CN109280073A - Nannocystins derivative and application thereof - Google Patents
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- CN109280073A CN109280073A CN201710592493.6A CN201710592493A CN109280073A CN 109280073 A CN109280073 A CN 109280073A CN 201710592493 A CN201710592493 A CN 201710592493A CN 109280073 A CN109280073 A CN 109280073A
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- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 229930014626 natural product Natural products 0.000 claims abstract description 5
- 239000003560 cancer drug Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 13
- PEOAVEOEVIQCMT-XWDGXJISSA-N (1R,4S,7R,10S,13S,14R,15E,17E,19R,21S)-4-[(2S)-butan-2-yl]-7-[(3,5-dichloro-4-hydroxyphenyl)methyl]-10-(2-hydroxypropan-2-yl)-19-methoxy-1,3,14,18-tetramethyl-13-phenyl-12,22-dioxa-3,6,9-triazabicyclo[19.1.0]docosa-15,17-diene-2,5,8,11-tetrone Chemical compound CC[C@H](C)[C@@H]1N(C)C(=O)[C@]2(C)O[C@H]2C[C@@H](OC)\C(C)=C\C=C\[C@@H](C)[C@H](OC(=O)[C@@H](NC(=O)[C@@H](Cc2cc(Cl)c(O)c(Cl)c2)NC1=O)C(C)(C)O)c1ccccc1 PEOAVEOEVIQCMT-XWDGXJISSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000000539 amino acid group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 claims description 4
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 claims description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 102000014914 Carrier Proteins Human genes 0.000 claims 1
- CZWARROQQFCFJB-UHFFFAOYSA-N L-2-Amino-5-hydroxypentanoic acid Chemical compound OC(=O)C(N)CCCO CZWARROQQFCFJB-UHFFFAOYSA-N 0.000 claims 1
- 108091008324 binding proteins Proteins 0.000 claims 1
- 238000003032 molecular docking Methods 0.000 abstract description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- PXEKBQAJOBYINU-BYPYZUCNSA-N N-hydroxy-L-valine Chemical group CC(C)[C@H](NO)C(O)=O PXEKBQAJOBYINU-BYPYZUCNSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- -1 epoxide amide Chemical class 0.000 description 2
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000863434 Myxococcales Species 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229930189543 chondramide Natural products 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- GQWYWHOHRVVHAP-DHKPLNAMSA-N jaspamide Chemical compound C1([C@@H]2NC(=O)[C@@H](CC=3C4=CC=CC=C4NC=3Br)N(C)C(=O)[C@H](C)NC(=O)[C@@H](C)C/C(C)=C/[C@H](C)C[C@@H](OC(=O)C2)C)=CC=C(O)C=C1 GQWYWHOHRVVHAP-DHKPLNAMSA-N 0.000 description 1
- GQWYWHOHRVVHAP-UHFFFAOYSA-N jasplakinolide Natural products C1C(=O)OC(C)CC(C)C=C(C)CC(C)C(=O)NC(C)C(=O)N(C)C(CC=2C3=CC=CC=C3NC=2Br)C(=O)NC1C1=CC=C(O)C=C1 GQWYWHOHRVVHAP-UHFFFAOYSA-N 0.000 description 1
- 108010052440 jasplakinolide Proteins 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001470 polyketone Polymers 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 229930186124 seragamide Natural products 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides 1 structure Nannocystins derivative of formula and application thereof, discovery is different from natural products with the binding protein EF-1 α binding site for carrying out molecular docking, the purposes in preparation treating cancer drug or the ancillary drug for the treatment of cancer.
Description
Technical field
The present invention relates to Nannocystins derivatives, and in preparation treating cancer drug or the adjuvant for the treatment of cancer
Purposes in object, belongs to field of medicinal chemistry.
