CN102125578A - Rebeccamycin analogue with anticancer activity and synthesis method thereof - Google Patents

Rebeccamycin analogue with anticancer activity and synthesis method thereof Download PDF

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CN102125578A
CN102125578A CN2010105696321A CN201010569632A CN102125578A CN 102125578 A CN102125578 A CN 102125578A CN 2010105696321 A CN2010105696321 A CN 2010105696321A CN 201010569632 A CN201010569632 A CN 201010569632A CN 102125578 A CN102125578 A CN 102125578A
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CN102125578B (en
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张贵生
王军强
师君红
刘小兵
刘青锋
毕晶晶
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Henan Normal University
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Abstract

The invention relates to a rebeccamycin analogue with anticancer activity and a synthesis method thereof. Groups, such as glycosyl, amino acid, basic group, alkyl, and the like are introduced into the N-6 site to synthesize the rebeccamycin analogue, therefore, a method for obtaining the rebeccamycin analogue with more favorable biological activity and favorable water solubility is provided.

Description

Butterfly mycin analog and synthetic method with active anticancer
Technical field
The present invention relates to the chemical compound that a class has active anticancer, particularly a kind of N-6 with active anticancer replaces butterfly mycin analog noval chemical compound and preparation method.
Background technology
1985, Doyle etc. found butterfly mycin (Rebeccamycin).It is to separate a kind of microbe metabolite that obtains from the culture fluid of actinomycetes Saccharothrix Aerocoligenes, its structure is by indole [2,3-a] pyrroles [3,4-c] carbazole nuclear (abbreviating indole carbazole nuclear as) and β-glucose two large divisions formation, as follows.
The butterfly mycin
Studies show that, the butterfly mycin is a kind of novel natural antibiotics, be after camptothecine, find to topoisomerase I (Topoisomerase I) thus have certain inhibitory action, can the inducible eukaryotic state the fracture of DNA produce material than powerful antitumor activity.DNA shows that in conjunction with testing butterfly mycin and DNA do the time spent, and in the indolocarbazole nuclear intercalation of DNA, glycosyl part can strengthen the DNA affinity with the groove effect, and the base series of pyrrole heterocyclic part energy specific recognition DNA size groove.
Yet, owing to relatively poor the causing of water solublity of butterfly mycin can't be made further pharmacology evaluation to it.In order to seek biological activity better medicament lead compound, probe into the structure activity relationship (Structure Activity Relationship) of butterfly mycin analog simultaneously, people mainly modify and transform synthetic various analog from three aspects to the structure of butterfly mycin, and the one, with other group hydrogen atom of hydrophilic radical replacement top amide groups particularly; The 2nd, on the phenyl ring of indolocarbazole ring, introduce other group such as halogen atom or hydroxyl, perhaps phenyl ring is changed into other heterocycle, as pyridine ring; The 3rd, with the glycosyl part of other sugar replacement butterfly mycin.As follows:
Figure BSA00000370498400021
The analog of butterfly mycin
Up to the present, people are by biological method and chemical method, general more than 300 kinds of analog have been obtained through complete synthesis and semi-synthetic, wherein the overwhelming majority obtains through preceding two kinds of method of modifying, and mainly be in order to improve butterfly mycin analog water solublity, wherein to have some analog to be used for clinical research.
At present, do not report as yet for the butterfly mycin analog of introducing groups such as base, aminoacid and glycosyl in butterfly mycin N-6 position, in view of base, aminoacid and sugar etc. self good water-solubility and pharmaceutically active, we introduce base, aminoacid and glycosyl etc., the butterfly mycin analog that has obtained to have better biological activity and good aqueous solubility at butterfly mycin N-6 position nitrogen-atoms.
Summary of the invention
For many years, the structure activity study of butterfly mycin is shown that indole carbazole nuclear and glycosyl are butterfly mycin and the necessary structure division of analog activity expression thereof, and during glycosidic bond maintenance beta comfiguration, medicine has better biological activity through Pharmaceutical Chemist.Find that simultaneously two chlorine atom pair biological activitys in the butterfly mycin structure have negative effect, to 4 on the modification of N-6 position and the sugar '-the O-methyl is little to the biological activity influence of analog.At present, though there is a large amount of butterfly mycin analog to be synthesized out,, finally all fail to be applied to clinical treatment because of these analog lack ideal water solublity.
Because base, sugar and aminoacid etc. have the important physical function in vivo, thereby different types of base, glycosyl and aminoacid etc. are incorporated into the N-6 position of butterfly mycin, in the hope of improving the water solublity of butterfly mycin analog, the more important thing is and wish to strengthen its targeting specific, thereby improve its anti-tumor bioactivity, by the pharmaceutically active screening, seek active better medicament lead compound and improve its structure activity relationship.Technical solution of the present invention is, has the new type water-solubility butterfly mycin analog and the synthetic method of active anticancer, it is characterized in that chemical compound has following structure:
Figure BSA00000370498400022
Wherein:
Substituent R is-CH 2CH 2R 1,
Figure BSA00000370498400031
H 2NCONH-, (HOCH 2) 3C-,
Figure BSA00000370498400032
Figure BSA00000370498400033
Deng;
Substituent R 3, R 4Be H, halogen, hydroxyl etc.;
R wherein 1Be glycosyl, as Deng; Base is as 5-fluorouracil
Figure BSA00000370498400035
Adenine
Figure BSA00000370498400036
Cytosine 5-azepine cytosine
Figure BSA00000370498400038
Morpholine Piperazine
Figure BSA000003704984000310
N-acetyl group piperazine
Figure BSA000003704984000311
Deng.
R wherein 2Be H, CH 3, HOCH 2-, HOOCCH 2CH 2-, Deng.
Wherein glycosyl is selected from following chemical compound:
Figure BSA000003704984000313
Figure BSA000003704984000314
Deng.
Have the preparation method of the new type water-solubility butterfly mycin analog of active anticancer, it is characterized in that:
Figure BSA00000370498400041
Description of drawings
Fig. 1 be part of compounds respectively under 40 μ M and 4 μ M concentration, the activity data figure in leukaemia's (K562 cell).
Fig. 2 be part of compounds respectively under 40 μ M and 4 μ M concentration, the activity data figure in breast cancer cell (MCF-7 cell).
Specific implementation method
1.N-glycosyl butterfly mycin analog I series compound is synthetic
We select following six kinds of glycosyl intermediate is example, and the synthetic of N-glycosyl butterfly mycin analog I series compound is described.
Figure BSA00000370498400042
We set out from various sugar and ethylaminoethanol, according to following synthetic route, have synthesized six kinds of glycosyl intermediate, and selecting following glycosyl intermediate is example, and the synthetic of butterfly mycin analog is described:
Figure BSA00000370498400043
1) the N-Phth ethylaminoethanol synthetic
In the 10mL round-bottomed flask, add phthalic anhydride (1mol), under agitation ethylaminoethanol (1eq) dropwise is added dropwise in the flask exothermic heat of reaction then.After dropwising, temperature is risen to 100 ℃, finish after reacting about 1h with oil bath.Solution temperature is reduced to room temperature, and solution becomes solid.In flask, add distilled water, slowly heat up, solid is dissolved to fully, cooling then, crystallization obtains the solid N-Phth ethylaminoethanol of white, and yield is 80%.
