CN102125578B - Rebeccamycin analogue with anticancer activity and synthesis method thereof - Google Patents
Rebeccamycin analogue with anticancer activity and synthesis method thereof Download PDFInfo
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- 0 *N(C(c1c(c(cccc2)c2[n]2)c2c2[n](C(C(C3O)O)OC(CO)C3O)c(cccc3)c3c2c11)=O)C1=O Chemical compound *N(C(c1c(c(cccc2)c2[n]2)c2c2[n](C(C(C3O)O)OC(CO)C3O)c(cccc3)c3c2c11)=O)C1=O 0.000 description 9
- PKEVPTOBQFCBMJ-UHFFFAOYSA-N CC(OCC(C(C(C1OC(C)=O)OC(C)=O)OC(C)=O)OC1OCCN(C(c1c2cccc1)=O)C2=O)=O Chemical compound CC(OCC(C(C(C1OC(C)=O)OC(C)=O)OC(C)=O)OC1OCCN(C(c1c2cccc1)=O)C2=O)=O PKEVPTOBQFCBMJ-UHFFFAOYSA-N 0.000 description 3
- ZCYMCBOUZXAAJG-UHFFFAOYSA-N CC(C(CC1)O)OC1O Chemical compound CC(C(CC1)O)OC1O ZCYMCBOUZXAAJG-UHFFFAOYSA-N 0.000 description 1
- SNJQIWCMBUCYDT-UHFFFAOYSA-N OC1(C2)C2OCCC1 Chemical compound OC1(C2)C2OCCC1 SNJQIWCMBUCYDT-UHFFFAOYSA-N 0.000 description 1
- CVWZDIGHHIIZPB-UHFFFAOYSA-N OCC(C(C(C1O)O)O)OC1[n](c1ccccc11)c(c2c3c4ccccc4[nH]2)c1c(C(O1)=O)c3C1=O Chemical compound OCC(C(C(C1O)O)O)OC1[n](c1ccccc11)c(c2c3c4ccccc4[nH]2)c1c(C(O1)=O)c3C1=O CVWZDIGHHIIZPB-UHFFFAOYSA-N 0.000 description 1
- MWFLUYFYHANMCM-UHFFFAOYSA-N OCCN(C(c1c2cccc1)=O)C2=O Chemical compound OCCN(C(c1c2cccc1)=O)C2=O MWFLUYFYHANMCM-UHFFFAOYSA-N 0.000 description 1
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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
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 SaccharothrixAerocoligenes, its structure is by indole [2,3-a] pyrroles [3,4-c] carbazole nuclear (referred to as indole carbazole nuclear) and β-glucose two large divisions formation, as shown below.
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 is in conjunction with testing demonstration, and during butterfly mycin Interaction with DNA, in the indolocarbazole nuclear intercalation of DNA, glycosyl part can strengthen the DNA affinity with the groove effect, and the base series of the big or small groove of pyrrole heterocyclic part energy specific recognition DNA.
Yet, owing to relatively poor the causing of water solublity of butterfly mycin can't be made further Pharmacological Evaluation to it.In order to seek the better lead compound of biological activity, probe into simultaneously the structure activity relationship (Structure ActivityRelationship) of butterfly mycin analog, 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, introduce other group such as halogen atom or hydroxyl at the phenyl ring of indolocarbazole ring, perhaps phenyl ring is changed into other heterocycle, such as pyridine ring; The 3rd, with the glycosyl part of other sugar replacement butterfly mycin.As shown below:
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 front 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, not yet report for the butterfly mycin analog of introducing the groups such as base, aminoacid and glycosyl in butterfly mycin N-6 position, in view of base, aminoacid and sugar etc. self good water solublity 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.
For many years, through Pharmaceutical Chemist the structure activity study of butterfly mycin is shown, 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.Find simultaneously, two chlorine atom pair biological activitys in the butterfly mycin structure have negative effect, on 4 on the modification of N-6 position and the sugar '-the O-methyl is little on the biological activity impact of analog.At present, although there is a large amount of butterfly mycin analog to be synthesized out, because these analog lack desirable water solublity, finally all fail to be applied to clinical treatment.
Because base, sugar and aminoacid etc. have important physiological function in vivo, thereby different types of base, glycosyl and aminoacid etc. are incorporated into the N-6 position of butterfly mycin, to improving the water solublity of butterfly mycin analog, the more important thing is and wish to strengthen its targeting specific, thereby improve its antineoplastic biological activity, by the pharmaceutically active screening, seek active better lead compound and improve its structure activity relationship.Technical solution of the present invention is, has new type water-solubility butterfly mycin analog and the synthetic method of active anticancer, it is characterized in that chemical compound has following structure:
Summary of the invention
Wherein:
Substituent R is-CH
2CH
2R
1,
H
2NCONH-, (HOCH
2)
3C-,
Deng;
Substituent R
3, R
4Be H, halogen, hydroxyl etc.;
R wherein
1Be glycosyl, as
Deng; Base is such as 5-fluorouracil
Adenine
Cytosine
5-azepine cytosine
Morpholine
Piperazine
N-acetyl group piperazine
Deng.