Background technique
It is the important source for finding new drug and its lead compound by the secondary metabolites that microorganism generates.It glues in recent years thin
Bacterium (myxobacteria) receives more and more attention as important drug induccd microorganism.Recently respectively by Br nstrup
It successively publishes an article with two dependent research groups of Hoepfner leader, reports two differences from slime bacteria Nannocyctis
The compound nannocystin with novel structure is had found in the fermentation culture of bacterial strain ST201196 and MB1016
A.The molecule is 21 yuan of macrocyclic structures, and skeleton is by polyketone and two segments of tripeptides are end to end forms, and contains 9 chiralitys in total
The trans olefins double bond at center and two conjugation.α in the molecule, beta epoxide amide are that nannocystin class compound is exclusive,
Summary of the invention not yet is found in other known natural products so far.
Br nstrup etc. tests Nannocystin A for the inhibitory effect of 14 kinds of cancerous cell lines, finds it with very high
Anticancer activity, IC50It is worth up to lower nanomolar concentration range.Especially the molecule is for common human breast cancer cell MDA-
MB231 and drug resistance breast cancer cell MDA-A1 show good inhibitory effect, IC50Value is respectively 6.5 nM and 12 nM;Phase
Than under, inhibitory effect (IC of the paclitaxel kind anti-cancer drugs docetaxel (docetaxel) for drug resistant cancer cells MDA-A150 =
570 nM) and MDA-MB231(IC50 =0.3 nM) it is many compared to then decline.Which show Nannocystin A as guide
Important value of the compound in Development of Novel anticancer drug.Other having now been found that have the work of " polyketone-tripeptides " structure
Property macrocyclic natural products include chondramide, jasplakinolide, seragamide, miuraenamide etc..It grinds
Study carefully and shows that the action target of these molecules is actin.It is interesting that Br nstrup etc. has found Nannocystin A energy
In the early evoking apoptosis of cell cycle, this is completely different with the mechanism of action of above compound.
Summary of the invention
The present invention provides the compound of such as 1 structure of following formula,
Wherein, R1=R2=Cl or R1=Br, R2=H。
Compound structure are as follows:
。
The protein-bonded combination of compound 1a, 1b and EF-1 α.Docking is the result shows that all contain dimethyl group compound
Dimethyl part all be located at amino acid residue Ala397In neighbouring hydrophobic cavity, but there is hydroxyvaline residue day
The combination of right product Nannocystin A and Nannocystin 6 is but different from hydroxy derivatives 1a and 1b.
The hydroxyl of Nannocystin A and Nannocystin 6 can be with amino acid residue Arg379The hydrogen bond that distance is 2.61 is formed,
However in 1a and 1b with Arg379Form hydrogen bond is its phenolic hydroxyl group part.
Purposes of the compound as described above in preparation treating cancer drug or the ancillary drug for the treatment of cancer, wherein cancer
For colon cancer.