2) glycosyl donor is synthetic
Figure BSA00000370498400051
Add glucose (1mmol) in round-bottomed flask, whether acetic anhydride (1mL) and ferric sulfate hydrate (2mol%) stir under the room temperature, finish with the TLC detection reaction.After reacting completely, can obtain chemical compound 1 through separating, using the same method to obtain chemical compound 2 and 3, and productive rate is about 98%.
In round-bottomed flask, 2-glucosamine 200mg is dissolved in the 3ml water, adds 192mg potassium carbonate and 1.4mg copper sulphate pentahydrate, add 6ml methanol and TfN after the stirring and dissolving 3Dichloromethane solution, and then add 6ml methanol, stirring at room 18h.Reaction is spin-dried for solvent after finishing, and adds pyridine and acetic anhydride, at room temperature stirs and spends the night.After reaction finished, column chromatography for separation was dissolved in the product that obtains among the DMF, and ice bath adds acetic acid hydrazine stirring reaction after 20 minutes, after reaction finishes, and through washing, drying, column chromatography for separation can obtain chemical compound 4, and yield is 70%; Using the same method obtains chemical compound 6, and yield is 99%.
In round-bottomed flask, add the 4g rhamnal and be dissolved in the 30ml water, rising reaction temperature to 80 ℃, stir 2h after, be cooled to room temperature, add 4ml acetic acid and 2g Hydrazoic acid,sodium salt, stir 3h under the room temperature after, through extraction, drying obtains thick product.Thick product is dissolved in the 60ml dichloromethane, and adding 2.6g imidazoles, slowly in solution, drip at 0 ℃ and to be dissolved with 3.6g tert-butyl chloro-silicane (tert-Butyldimethylchlorosilane, TBDMS-Cl) dichloromethane solution, under the zero degree condition, react 24h, obtain chemical compound 5 through column chromatography for separation, yield is 50%.
3) the glycosyl intermediate is synthetic
Figure BSA00000370498400052
Under nitrogen protection, in flask, add 1 (5.12mmol) and N-Phth ethylaminoethanol (6.17mmol), add the 20mL dichloromethane, stirred 10 minutes under the condition of ice bath, dropwise add 3.632mL BF then 3Et 2O solution continues ice bath reaction 1h.Reaction is spent the night under the room temperature then, and after washing, drying, column chromatography for separation obtains chemical compound 7, and yield is 50%; Same method can obtain chemical compound 8 and 9, and yield is respectively 49% and 64%.
Figure BSA00000370498400061
Under nitrogen protection and-20 ℃ of conditions, the 30mg sodium hydride is dissolved in the 5ml oxolane, the tetrahydrofuran solution that will be dissolved with 0.2g chemical compound 4 then dropwise is added in the tetrahydrofuran solution of sodium hydride, after dropwising, stirs 1h.Along with the carrying out of reaction, solution colour is deepened gradually, and temperature slowly is raised to 0 ℃.Tetrahydrofuran solution with the ready 0.16g of being dissolved with N-Phth ethylaminoethanol triflate dropwise joins in the previous reaction liquid more at last.Reaction is spent the night under the condition of ice bath.After reaction finished, the pressure reducing and steaming oxolane added the dichloromethane dissolving then, and through washing, drying, column chromatography for separation get chemical compound 10, and yield is 30%; Same method can obtain chemical compound 12, and yield is 65%.
Figure BSA00000370498400062
With chemical compound 5 (0.36mmol), ethylaminoethanol (0.69mmol) and 400mg
Figure BSA00000370498400063
Mealy molecular sieve adds in the exsiccant dichloromethane of 10ml, and stirring at room 1h reduces to the temperature of reaction system-35 ℃ then, slowly splashes into 0.55mmol trifluoromethanesulfonic acid trimethylsilyl group (TMSOTf), reacts 2h under-35 ℃ of conditions.Use triethylamine quencher reaction at last.Then after filtration, washing, column chromatography purification can obtain chemical compound 11, and yield is 88%.
4) N-glycosyl butterfly mycin analog I series compound is synthetic
Figure BSA00000370498400064
Adopt indoline glucosides method, directly sugared and substrate can obtain chemical compound JDC-108 through three-step reaction.Then chemical compound JDC-108 is added sodium hydroxide and reflux in water, reaction drips 2molL after finishing in solution -1Dilute hydrochloric acid, then through the extraction and the washing, can obtain chemical compound 13 through column chromatography for separation, yield is 87%.
Figure BSA00000370498400071
In flask, add the alcoholic solution (30mL) of chemical compound 7-12 (1mmol) and methylamine respectively, stir 6h under the first room temperature, reflux again and stir 6h.The TLC detection reaction finishes, and the pressure reducing and steaming solvent adds DMF solution 5mL then, adds chemical compound 13 (1mmol) and is heated to 80 ℃ of reaction 4h, and after reaction finished, removal of solvent under reduced pressure obtained thick product.Then under pyridine catalysis; with the acetic anhydride direct reaction, after TLC detected acetylation fully, pyridine and acetic anhydride reduced pressure away; column chromatography for separation obtains the acetylation solid chemical compound; at room temperature carry out deprotection at last and can obtain Compound I-1, I-2, I-3 with Feldalat NM; I-4; I-5, I-6, yield is respectively about 85%.Compound I-4 wherein, I-5, I-6 can obtain Compound I-7 through the reduction of triphenyl phosphorus and with 0.01M HCl salify, I-8, I-9, yield is respectively 98%, 97%, and 97%.
Figure BSA00000370498400072
Figure BSA00000370498400081
Synthesizing of 2N-aminoacid butterfly mycin analog II series compound
Figure BSA00000370498400082
Substrate 1mmol chemical compound 13 and aminoacid (2eq) are dissolved among the 5ml DMF, are heated to 150 ℃ of reaction 1h, stopped reaction.After reaction finished, DMF was removed in decompression, obtains target product II-1 through column chromatography for separation, II-2, and II-3, II-4, II-5, II-6, II-7, yield is respectively 90%, 74%, and 79%, 51%, 38%, 59%, 72%.
Figure BSA00000370498400091
3.N-base butterfly mycin analog III series compound is synthetic
We are example to introduce adenine on the N-6 position, and the synthetic of the butterfly mycin analog of introducing base is described.
Figure BSA00000370498400101
In round-bottomed flask, add 2-chloroethyl amine hydrochlorate 1mol and phthalic anhydride 1mol and glacial acetic acid, reflux.Reaction through extracting and washing, can obtain compound N-Phth-2-chlorethamin after finishing.Under the effect of sodium hydride, react then, behind the methylamine alcohol solution deprotection, can obtain chemical compound 14 with adenine.
Figure BSA00000370498400102
Add chemical compound 13 and the serial base that contains amino in the 50ml round-bottomed flask, with N, dinethylformamide is a solvent, reacts under 100 ℃ of conditions, the TLC detection reaction obtains thick product, and column chromatography for separation obtains series compound III, and yield is respectively 92%, 84%, 83%, 61%.
