compound 11
Tyrosine methyl ester hydrochloride was replaced with isoleucine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 11, with yield: 58 percent.
The nuclear magnetic data for compound 11 are as follows:
1H NMR(700MHz,MeOD)δ5.38(d,J＝5.3Hz,1H),5.30(dd,J＝10.5,5.0Hz,1H),5.17(d,J＝8.9Hz,1H),4.92(d,J＝15.1Hz,1H),4.66(d,J＝15.1Hz,1H),4.47(d,J＝5.8Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.88(dd,J＝10.7,8.5Hz,1H),3.73(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),2.83–2.70(m,2H),2.47(d,J＝17.0Hz,1H),2.36–2.22(m,3H),2.19–1.89(m,5H),1.78(ddd,J＝18.5,14.5,10.9Hz,3H),1.71–1.60(m,7H),1.57(s,3H),1.53–1.43(m,1H),1.24(d,J＝7.1Hz,3H),0.98–0.86(m,9H).13C NMR(176MHz,MeOD)δ210.12,173.27,171.57,162.73,149.96,138.83,137.53,133.80,130.09,125.36,122.92,77.07,68.80,66.06,57.74,52.57,51.17,50.87,41.33,40.42,39.31,38.66,35.90,30.86,29.77,26.27,24.80,16.80,15.97,15.65,15.47,14.95,11.72,10.45.
example 12: synthesis of Compound 12
Tyrosine methyl ester hydrochloride was replaced with leucine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 12 with yield: 74 percent.
The nuclear magnetic data for compound 12 is as follows:
1H NMR(700MHz,MeOD)δ5.38(d,J＝5.2Hz,1H),5.30(dd,J＝10.3,4.9Hz,1H),5.17(d,J＝8.8Hz,1H),4.95(d,J＝15.2Hz,1H),4.63(d,J＝15.2Hz,1H),4.55(dd,J＝9.8,4.9Hz,1H),3.98(dd,J＝9.9,4.0Hz,1H),3.88(dd,J＝10.6,8.6Hz,1H),3.72(s,3H),3.69(dd,J＝10.7,6.3Hz,1H),2.78(t,J＝11.1Hz,2H),2.47(d,J＝16.6Hz,1H),2.37–2.23(m,3H),2.13(t,J＝12.8Hz,1H),2.10–1.94(m,3H),1.87–1.73(m,3H),1.72–1.59(m,11H),1.56(s,3H),1.23(d,J＝7.1Hz,3H),0.96(t,J＝3.1Hz,6H),0.92(d,J＝6.4Hz,3H).13C NMR(176MHz,MeOD)δ210.09,174.32,171.76,162.53,149.94,138.83,137.51,133.80,130.09,125.35,122.93,77.06,68.65,66.07,52.77,51.71,51.17,50.75,41.56,41.33,40.46,39.21,35.90,30.86,29.79,25.86,24.80,23.38,21.81,16.80,15.66,15.47,14.91,10.46.
example 13: synthesis of Compound 13
Tyrosine methyl ester hydrochloride was replaced with methionine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 13 with yield: and 55 percent.
The nuclear magnetic data for compound 13 is as follows:
1H NMR(700MHz,MeOD)δ5.38(d,J＝5.4Hz,1H),5.30(dd,J＝10.4,5.2Hz,1H),5.18(s,1H),4.92(d,J＝15.2Hz,2H),4.67(dd,J＝9.1,4.6Hz,1H),4.62(d,J＝15.2Hz,2H),3.98(dd,J＝9.9,4.1Hz,1H),3.88(dd,J＝10.7,8.5Hz,1H),3.74(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),2.78(ddd,J＝17.4,13.2,4.5Hz,2H),2.59(ddd,J＝28.8,17.1,13.0Hz,1H),2.55–2.50(m,1H),2.47(d,J＝17.0Hz,1H),2.35–2.23(m,3H),2.21–2.11(m,2H),1.65(s,6H),1.57(s,3H),1.24(d,J＝7.1Hz,3H),0.96(s,3H).13C NMR(176MHz,MeOD)δ210.09,173.51,171.89,162.65,149.98,138.86,137.52,133.79,130.08,125.36,122.94,77.06,68.83,66.07,52.91,52.30,51.17,50.77,41.35,40.44,39.25,35.90,32.00,31.04,30.86,29.79,24.80,16.83,15.65,15.50,15.20,14.94,10.46.