Detailed description of the invention
The structure of Fig. 1 Nannocystin A and Nannocystin 6
Fig. 2 compound N annocystin A, 6 Nannocystin and 1a, 1b molecular docking result
Specific embodiment
Embodiment 1: Nannocystin derivative 1a(R has been synthesized1=R2=Cl)
The related data of compound 1a: [α]D 27 = - 16.8 (c 0.45, CHCl3); IR (KBr) νmax:3835,
3612, 3291, 2963, 2926, 2855, 1736, 1688, 1664, 1495, 1461, 1262, 1094, 1023,
801 cm-1; 1H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 8.55 (d, J = 9.7 Hz, 1H),
7.97 (d, J = 9.5 Hz, 1H), 7.43 – 7.26 (m, 7H), 6.43 – 6.33 (m, 1H), 6.16 –
6.06 (m, 3H), 4.75 – 4.64 (m, 2H), 4.47 (d, J = 11.3 Hz, 1H), 3.59 (d, J =
10.5 Hz, 1H), 3.07 (s, 3H), 2.97 (s, 3H), 2.80 (d, J = 12.6 Hz, 1H), 2.69
(br, 1H), 2.63 – 2.53 (m, 2H), 2.32 (br, 1H), 2.12 (t, J = 12.5 Hz, 1H), 1.79
– 1.70 (m, 1H), 1.68 (s, 3H), 1.42 (s, 4H), 1.21 (br, 1H), 0.96 (d, J = 6.0
Hz, 3H), 0.89 (s, 1H), 0.85 (d, J = 6.0 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H),
0.72 (d, J = 6.3 Hz, 3H), 0.39 (d, J = 5.6 Hz, 3H); 13C NMR (100 MHz, DMSO) δ
171.0, 170.9, 169.3, 168.6, 147.3, 139.6, 137.7, 133.5, 130.9, 129.7, 129.3,
128.3, 127.5, 125.4, 125.0, 121.6, 84.1, 77.2, 61.4, 59.2, 58.0, 55.1, 52.9,
41.6, 37.5, 31.0, 30.9, 30.7, 29.7, 24.3, 19.3, 16.5, 14.9, 14.6, 10.6, 10.1,
9.4; HRMS–MALDI (m/z): [M+Na]+ calcd for C42H55Cl2N3O8Na+, 822.3258; found:
822.3263.
Embodiment 2: Nannocystin derivative 1b (R has been synthesized1=Br, R2=H)
The related data of compound 1b: [α]D 26 = - 36.02 (c 0.1, CHCl3);IR (KBr) νmax: 3337,
2963, 1741, 1663, 1498, 1414, 1261, 1096, 1021, 800cm-1;1H NMR (400 MHz, DMSO)
δ 9.89 (s, 1H), 8.56 (d, J = 9.6 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.46 (s,
1H), 7.36 (dt, J = 17.4, 8.0 Hz, 5H), 7.10 (d, J = 8.1 Hz, 1H), 6.75 (d, J =
8.3 Hz, 1H), 6.43 – 6.33 (m, 1H), 6.11 (dd, J = 16.5, 11.5 Hz, 3H), 4.78 –
4.63 (m, 2H), 4.47 (d, J = 11.1 Hz, 1H), 3.61 (d, J = 10.1 Hz, 1H), 3.08 (s,
3H), 2.97 (s, 3H), 2.82 (d, J = 12.5 Hz, 1H), 2.70 (s, 1H), 2.63 (d, J = 10.3
Hz, 1H), 2.56 (d, J = 12.3 Hz, 1H), 2.32 (s, 1H), 2.12 (t, J = 12.3 Hz, 1H),
1.75 (d, J = 28.0 Hz, 1H), 1.69 (s, 3H), 1.41 (d, J = 17.0 Hz, 4H), 1.24 (s,
1H), 0.97 (d, J = 6.2 Hz, 3H), 0.85 (d, J = 6.4 Hz, 4H), 0.78 (t, J = 7.1 Hz,
3H), 0.73 (d, J = 6.4 Hz, 3H), 0.39 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
DMSO) δ 171.2, 170.9, 169.4, 168.6, 152.3, 139.6, 137.6, 133.6, 133.4, 129.9,
129.1, 128.3, 127.4, 125.5, 125.1, 115.6, 108.7, 84.03, 77.2, 61.3, 59.2,
58.0, 55.2, 55.1, 52.9, 41.6, 37.7, 31.0, 30.9, 30.7, 29.7, 24.2, 19.2, 16.6,
14.9, 14.8, 10.6, 10.1, 9.5; HRMS–MALDI (m/z): [M+Na]+ calcd for C42H56BrN3O8Na+, 832.3143; found:832.3148.