Figure BSA00000370498400103
4.N-alkyl and other substituent group butterfly mycin analog IV series compound is synthetic
The synthetic method of the synthetic and N-aminoacid butterfly mycin analog of this compounds is similar, with substrate 1mmol chemical compound 13 and contain amino-compound (2eq) as semicarbazides, phenylhydrazine etc., be dissolved among the 5ml DMF, be heated to 100 ℃ of reactions.After reaction finished, DMF was removed in decompression, obtains target compound IV series through column chromatography for separation, and productive rate is between 69%~90%.
Figure BSA00000370498400111
5. the activity data analysis of part of compounds Preliminary Determination
In leukemia cell line K562 and breast cancer cell MCF-7 with the MTS test determines synthetic anthracycline antibiotics simple structure analog IV, the active anticancer of V and VI series.Leukemia cell line K562 and breast cancer cell MCF-7 (2000-10000) are seeded on 96 orifice plates of RPMI-1640 culture fluid and cultivate 24h.The cancerous cell that these increase with exponential form, (5%CO under 37 ℃ 2, 95% wet air) and the compound effects 72h of variable concentrations.After the 72h, [3-(4 with the salt of tetrazole, 5-dimethythiazol-2-yl)]-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS, ultimate density 2mg/mL) and the mixture of azophenlyene Methylsulfate (DMS, ultimate density 25 μ M) directly join in the celliferous culture medium.Behind effect 3h under 37 ℃, the survivaling cell rate is measured by its metabolite absorptance under the 490nm wavelength to the MTS effect.We are chosen under 40 μ M and the 4 μ M concentration conditions this series compound have been carried out active testing.
Preliminary biological activity test shows, Compound I, and II, III and IV series have good inhibitory effect to cancerous cell in breast cancer cell (MCF-7 cell) and leukaemia's (K562 cell).Under 40 μ M concentration conditions, Compound I-6, III-4, IV-4 and IV-7 have biological activity preferably in the leukaemia, especially Compound I-6 can all be killed leukaemia's (accompanying drawing 1), and breast cancer cell only has the survival rate (accompanying drawing 2) about 10% under the effect of Compound I-6.Compound I-1 1H NMR (400MHz, DMSO-d 6) δ 2.96 (t, 1H, J=8.0Hz), 3.03 (t, 1H, J=8.4Hz), 3.09-3.15 (m, 2H), 3.52 (d, 1H, J=9.6Hz), 3.57-3.65 (m, 2H), 3.76-3.84 (m, 2H), 3.91-3.96 (m, 3H), 3.98-4.05 (m, 2H), 4.11 (d, 1H, J=10.8Hz), 4.23 (d, 1H, J=8.0Hz), 4.52 (s, 1H), 5.05 (d, 3H, J=22.4Hz), 5.45 (s, 1H), 6.04 (s, 1H), 6.27 (d, 1H, J=9.2Hz), 6.60 (s, 1H), 7.36 (dd, 2H, J=6.8Hz, J=12.8Hz, Ar-H), 7.57 (dd, 2H, J=8.4Hz, J=17.2Hz, Ar-H), 7.73 (d, 1H, J=8.0Hz), 7.97 (d, 1H, J=8.8Hz, Ar-H), 8.47 (s, 1H), 9.08 (d, 1H, J=8.0Hz, Ar-H), 9.16 (d, 1H, J=8.4Hz, Ar-H), 11.73 (s, 1H, N Indole-H) ppm 13C NMR (100MHz, DMSO-d 6) δ 169.9,169.9,142.7,141.3,130.1,128.7,127.5,127.3,124.7,121.7,121.4,121.1,120.1,120.3,119.0,118.7,117.5,112.8,112.3,103.5,84.9,79.6,79.4,77.4,77.1,76.8,73.8,73.6,70.4,67.8,66.1,61.4,58.6,37.7ppm.
Compound I-2 1H NMR (400MHz, DMSO-d 6) δ 3.31-3.52 (3H, m), 3.49-3.66 (4H, m), 3.76-3.84 (2H, m), 3.75-3.81 (2H, m), 3.81-4.06 (5H, m), 4.12 (1H, d, J=8.8Hz), 4.53 (1H, s), 4.64 (1H, s), 4.73-4.74 (2H, m), 4.81 (2H, m), 5.07 (1H, s), 5.39 (1H, s), 5.80 (1H, s), (6.30 1H, d, J=8.8Hz, H-1 '), 6.38 (1H, s), and 7.35-7.41 (2H, m, Ar-H), 7.58 (2H, dd, J=8.4Hz, J=15.6Hz, Ar-H), 7.74 (1H, d, J=8.0Hz, Ar-H), 7.99 (1H, d, J=8.8Hz, Ar-H), 8.46 (1H, s), 9.10 (1H, d, J=8.0Hz, Ar-H), 9.18 (1H, d, J=8.0Hz, Ar-H), 11.72 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) δ 169.9,169.8,142.7,141.3,130.1,128.7,127.5,127.3,124.8,121.7,121.4,121.1,120.2,118.9,118.6,117.5,112.8,112.3,99.9,84.9,79.3,76.8,74.5,73.6,72.4,71.2,70.6,70.4,67.8,67.1,63.7,61.4,60.6,58.6,37.4ppm.
Compound I-3 1H NMR (400MHz, DMSO-d 6) δ 3.26-3.63 (and 6H, m), 3.78-3.89 (3H, m) 3.94-4.04 (5H, m), 4.18 (1H, d, J=10.8Hz), 4.18 (1H, d, J=6.8Hz, H-1 "); 5.04 (1H, brs), 5.36 (1H, brs), 5.80 (1H, brs); 6.28 (1H, d, J=8.8Hz, H-1 '), 6.40 (1H; s), 7.35-7.41 (2H, m, Ar-H), 7.58 (2H; dd, J=8.4Hz, J=17.2Hz, Ar-H), 7.74 (1H; d, J=8.0Hz, Ar-H), 7.99 (1H, d, J=8.4Hz, Ar-H), 8.46 (1H, s), 9.10 (1H, d, J=8.0Hz, Ar-H), 9.18 (1H, d, J=8.0Hz, Ar-H), 11.72 (1H, s, N Indole-H) ppm. 13CNMR (100MHz, DMSO-d 6) δ 169.9,169.8,142.7,141.3,130.1,128.7,127.5,127.3,124.8,121.7,121.4,121.1,120.8,120.3,118.9,118.6,117.5,112.7,112.3,104.1,84.9,79.3,76.8,75.7,73.8,73.6,72.4,70.9,70.4,68.4,67.9,66.0,61.4,60.6,58.6,37.8ppm.