R wherein
2Be H, CH
3, HOCH
2-, HOOCCH
2CH
2-,
Deng.
Wherein glycosyl is selected from following chemical compound:
Have the preparation method of the new type water-solubility butterfly mycin analog of active anticancer, it is characterized in that:
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.
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:
1) the N-Phth ethylaminoethanol synthetic
In the 10mL round-bottomed flask, add phthalic anhydride (1mol), then under agitation ethylaminoethanol (1eq) dropwise is added dropwise in the flask exothermic heat of reaction.After dropwising, with oil bath temperature is risen to 100 ℃, react approximately and finish behind the 1h.Solution temperature is down to room temperature, and solution becomes solid.Add distilled water in flask, slowly heat up, make dissolution of solid to fully, then lower the temperature, crystallization obtains the solid N-Phth ethylaminoethanol of white, and yield is 80%.
2) glycosyl donor is synthetic
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 drip in the solution 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
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, then dropwise add 3.632mL BF
3Et
2O solution continues ice bath reaction 1h.Then reaction is spent the night under the room temperature, 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%.
Under nitrogen protection and-20 ℃ of conditions, the 30mg sodium hydride is dissolved in the 5ml oxolane, the tetrahydrofuran solution that then will be dissolved with 0.2g chemical compound 4 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, then the pressure reducing and steaming oxolane added the dichloromethane dissolving, 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%.
With chemical compound 5 (0.36mmol), ethylaminoethanol (0.69mmol) and 400mg
Mealy molecular sieve adds in the dichloromethane of 10ml drying, and then stirring at room 1h is down to the temperature of reaction system-35 ℃, slowly splashes into 0.55mmol trifluoromethanesulfonic acid trimethylsilyl group (TMSOTf), reacts 2h under-35 ℃ of conditions.Use at last triethylamine quencher reaction.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
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%.
In flask, add respectively the alcoholic solution (30mL) of chemical compound 7-12 (1mmol) and methylamine, stir 6h under the first room temperature, again return stirring 6h.The TLC detection reaction finishes, and then the pressure reducing and steaming solvent adds DMF solution 5mL, 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 with Feldalat NM at last and can obtain compound I-1, I-2, I-3; 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%.
Synthesizing of 2N-aminoacid butterfly mycin analog II series compound
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%.
3.N-base butterfly mycin analog III series compound is synthetic
We to be to introduce adenine as example in the N-6 position, and the synthetic of the butterfly mycin analog of introducing base is described.
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.Then under the effect of sodium hydride, react with adenine, behind the methylamine alcohol solution deprotection, can obtain chemical compound 14.
In the 50ml round-bottomed flask, add chemical compound 13 and the serial base that contains amino, take DMF as solvent, under 100 ℃ of conditions, react, the TLC detection reaction obtains thick product, and column chromatography for separation obtains series compound III, and yield is respectively 92%, 84%, 83%, 61%.
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, obtained target compound IV series through column chromatography for separation, and productive rate is between 69%～90%.
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 anthracycline antibiotics simple structure analog IV that is synthesized, 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 37 ℃ of lower effect 3h, 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 preferably inhibitory action 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 preferably biological activity in the leukaemia, especially compound I-6 can all be killed leukaemia (Fig. 1), and breast cancer cell only has the survival rate (Fig. 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), 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 (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), 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), 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), 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), 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 '), 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), 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), 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 (H-6 ' b) for m, 1H, (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 '), 3.78-3.81 (m, 1H, H-6 ' b), 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), 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 '), 3.70-3.73 (m, 1H, H-6 ' b), 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 '), 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 '), 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), 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 '), 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-
(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 (2)
1. the new type water-solubility butterfly mycin analog that has active anticancer, its structure are that chemical compound and pharmacy thereof with following formula structure can be accepted acid or the formed salt of alkali:
Wherein:
Substituent R is selected from-CH
2CH
2R
1, R wherein
1Be selected from glycosyl:
Wherein, substituent R
3, R
4Be selected from H.
2. the preparation method with new type water-solubility butterfly mycin analog of active anticancer according to claim 1 is characterized in that:
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| EP0269025A2 (en) * | 1986-11-21 | 1988-06-01 | Bristol-Myers Squibb Company | Rebeccamycin analogs |
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