example 14: synthesis of Compound 14
Tyrosine methyl ester hydrochloride was replaced with serine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 14 with yield: 26 percent.
The nuclear magnetic data for compound 14 is as follows:
1H NMR(700MHz,MeOD)δ5.39(d,J＝5.2Hz,1H),5.31(dd,J＝10.5,5.2Hz,1H),5.23–5.14(m,1H),4.81(d,J＝15.2Hz,1H),4.72(d,J＝15.2Hz,1H),4.66–4.57(m,2H),3.97(ddd,J＝15.5,10.7,4.2Hz,2H),3.91–3.81(m,2H),3.77(d,J＝3.0Hz,3H),3.70(dd,J＝10.7,6.5Hz,1H),2.79(ddd,J＝21.8,13.0,4.6Hz,2H),2.47(d,J＝17.1Hz,1H),2.31(ddd,J＝20.1,11.6,7.1Hz,3H),2.13(t,J＝13.0Hz,1H),2.10–1.97(m,3H),1.85–1.72(m,3H),1.65(s,7H),1.57(s,3H),1.26(d,J＝7.1Hz,3H),0.97(s,3H).13C NMR(176MHz,MeOD)δ210.20,171.96,171.51,163.56,149.97,138.88,137.54,133.81,130.06,125.37,122.89,77.06,69.05,66.13,62.75,55.71,52.97,51.15,50.83,41.33,40.33,39.29,35.90,30.86,29.72,24.80,16.82,15.65,15.48,14.97,10.45.
example 15: synthesis of Compound 15
Tyrosine methyl ester hydrochloride was replaced with proline methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 15 with yield: and 47 percent.
Nuclear magnetic data for compound 15 are as follows:
1H NMR(700MHz,MeOD)δ5.39(d,J＝5.3Hz,1H),5.29(dt,J＝26.8,13.4Hz,1H),5.20–5.13(m,1H),4.86(d,J＝18.1Hz,22H),4.77(d,J＝15.3Hz,1H),4.53(d,J＝2.7Hz,1H),4.34(qd,J＝6.4,2.7Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.88(dt,J＝12.8,6.4Hz,1H),3.76(s,3H),3.73–3.65(m,1H),2.80(dd,J＝11.2,2.1Hz,1H),2.76(dt,J＝14.0,7.0Hz,1H),2.47(d,J＝17.0Hz,1H),2.31(ddd,J＝24.2,11.2,7.9Hz,3H),2.13(t,J＝13.2Hz,1H),2.10–1.95(m,3H),1.85–1.72(m,3H),1.67–1.62(m,7H),1.57(s,3H),1.26(dd,J＝12.6,4.6Hz,3H),1.19(t,J＝7.8Hz,3H),0.98(d,J＝7.3Hz,3H).13C NMR(176MHz,MeOD)δ210.03,172.22,171.93,163.30,149.82,138.85,137.54,133.80,130.08,125.36,122.91,77.07,68.93,68.36,66.11,58.67,52.92,51.16,50.91,41.33,40.37,39.35,35.90,30.86,29.73,24.80,20.44,16.82,15.65,15.48,14.99,10.45.
example 16: synthesis of Compound 16
Tyrosine methyl ester hydrochloride was replaced with phenylalanine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 16 with a yield: 42 percent.