Compound I-4 1H NMR (400MHz, DMSO-d 6) δ 3.02-3.16 (5H, m), 3.26-3.66 (9H, m), 3.78 (1H, d, J=9.6Hz), 3.86-4.05 (5H, m), 4.08-4.12 (2H, m), 4.37 (1H, d, J=8.0Hz), 6.27 (1H, d, J=8.8Hz, H-1 '), 7.32-7.38 (2H, m, Ar-H), and 7.53-7.59 (2H, m, Ar-H), 7.71 (1H, d, J=8.0Hz, Ar-H), 7.96 (1H, d, J=8.4Hz, Ar-H), 8.44 (1H, s), 9.09 (1H, d, J=8.0Hz, Ar-H), 9.17 (1H, d, J=8.0Hz, Ar-H), 11.62 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) δ 168.9,168.8,141.7,140.4,129.2,126.6,126.4,123.9,120.9,120.6,120.1,119.9,119.5,118.1,117.8,116.7,111.7,100.2,83.9,78.4,76.5,76.0,74.1,72.7,69.5,67.0,66.1,65.2,62.6,60.2,57.8,36.7ppm.
Compound I-5 1H NMR (400MHz, DMSO-d 6) δ 3.15 (1H, d, J=3.6Hz), 3.29-3.37 (2H, m), 3.42-3.46 (2H, m), and 3.53-3.59 (3H, m), 3.78-3.82 (1H, m), 3.89-4.01 (5H, m), 4.08 (2H, d, J=9.2Hz), 4.29 (1H, d, J=7.6Hz), 4.65 (1H, s), 4.69 (1H, d, J=4.8Hz), 4.95 (1H, d, J=5.2Hz), 5.21 (2H, s), 5.49 (1H, d, J=4.0Hz), 6.09 (1H, s), 6.28 (1H, d, J=8.8Hz, H-1 '), 7.33-7.38 (2H, m, Ar-H), 7.53-7.60 (2H, m, Ar-H), 7.71 (1H, d, J=8.4Hz, Ar-H), 7.96 (1H, d, J=8.4Hz, Ar-H), 9.09 (1H, d, J=8.0Hz, Ar-H), 9.17 (1H, d, J=8.0Hz, Ar-H), 11.65 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) δ 169.8,169.7,142.6,141.3,130.1,128.6,127.5,127.3,124.8,121.8,121.4,121.1,120.8,120.4,118.9,118.7,117.5,112.6,112.3,101.6,84.8,79.1,76.9,75.6,73.8,71.8,67.9,67.8,66.0,64.6,62.6,60.4,36.7ppm.
Compound I-6 1H NMR (400MHz, DMSO-d 6) δ 1.06 (1H, d, J=6.0Hz), 1.49 (1H, ddd, J=3.2Hz, J=12.8Hz, J=25.6Hz), 1.89 (1H, dd, J=4.4Hz, J=12.4Hz), 2.91 (1H, q, J=6.8Hz), 3.51-3.58 (4H, m), 3.73-3.75 (1H, m), 3.82-3.91 (3H, m), and 3.95-4.02 (3H, m), 4.08 (1H, dd, J=3.2Hz, J=11.2Hz), 4.88 (1H, d, J=5.6Hz), 5.10 (1H, d, J=4.8Hz), 5.36 (1H, d, J=4.8Hz), 5.44 (1H, d, J=6.4Hz), 5.99 (1H, s), 6.28 (1H, d, J=8.4Hz, H-1 '), 7.34-7.39 (2H, m, Ar-H), 7.54-7.60 (2H, m, Ar-H), 7.71 (1H, d, J=8.4Hz, Ar-H), 7.96 (1H, d, J=8.4Hz, Ar-H), 9.10 (1H, d, J=8.0Hz, Ar-H), 9.17 (1H, d, J=8.0Hz, Ar-H), 11.67 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) δ 168.9,141.7,140.4,131.2,129.2,127.8,126.6,126.4,123.9,120.9,120.6,120.2,119.9,119.4,118.1,117.7,116.6,111.7,94.8,84.0,78.2,76.2,74.8,72.6,71.8,67.7,67.1,62.9,59.4,57.8,55.4,36.6,34.5,30.2,29.1,17.2ppm.
Compound I-7 1H NMR (400MHz, CD 3OD) δ 2.77 (1H, dd, J=8.8Hz, J=10.4Hz), 3.24-3.29 (2H, m), and 3.49-3.65 (3H, m), 3.74-3.89 (5H, m), 3.91-4.09 (3H, m), 4.26-4.31 (2H, m), 4.64 (1H, d, J=8.4Hz), 6.20 (1H, d, J=8.8Hz, H-1 '), and 7.19-7.29 (2H, m, Ar-H), 7.42-7.53 (2H, m, Ar-H), 7.62 (1H, d, J=8.0Hz, Ar-H), 7.77 (1H, d, J=8.4Hz, Ar-H), 8.84 (1H, d, J=8.0Hz, Ar-H), 9.02 (1H, d, J=8.0Hz, Ar-H), 11.39 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, CD 3OD) δ 170.1,170.0, and 142.4,141.3,130.0,128.4,126.8,124.6,124.4,121.6,121.5,120.5,120.0,119.8,119.2,118.0,117.7,111.5,110.6,100.2,98.6,85.1,79.2,77.0,76.9,73.5,72.4,70.2,67.9,67.2,60.7,58.7,56.1,37.0ppm.
Compound I-8 1H NMR (400MHz, CD 3OD) δ 3.02-3.07 (1H, m), 3.49-3.65 (4H, m), 3.68-3.74 (3H, m), and 3.78-3.92 (5H, m), 4.03-4.09 (3H, m), 4.26-4.31 (2H, m), 4.59 (1H, d, J=8.4Hz), (6.20 1H, d, J=8.8Hz, H-1 '), 7.20-7.28 (2H, m, Ar-H), 7.44-7.53 (2H, m, Ar-H), 7.63 (1H, d, J=8.0Hz, Ar-H), 7.78 (1H, d, J=8.4Hz, Ar-H), 8.85 (1H, d, J=8.0Hz, Ar-H), 9.02 (1H, d, J=8.0Hz, Ar-H), 11.39 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, CD 3OD) δ 170.1,170.0, and 142.4,141.3,130.0,128.4,126.8,124.6,124.4,121.7,121.6,120.5,120.0,119.9,119.3,118.0,117.8,111.5,110.6,100.2,99.0,85.1,79.2,77.0,75.6,73.5,69.7,68.0,67.6,67.4,67.1,60.5,58.7,53.5,37.0,25.0ppm.
Compound I-9 1H NMR (400MHz, CD 3OD) δ 1.10 (1H, d, J=6.0Hz), 1.70 (1H, ddd, J=3.2Hz, J=12.8Hz, J=25.6Hz), 2.02 (1H, dd, J=4.4Hz, J=12.4Hz), 3.00 (1H, t, J=9.6Hz), 3.15-3.22 (2H, m), 3.48-3.55 (2H, m), 3.62-3.65 (1H, m), 3.74-3.84 (3H, m), 3.94 (1H, t, J=9.2Hz), 4.02-4.07 (2H, m), and 4.26-4.31 (2H, m), 4.88 (1H, d, J=2.4Hz), 6.20 (1H, d, J=8.8Hz, H-1 '), 7.23-7.27 (2H, m, Ar-H), 7.42-7.51 (2H, m, Ar-H), 7.58 (1H, d, J=8.0Hz, Ar-H), 7.76 (1H, d, J=8.4Hz, Ar-H), 8.87 (1H, d, J=8.0Hz, Ar-H), 9.04 (1H, d, J=8.0Hz, Ar-H), 11.36 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, CD 3OD) δ 168.9,141.4, and 140.4,129.1,127.5,125.8,123.8,123.5,120.8,120.7,119.5,119.1118.9,118.2,117.1,116.9,110.6,109.7,94.1,84.2,78.3,76.1,72.6,71.8,67.4,67.1,62.8,57.8,48.9,35.7,32.6,15.4ppm.