Embodiment 3: molecular docking simulation calculates
In order to probe into the binding pattern of Nannocystin series compound, we tie derivative 1a, 1b and EF-1 α of synthesis
Hop protein carries out docking simulation.It just reports as in the previous, compound N annocystins can be with the surface cavities knot of EF-1 α
It closes.Docking is the result shows that all dimethyl parts containing dimethyl group compound are all to be located at amino acid residue Ala397It is attached
In close hydrophobic cavity, but there is hydroxyvaline residue natural products Nannocystin A and Nannocystin 6(knot
Structure is shown in attached drawing 1) combination be but different from hydroxy derivatives 1a and 1b.Nannocystin A's and Nannocystin 6
Hydroxyl can be with amino acid residue Arg379Formed distance be 2.61 hydrogen bond, however in 1a and 1b with Arg379Form hydrogen bond
Be its phenolic hydroxyl group part (see attached drawing 2).These docking results and our life measured data are identical.
Embodiment 4:Nannocystin derivative 1a, 1b pharmacological action
The culture of HCT-116 cell strain is in the DMEM culture medium containing 10% fetal calf serum, at 37 degree, the incubator of 5% carbon dioxide
Middle growth.Logarithmic phase cell kind is on the impermeable tabula rasa in 96 holes, every 100 uL fresh culture of hole, overnight growth.A series of chemical combination
Final concentration 100-0.005nM in cell hole is added after object dilution.96 orifice plates take out from incubator after 72 hours, and equilibrium at room temperature 30 divides
Clock.100 uLCGLK(PROMEGA are added in every hole) reagent, and shaken 2 minutes in constant-temperature table, after room temperature 10 minutes are incubated for, use
Microplate reader measures fluorescence signal, and data are statisticallyd analyze with GraphPad 5.Compound 1a, 1b has HCT-116 good as the result is shown
Good inhibitory activity, IC50Respectively 7.0 ± 4.8 nM and 3.3 ± 0.5 nM.
Claims (4)
1. it is related to the compound such as 1 structure of following formula,
Wherein, R1=R2=Cl or R1=Br, R2=H。
2. according to claim 1, compound structure are as follows:
。
3. the new combination of compound 1a, 1b and EF-1 α binding protein is docked the result shows that all contain dimethyl group
The dimethyl part for closing object is all to be located at amino acid residue Ala397In neighbouring hydrophobic cavity, but have hydroxyvaline residual
The combination of base natural products Nannocystin A and Nannocystin 6 is but different from hydroxy derivatives 1a and 1b,
The hydroxyl of Nannocystin A and Nannocystin 6 can be with amino acid residue Arg379The hydrogen bond that distance is 2.61 is formed,
However in 1a and 1b with Arg379Form hydrogen bond is its phenolic hydroxyl group part.
4. use of the compound described in claim 1 and 2 in preparation treating cancer drug or the ancillary drug for the treatment of cancer
On the way, wherein cancer is colon cancer.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109796468A (en) * | 2019-03-26 | 2019-05-24 | 南开大学 | Big ring nannocystin derivative, and its preparation method and application |
CN112321677A (en) * | 2020-10-23 | 2021-02-05 | 北京大学深圳研究生院 | Nannocystin A analogue and preparation method and application thereof |
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2017
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CN101687884A (en) * | 2007-07-04 | 2010-03-31 | 塞诺菲-安万特股份有限公司 | macrolactone derivatives |
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Title |
---|
"Nannocystin A的全合成", 《有机化学》 * |
HOLGER HOFFMANN等: "Discovery, Structure Elucidation, and Biological Characterization of Nannocystin A, a Macrocyclic Myxobacterial Metabolite with Potent Antiproliferative Properties", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 * |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109796468A (en) * | 2019-03-26 | 2019-05-24 | 南开大学 | Big ring nannocystin derivative, and its preparation method and application |
CN109796468B (en) * | 2019-03-26 | 2021-08-31 | 南开大学 | Macrocyclic nannocystin derivatives, preparation method and application thereof |
CN112321677A (en) * | 2020-10-23 | 2021-02-05 | 北京大学深圳研究生院 | Nannocystin A analogue and preparation method and application thereof |
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