The nuclear magnetic data for compound 16 is as follows:
1H NMR(700MHz,MeOD)δ7.28(t,J＝7.4Hz,1H),7.24–7.21(m,1H),7.21–7.18(m,1H),5.38(d,J＝5.4Hz,1H),5.30(dd,J＝10.3,5.0Hz,1H),5.18(s,1H),4.81(d,J＝15.1Hz,1H),4.77(dd,J＝7.9,5.6Hz,1H),4.56(d,J＝15.1Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.81(dd,J＝10.6,8.4Hz,1H),3.71(s,1H),3.66(dd,J＝10.7,6.4Hz,1H),3.22–3.15(m,1H),3.07(dd,J＝13.9,7.9Hz,1H),2.77(dd,J＝11.2,2.2Hz,1H),2.72(dd,J＝14.9,6.9Hz,1H),2.45(d,J＝17.2Hz,1H),2.36–2.20(m,1H),2.13(t,J＝12.9Hz,1H),2.10–1.94(m,1H),1.85–1.72(m,1H),1.64(d,J＝5.7Hz,4H),1.57(s,2H),1.17(d,J＝7.1Hz,1H),0.96(s,1H).13C NM R(176MHz,MeOD)δ210.05,173.00,171.31,163.43,149.91,138.86,137.81,137.52,133.80,130.33,130.07,129.59,128.00,125.37,122.90,77.07,68.84,66.10,54.69,52.81,51.11,50.85,41.33,40.33,39.26,38.34,35.91,30.87,29.71,24.80,16.83,15.65,15.49,15.02,10.46.
example 17: synthesis of Compound 17
Tyrosine methyl ester hydrochloride was replaced with tryptophan methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 17 with yield: 58 percent.
The nuclear magnetic data for compound 17 is as follows:
1H NMR(700MHz,MeOD)δ7.49(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,1H),7.10(s,1H),7.09–7.06(m,1H),7.01–6.98(m,1H),5.37(d,J＝5.2Hz,1H),5.28(dd,J＝10.4,5.0Hz,1H),5.21–5.14(m,1H),4.83(d,J＝5.9Hz,1H),4.75(d,J＝15.1Hz,1H),4.61(d,J＝15.1Hz,1H),3.97(dd,J＝9.9,4.1Hz,1H),3.73(dd,J＝10.7,8.4Hz,1H),3.69(s,3H),3.58(dd,J＝10.7,6.4Hz,1H),2.75(dd,J＝11.2,2.1Hz,1H),2.69–2.58(m,1H),2.42(d,J＝16.9Hz,1H),2.37–2.24(m,3H),2.17–2.06(m,2H),2.03(dd,J＝19.0,6.6Hz,1H),2.00–1.91(m,1H),1.85–1.73(m,3H),1.64(d,J＝14.9Hz,7H),1.57(s,3H),1.04(d,J＝7.1Hz,3H),0.95(s,3H).13C NMR(176MHz,MeOD)δ210.04,173.45,171.22,163.53,149.82,138.84,138.04,137.50,133.79,130.08,128.80,125.38,124.61,122.89,122.47,119.93,119.12,112.37,110.06,77.06,68.95,66.08,54.34,52.84,51.08,50.87,41.33,40.30,39.23,35.91,30.87,29.68,28.33,24.80,16.83,15.64,15.49,14.88,10.48.MS-ESI(m/z):415.1(M+H)+
example 18: evaluation of Compound for inhibiting Activity of hypoxic factor protein
Inoculating the cells to be tested into MEM (minimum essential medium) basic culture solution containing 10% fetal calf serum for culturing for 24 hours, taking the cells to be tested into a culture medium (Dulbecco's modified Eagle's medium/Nutrient Mixture F-12(Gibco) culturing 1X B-27serum-free supplement) without serum after the cancer cells grow normally, continuing culturing for 16 hours (starvation culturing), adding the cells into groups (2.5 mu M) or processing the cells with blank control for 1 hour, and continuing to add 1% O2In a hypoxic incubator (containing 5% CO)2And N2Equilibrium) for 4h, detecting the expression quantity of HIF-1 alpha by using Western Blot, analyzing the net optical density value of a target zone by using a gel image imaging system, and calculating the average inhibition rate by 3 groups of parallel experiments in each group.