Compound I I-1 1H NMR (400MHz, DMSO-d 6) δ 11.74 (s, 1H, N Indole-H), 9.18 (d, J=8.0Hz, 1H, Ar-H), 9.09 (d, J=8.0Hz, 1H, Ar-H), 8.47 (br.s, 1H), 7.97 (d, J=6.4Hz, 1H, Ar-H), 7.76 (d, J=8.4Hz, 1H, Ar-H), 7.57 (t, J=7.6Hz, 1H, Ar-H), 7.51 (t, J=7.6Hz, 1H, Ar-H), 7.29-7.39 (m, 2H, Ar-H), 6.87 (br.s, 1H), 6.27 (d, J=8.8Hz, 1H, H-1 '), 5.67 (b r.s, 1H), 5.22 (br.s, 1H), 4.13-4.16 (m, 1H, H-6 ' a), 4.01-4.06 (m, 3H, NCH 2COOH, H-4 '), 3.89-3.92 (m, 1H, H-5 '), 3.75-3.78 (m, 1H, H-6 ' b), 3.59-3.63 (m, 1H, H-3 '), 3.51-3.55 (m, 1H, H-2 ') ppm. 13C NMR (100MHz, DMSO-d 6) δ 170.3,170.2,160.9,142.6,141.3,129.9,128.6,127.3,127.1,124.8,124.7,121.8,121.5,121.0,120.9,120.7,119.4,118.8,117.4,112.7,112.3,84.9,79.6,76.7,73.5,67.7,58.6,49.0ppm.
Compound I I-2 1H NMR (400MHz, DMSO-d 6) δ 11.72 (s, 1H, N Indole-H), 9.20 (d, J=8.0Hz, 1H, Ar-H), 9.11 (d, J=8.0Hz, 1H, Ar-H), 8.48 (br.s, 1H), 7.97 (d, J=8.8Hz, 1H, Ar-H), 7.77 (d, J=8.4Hz, 1H, Ar-H), 7.57 (t, J=7.6Hz, 1H, Ar-H), 7.51 (t, J=7.6Hz, 1H, Ar-H), 7.30-7.38 (m, 2H, Ar-H), 6.86 (br.s, 2H), 6.27 (d, J=8.8Hz, 1H, H-1 '), 5.20 (b r.s, 1H), 4.64 (q, J 1=7.2Hz, J 2=14.8Hz, 1H, NCHCOOH), 4.14-4.17 (m, 1H, H-6 ' a), 4.02-4.07 (m, 1H, H-4 '), 3.90-3.92 (m, 1H, H-5 '), 3.75-3.78 (m, 1H, H-6 ' b), 3.60-3.65 (m, 1H, H-3 '), 3.51-3.56 (m, 1H, H-2 ') ppm. 13CNMR (100MHz, DMSO-d 6) δ 170.4,160.5,142.6,141.3,129.9,128.6,127.3,127.1,124.9,124.8,121.8,121.5,121.0,120.9,120.6,119.3,118.7,117.3,112.7,112.2,84.9,79.6,76.7,73.5,67.7,58.6,50.4,16.8ppm.
Compound I I-3 1H NMR (400MHz, CD 3OD) δ 9.21 (d, J=8.0Hz, 1H, Ar-H), 9.08 (d, J=8.0Hz, 1H, Ar-H), 7.79 (d, J=8.4Hz, 1H, Ar-H), 7.77 (d, J=8.4Hz, 1H, Ar-H), 7.54 (t, J=7.6Hz, 1H, Ar-H), 7.46 (t, J=7.6Hz, 1H, Ar-H), 7.25-7.34 (m, 4H, Ar-H), 7.10 (t, J=7.6Hz, 2H, Ar-H), 6.99 (t, J=7.6Hz, 1H, Ar-H), 6.17 (d, J=8.8Hz, 1H, H-1 '), 5.11-5.13 (m, 1H, NCHCOOH), 4.21-4.27 (m, 2H, H-3 ', H-5 '), 3.96-4.02 (m, 1H, H-6 '), 3.59-3.83 (m, 4H, H-2 ', H-3 ', PhCH 2) ppm. 13C NMR (100MHz, CD 3OD) δ 170.1,169.9, and 142.3,139.3,129.9,128.6,128.3,127.8,126.5,125.7,124.9,124.7,122.0,121.9,120.5,120.3,119.8,119.1,118.6,117.8,111.4,110.4,85.0,79.1,77.0,73.2,67.8,58.6,55.8,35.4ppm.
Compound I I-4 1H NMR (400MHz, DMSO-d 6) δ 12.15 (s, 1H, NH), 11.70 (s, 1H, N Indole-H), 11.70 (s, 1H), 9.17 (d, J=8.0Hz, 1H, Ar-H), 9.07 (d, J=8.0Hz, 1H, Ar-H), 7.95 (d, J=8.4Hz, 1H, Ar-H), 7.71 (d, J=8.4Hz, 1H, Ar-H), 7.56 (t, J=7.6Hz, 1H, Ar-H), 7.49 (t, J=7.6Hz, 1H, Ar-H), 7.27-7.39 (m, 3H, Ar-H), 6.71 (br.s, 1H), 6.52 (br.s, 1H), (6.24 d, J=8.4Hz, 1H, H-1 '), 5.95 (br.s, 1H), 5.38 (br.s, 1H), 4.99 (br.s, 1H), 4.52 (m, 1H, NCHCOOH), 4.09-4.12 (m, 1H, H-6 ' a), 3.99-4.04 (m, 3H, H-4 '), 3.90-3.93 (m, 1H, H-5 '), (H-6 ' is b) for m, 1H for 3.78-3.81,3.45-3.60 (m, 4H, H-2 ', H-3 ', CH2CHCOOH) ppm. 13C NMR (100MHz, DMSO-d 6) δ 170.4,142.6,141.2,134.8,129.9,128.6,127.3,127.1,124.9,124.8,121.8,121.5,120.9,120.6,119.3,118.7,117.2,112.6,112.2,84.9,79.3,76.8,73.4,67.8,58.6,55.3,49.0,22.0,19.3ppm.
Compound I I-5 1H NMR (400MHz, DMSO-d 6) δ 11.70 (s, 1H, N Indole-H), 9.18 (d, J=8.4Hz, 1H, Ar-H), 9.10 (d, J=8.0Hz, 1H, Ar-H), 8.48 (b r.s, 1H), 7.96 (d, J=8.8Hz, 1H, Ar-H), 7.73 (d, J=8.4Hz, 1H, Ar-H), 7.50-7.59 (m, 2H, Ar-H), 7.31-7.36 (m, 2H, Ar-H), 6.58 (b r.s, 1H), 6.26 (d, J=8.8Hz, 1H, H-1 '), 6.07 (br.s, 1H), 5.47 (br.s, 1H), 5.06 (br.s, 1H), 4.52 (d, J=8.0Hz, 1H, NCHCOOH), 4.25 (q, J 1=7.6Hz, J 2=10.4Hz, 1H, HOCH 2CHCOOH), 4.10-4.13 (m, 1H, H-6 ' a), 3.91-4.04 (m, 3H, H-4 ', H-5 ', HOCH 2CHCOOH), 3.78-3.81 (m, 1H, H-6 ' b), 3.50-3.66 (m, 2H, H-2 ', H-3 ') ppm. 13C NMR (100MHz, DMSO-d 6) δ 170.6,170.3,161.27,142.6,141.2,130.0,128.6,127.3,127.1,124.9,124.8,121.8,121.5,120.9,120.8,120.6,119.3,118.7,117.2,112.7,112.2,84.9,79.5,76.7,73.5,67.7,60.5,58.6,56.5ppm.
Compound I I-6 1H NMR (400MHz, CD 3OD) δ 9.30 (d, J=8.0Hz, 1H, Ar-H), 9.08 (d, J=8.0Hz, 1H, Ar-H), 7.82 (d, J=8.8Hz, 1H, Ar-H), 7.67 (d, J=7.6Hz, 1H, Ar-H), 7.53-7.57 (m, 1H, Ar-H), and 7.44-7.48 (m, 1H, Ar-H), 7.29-7.35 (m, 1H, Ar-H), 7.23-7.27 (m, 1H, Ar-H), (6.20 d, J=9.2Hz, 1H, H-1 '), 4.86 (t, J=8.0Hz, 1H, NCHCOOH), 4.25-4.30 (m, 2H, H-4 ', H-6 ' a), 3.99-4.06 (m, 1H, H-5 ', H-6 ' b), 3.83-3.90 (m, 1H, H-2 '), 3.74-3.79 (m, 1H, H-3 '), 2.69-2.75 (m, 1H, CH 2CH 2COOH), 2.26-2.34 (m, 1H, CH 2CH 2COOH) ppm. 13C NMR (100MHz, CD 3OD) δ 180.7,176.1, and 170.3,142.4,141.3,129.9,128.4,126.4,125.1,124.7,122.0,120.8,120.2,119.8,119.3,118.9,117.9,111.3,110.4,85.1,79.1,77.0,73.3,67.8,58.6,54.7,35.5,26.9,20.3ppm.
Compound I I-7 1H NMR (400MHz, DMSO-d 6) δ 11.63 (s, 1H, N Indole-H), 9.10 (d, J=8.4Hz, 1H, Ar-H), 8.99 (d, J=8.0Hz, 1H, Ar-H), 8.43 (b r.s, 1H), 7.90 (d, J=8.8Hz, 1H, Ar-H), 7.66 (d, J=8.0Hz, 1H, Ar-H), 7.51 (t, J=7.6Hz, 1H, Ar-H), 7.44 (t, J=7.6Hz, 1H, Ar-H), 7.22-7.31 (m, 2H, Ar-H), 6.94 (d, J=8.0Hz, 2H, Ar-H), 6.61 (br.s, 1H), 6.48 (d, J=8.4Hz, 2H, Ar-H), 6.19 (d, J=8.8Hz, 1H, H-1 '), 5.02 (br.s, 1H), 4.67 (br.s, 1H, NCHCOOH), 4.04-4.08 (m, 1H, H-6 ' a), 3.93-3.98 (m, 1H, H-4 '), 3.83-3.86 (m, 1H, H-5 '), (H-6 ' is b) for m, 1H for 3.70-3.73,3.39-3.55 (m, 4H, H-2 ', H-3 ', PhCH 2) ppm. 13C NMR (100MHz, DMSO-d 6) δ 170.6,155.7,142.6,141.2,131.1,130.6,129.9,129.7,128.5,127.3,127.1,124.8,121.7,121.5,120.9,120.6,119.2,118.6,117.1,115.5,115.0,112.6,112.2,84.9,79.4,76.7,73.4,67.7,58.6,57.5,49.0pp m.
Compound III-1 1H NMR (400MHz, DMSO-d 6.). δ 3.53-3.76 (2H, m), 3.77 (1H, d, J=9.6Hz), 3.93 (1H, d, J=9.6Hz), 4.01-4.06 (1H, m), 4.13-4.19 (m, 3H), 4.53 (2H, t, J=5.2Hz), (6.29 d, J=9.2Hz, 1H, H-1 '), 7.12 (2H, s ,-NH 2), 7.33-7.37 (2H, m, Ar-H), 7.66 (dd, 2H, J=10.4Hz, J=8.4HzAr-H), 7.75 (d, 1H, J=8.4Hz, Ar-H), (7.91 1H, s, H-8 ') 7.98 (1H, d, J=8.8Hz, Ar-H), 8.18 (1H, s, H-2 '), 8.97 (d, 1H, J=8.0Hz, Ar-H), 9.04 (1H, d, J=8.0Hz, Ar-H), 11.70 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) .169.6,169.5,156.3,152.7,150.2,142.6,141.3,130.2,128.6,127.5,127.3,124.7,121.7,121.3,121.0,120.8,120.2,119.0,118.9,117.5,112.7,112.3,84.8,79.4,76.7,73.7,72.4,70.4,67.8,63.2,60.6,58.6ppm.
Compound III-2 1H NMR (400MHz, DMSO-d 6.) δ 3.80 (1H, d, J=10.4Hz), 3.88-4.10 (7H, m), 5.52 (1H, d, J=7.2Hz, H-5 '), 6.30 (1H, d, J=8.8Hz, H-1 '), 6.86 (1H, s), 7.00 (1H, s), 7.36 (2H, s, Ar-H), 7.54-7.60 (3H, m), 7.70 (1H, d, J=8.4Hz, Ar-H), 7.98 (1H, d, J=8.8Hz, Ar-H), 9.05 (1H, d, J=8.0Hz, Ar-H), 9.12 (1H, d, J=8.0Hz, Ar-H), 11.68 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) 169.7,169.6,166.4,156.4,146.3,142.6,141.3,130.1,128.7,127.5,127.3,124.8,121.8,121.4,121.1,120.8,120.4,118.9,118.7,117.5,112.6,112.3,93.9,84.5,79.1,77.0,73.5,67.9,58.7,56.4,49.0,48.0ppm.