Specific results are shown in table 1:
table 1: compounds that inhibit hypoxic factor (HIF-1 alpha) activity
Note:ashowing the expression level of HIF-1 alpha in cancer cells under normoxic and hypoxic conditions, as an experimental control
b4-200 is compound N- (4-hydroxyphenyl) - [1,1' -biphenyl ]]-4-sulfonamide, which has inhibitory activity against HIF-1 α, is a positive control.
Claims (9)
1.TerpestacinO17-CH2CO-NHCHRCO2Me derivatives or pharmaceutically acceptable salts thereof, the structural formula of which is shown in formula (I):
wherein R is H, CH3,CH(CH3)2,CH3CHCH2CH3,CH2CH(CH3)2,CH2CH2SCH3,CH2OH,CHCH2OH,CH2Ph,CH2-3-indolyl,CH2Ph-4-OH,CH2-4-imidazolyl,CH2CH2CO2Me,CH2CH2CONH2,CH2CO2Me,CH2CONH2Or CH2CH2CH2。
2. The TerestacinO of claim 117-CH2CO-NHCHRCO2Me derivative or pharmaceutically acceptable salt thereof, characterized in that the TerestacinO is17-CH2CO-NHCHRCO2The Me derivative or the pharmaceutically acceptable salt thereof is any one of the following compounds:
3. the Terestacino of claim 117-CH2CO-NHCHRCO2A process for the preparation of Me derivatives, characterized in that it comprises the following steps:
adding Et3Dissolving N and L-amino acid methyl ester or salt thereof in dichloromethane, slowly dripping chloroacetyl chloride dichloromethane solution into the solution, adding water and dichloromethane for washing, extracting and separating after the reaction is finished, and purifying the extract to obtain an intermediate product
The intermediate product is reacted with TThe erpestacin is dissolved in DMF and catalytic amount of KI is added, then Cs is added2CO3Stirring, adding water after the reaction is finished, extracting with ethyl acetate, and separating and purifying the product to obtain the target product
Wherein R is H, CH3,CH(CH3)2,CH3CHCH2CH3,CH2CH(CH3)2,CH2CH2SCH3,CH2OH,CHCH2OH,CH2Ph,CH2-3-indolyl,CH2Ph-4-OH,CH2-4-imidazolyl,CH2CH2CO2Me,CH2CH2CONH2,CH2CO2Me,CH2CONH2,CH2CH2CH2。
4. The process according to claim 3, wherein Et is used as the reagent3N, L-amino acid methyl ester and chloroacetyl chloride in a ratio of 3:1:1.5 to 3:1: 3.
5. The process according to claim 4, wherein Et is used as a detergent3N, L-amino acid methyl ester and chloroacetyl chloride react for 1-3 hours at 0 ℃, and the reaction solvent is dichloromethane.
6. The method according to claim 3,
Cs2CO3the mass ratio of the Terestacin to the Terestacin is 5:3: 1-3: 3: 1.
7. The production method according to claim 6,
Cs2CO3the reaction condition of the Terestacin and Terestacin is room temperature reaction for 1-3 hours, and the reaction solvent is N, N-dimethylformamide.
8. Terestacino as claimed in claim 1 or 217-CH2CO-NHCHRCO2The application of Me derivatives or medicinal salts thereof in preparing cancer cell hypoxia factor inhibitors.
9. A cancer cell hypoxia factor inhibitor comprising Terestacino as defined in claim 1 or 217-CH2CO-NHCHRCO2Me derivatives or pharmaceutically acceptable salts thereof as active ingredients.
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| HYE JIN JUNG，ET AL.: "Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing", 《THE JOURNAL OF BIOLOGICAL CHEMISTRY》, vol. 285, no. 15, pages 11584 - 11595, XP055205039, DOI: 10.1074/jbc.M109.087809 * |
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