Compound III-3 1H NMR (400MHz, DMSO-d 6.) δ 3.46-3.59 (2H, m), 3.76 (1H, d, J=10.0Hz), 3.86-3.92 (1H, m), 4.00 (1H, t, J=9.2Hz), 4.09-4.20 (3H, m), 6.24 (1H, d, J=8.8Hz, H-1 '), and 7.24-7.29 (2H, m, Ar-H), 7.52 (2H, t, J=7.2Hz, Ar-H), 7.70 (1H, d, J=8.0Hz, Ar-H), 7.91 (1H, d, J=8.4Hz, Ar-H), 8.46 (1H, s, H-6 '), 8.97 (1H, d, J=8.0Hz, Ar-H), 9.04 (1H, d, J=7.6Hz, Ar-H), 11.91 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) 170.0,169.9,142.5,141.3,130.1,128.7,127.5,127.3,124.7,121.7,121.3,121.0,120.8,120.2,118.9,118.6,117.6,112.7,112.2,84.9,79.4,76.8,73.5,67.8,58.6ppm.
Compound III-4 1H NMR (400MHz, DMSO-d 6+ D 2O) δ 3.57-3.61 (2H, m), 3.28-3.81 (1H, m), 3.93-4.02 (3H, m), 4.08-4.11 (3H, m), 4.50 (2H, t, J=5.2Hz), 6.27 (1H, d, J=8.8Hz, H-1 '), and 7.35-7.40 (2H, m, Ar-H), 7.55-7.61 (2H, m, Ar-H), 7.72 (1H, d, J=8.0Hz, Ar-H), 7.88 (1H, d, J=3.2Hz, H-6 '), 7.98 (1H, d, J=8.8Hz, Ar-H), 9.07 (1H, d, J=8.0Hz, Ar-H), 9.14 (1H, d, J=7.6Hz, Ar-H) ppm. 13C NMR (100MHz, DMSO-d 6) 169.8,169.7,160.3,155.3,143.8,142.7,141.3,141.2,140.2,140.0,132.0,128.7,127.6,127.4,124.7,121.6,121.4,121.1,120.9,120.2,119.0,118.6,117.4,112.7,112.3,84.8,79.1,76.7,73.4,67.8,64.1,58.6pp m.
Compound IV-1 1H NMR (400MHz, DMSO-d 6+ D 2O.) δ 3.43 (1H, d, J=7.2Hz), 3.50 (1H, t), 3.61 (1H, s), 3.80 (1H, d, J=10.8Hz)), 6.25 (1H, d, J=8.0Hz, H-1 '), 7.38 (2H, d, J=4.8Hz, Ar-H), 7.56-7.62 (2H, m, Ar-H), 7.68 (1H, d, J=7.6Hz, Ar-H), 7.93 (1H, d, J=9.2Hz, Ar-H), 9.02 (1H, d, J=7.6Hz, Ar-H), 9.09 (1H, d, J=6.8Hz, Ar-H) ppm. 13C NMR (100MHz, DMSO-d 6) .168.3,168.1,160.8,159.9,142.7,141.3,130.3,128.9,127.6,127.4,124.7,121.7,121.4,121.2,121.1,119.0,117.5,112.8,112.5,84.9,76.7,73.7,67.9,49.0ppm.
Compound IV-2 1H NMR (400MHz, DMSO-d 6.) δ 3.81 (1H, d, J=10.8Hz), 3.94-4.09 (2H, m), 4.12 (6H, s), 6.27 (1H, d, J=8.0Hz, H-1 '), 7.33-7.37 (2H, d, Ar-H), 7.53-7.60 (2H, m, Ar-H), 7.72 (1H, d, J=8.0Hz, Ar-H), 7.97 (1H, d, J=8.8Hz, Ar-H), 9.10 (1H, d, J=8.0Hz, Ar-H), 9.17 (1H, d, J=7.6Hz, Ar-H), 11.6 (1H, s) ppm. 13C NMR (100MHz, DMSO-d 6) 170.0,169.9,142.8,141.4,130.1,128.7,127.5,127.3,121.7,121.4,121.2,121.1,120.3,118.9,118.8,117.5,112.8,112.4,84.8,79.5,76.7,73.6,67.7,55.9ppm.
Compound IV-3 1H NMR (400MHz, DMSO-d 6.) δ 3.59 (1H, t, J=4.8Hz), 3.86 (1H, d, J=10.0Hz), 4.01 (1H, t, J=10.0Hz), 4.12 (2H, d, J=9.2Hz), 4.94 (1H, d, J=4.4Hz), 5.17 (d, 1H, J=3.2Hz), 5.42 (d, 1H, J=2.8Hz), 6.06 (1H, s), 7.38 (2H, t, J=7.2Hz, Ar-H), 7.50 (1H, d, J=6.4Hz, Ar-H), 7.60 (6H, t, J=8.4Hz, Ar-H), 7.75 (1H, d, J=8.0Hz, Ar-H), 8.01 (1H, d, J=8.4Hz Ar-H), 9.12 (1H, d, J=8.0Hz, Ar-H), 9.19 (1H, d, J=8.0Hz, Ar-H), 11.76 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) .169.1,169.0,162.8,142.8,141.3,132.9,130.4,129.3,129.0,128.2,127.7,127.5,124.9,121.8,124.4,121.2,121.0,119.1,118.5,117.6,112.7,112.4,84.9,79.0,77.0,73.5,67.7,62.5,58.7ppm.
Compound IV-4 1H NMR (400MHz, DMSO-d 6+ D 2O.) δ 3.54 (1H, t, J=9.2Hz), 3.81 (1H, d, J=4.0Hz), 4.01 (2H, d, J=6.4Hz), 4.07 (1H, d, J=11.2Hz), 6.29 (1H, d, J=8.8Hz), 6.81 (3H, m, Ar-H), 7.20 (2H, t, J=8.0Hz, Ar-H), 7.37 (m, 2H, Ar-H), 7.58 (2H, m, Ar-H), 7.71 (1H, d, J=8.0Hz, Ar-H), 7.98 (1H, d, J=8.4Hz, Ar-H), 9.04 (1H, d, J=8.0Hz, Ar-H), 9.11 (1H, d, J=8.0Hz, Ar-H) ppm. 13C NMR (100MHz, DMSO-d 6) 168.7,168.6,147.8,142.7,141.2,130.3,129.6,127.9,127.7,124.7,121.6,121.3,121.1,120.2,119.2,118.0,117.6,116.3,112.6,112.4,84.8,78.9,76.7,73.4,70.9,67.9,58.6ppm.
Compound IV-5 1H NMR (400MHz, DMSO-d 6.) δ 3.54-3.59 (1H, m), 3.64-3.66 (1H, m), 3.82 (1H, d, J=10.4Hz), 3.97-4.14 (2H m), 4.13 (d, 1H, J=11.2Hz), 6.24 (1H, s), 6.34 (1H, d, J=8.8Hz, H-1 '), 6.87 (1H, s), 7.37-7.42 (2H, m, Ar-H), 7.61 (2H, dd, J=8.4Hz, J=16.4Hz Ar-H), and 7.76-7.78 (3H, m), 8.03 (1H, d, J=8.4Hz, Ar-H), 8.78 (2H, d, J=1.6Hz, J=1.2Hz), 9.13 (1H, d, J=8.0Hz, Ar-H), 9.13 (1H, d, J=7.6Hz, Ar-H), 11.81 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) .168.1,168.0,151.9,150.8,142.8,141.4,140.5,139.7,130.5,129.1,128.5,127.8,127.6,125.3,124.8,121.7,121.3,121.2,121.1,120.0,119.2,118.4,117.7,112.8,112.5,84.9,79.2,76.9,73.6,67.9,58.7ppm.
Compound IV-6 1H NMR (400MHz, DMSO-d 6.) δ 3.57-3.64 (3H, m), 3.83 (1H, d, J=10.4Hz), 3.97-4.06 (m, 2H), 4.12 (1H, d, J=9.6Hz), 5.05 (1H, d, J=5.2Hz), 5.34 (1H, d, J=5.2Hz), 5.65 (1H, s, J=5.2Hz), 6.33 (1H, s), 6.35 (1H, d, J=8.8Hz, H-1 '), 7.37-7.42 (2H, m, Ar-H), 7.61 (2H, dd, J=8.4Hz, J=16.4Hz, Ar-H), 7.74 (1H, d, J=8.0Hz, Ar-H), 7.99-8.05 (3H, m), 8.87 (2H, d, J=5.2Hz), 9.05 (1H, d, J=8.0Hz, Ar-H), 9.12 (1H, d, J=7.6Hz, Ar-H), 11.81 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) ..167.5,167.4,165.2,151.1,149.7,142.8,141.4,139.3,130.5,129.1,127.8,127.6,124.6,122.0,121.6,121.3,121.1,119.2,118.3,117.7,116.6,112.9,112.5,84.9,79.2,76.8,73.6,68.0,58.7ppm.
Compound IV-7 1HNMR (400MHz, DMSO-d 6.) δ 2.46-2.70 (2H, m), 2.52-2.60 (2H, m), 3.29-3.36 (4H, m), 3.51-3.62 (2H, m), 3.82-4.10 (7H, m)., 4.93 (1H, d, J=5.2Hz), 5.17 (1H, d, J=5.2Hz), 5.42 (1H, d, J=4.4Hz), 6.04 (1H, t, J=5.2Hz), 6.30 (d, J=8.4Hz, 1H, H-1 '), and 7.35-7.40 (2H, m, Ar-H), 7.55-7.60 (m, 2H, Ar-H), 7.70 (1H, d, J=8.4Hz, Ar-H), 7.97 (2H, m, Ar-H), 9.10 (1H, d, J=8.0Hz, Ar-H), 9.17 (1H, d, J=7.6Hz, Ar-H), 11.69 (1H, s N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) 170.0,161.6,142.5,141.1,129.9,128.5,127.8,127.6,124.7,121.6,121.3,121.0,120.2,119.0,118.6,117.5,112.5,112.1,84.8,78.8,76.7,74.4,73.3,71.0,72.4,67.9,58.6,55.7,53.4,52.3,45.3,60.6,58.6,37.8ppm.
Compound IV-8 1HNMR (400MHz, DMSO-d 6.) δ 2.0 (3H, s), 2.46-
Figure BSA00000370498400191
(2H, m), 3.16 (2H, s), 3.52 (1H, t, J=8Hz), 3.61 (1H, t, J=8.8Hz), 3.82-4.10 (7H, m)., 3.78 (d, 1H, J=5.2Hz), 3.88-3.93 (3H, m), 4.03 (1H, t, J=9.6Hz), 4.05-4.44 (3H, m), 6.31 (1H, d, J=11.6Hz, H-1 '), 7.34-7.39 (2H, m, Ar-H), 7.54-7.69 (2H, m, Ar-H), 7.83 (1H, d, J=8.4Hz, Ar-H), 7.98 (d, 1H, J=8.4Hz, Ar-H), 9.10 (1H, d, J=8.0Hz, Ar-H), 9.17 (1H, d, J=7.6Hz, Ar-H), 11.69 (1H, s, N Indole-H) ppm. 13C NMR (100MHz, DMSO-d 6) .170.0,169.9,168.6,142.7,141.4,130.1,128.7,127.5,127.3,124.7,121.7,121.4,121.1,120.8,120.3,118.9,118.6,117.5,112.8,112.4,84.9,79.5,76.7,73.6,67.8,58.6,56.4,55.9,53.2,49.0,41.3,21.6ppm.

Claims (5)

1. the chemical compound and the pharmacy thereof that have the following formula structure can be accepted acid or the formed salt of alkali:
Figure FSA00000370498300011
Wherein:
Substituent R is-CH 2CH 2R 1,
Figure FSA00000370498300012
H 2NCONH-, (HOCH 2) 3C-,
Figure FSA00000370498300013
Figure FSA00000370498300014
Deng;
Substituent R 3, R 4Be halogen, hydroxyl etc.
2. chemical compound according to claim 1 and salt, wherein R 1Be glycosyl, as Deng; Base is as 5-fluorouracil
Figure FSA00000370498300016
Adenine
Figure FSA00000370498300017
Cytosine
Figure FSA00000370498300018
5-azepine cytosine Morpholine
Figure FSA000003704983000110
Piperazine
Figure FSA000003704983000111
N-acetyl group piperazine
Figure FSA000003704983000112
Deng.
3. chemical compound according to claim 1 and salt, wherein R 2Be H, CH 3, HOCH 2-, HOOCCH 2CH 2-, Deng.
4. chemical compound according to claim 2 and salt thereof, wherein glycosyl is selected from following chemical compound:
Figure FSA00000370498300021
Deng.
5. the preparation method with new type water-solubility butterfly mycin analog of active anticancer according to claim 1 is characterized in that:
Figure FSA00000370498300022
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2548045C1 (en) * 2014-02-27 2015-04-10 Федеральное государственное бюджетное учреждение "Российский онкологический научный центр имени Н.Н. Блохина" Российской академии медицинских наук (ФГБУ "РОНЦ им. Н.Н. Блохина" РАМН) N-GLYCOSIDES OF INDOLO[2,3-a]PYRROLO[3,4-c]CARBAZOLES HAVING ANTITUMOUR ACTIVITY
CN104710412A (en) * 2015-03-27 2015-06-17 河南师范大学 3,4-bi(3-benzpyrole)-2,5-dione-1-pyrroleimine thiourea compound with antitumor activity and preparation method and application thereof

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EP0269025A2 (en) * 1986-11-21 1988-06-01 Bristol-Myers Squibb Company Rebeccamycin analogs

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0269025A2 (en) * 1986-11-21 1988-06-01 Bristol-Myers Squibb Company Rebeccamycin analogs

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2548045C1 (en) * 2014-02-27 2015-04-10 Федеральное государственное бюджетное учреждение "Российский онкологический научный центр имени Н.Н. Блохина" Российской академии медицинских наук (ФГБУ "РОНЦ им. Н.Н. Блохина" РАМН) N-GLYCOSIDES OF INDOLO[2,3-a]PYRROLO[3,4-c]CARBAZOLES HAVING ANTITUMOUR ACTIVITY
CN104710412A (en) * 2015-03-27 2015-06-17 河南师范大学 3,4-bi(3-benzpyrole)-2,5-dione-1-pyrroleimine thiourea compound with antitumor activity and preparation method and application thereof

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