CN115286684A - Conjugate of sugar and triptolide or derivatives thereof, and preparation method and application thereof - Google Patents

Conjugate of sugar and triptolide or derivatives thereof, and preparation method and application thereof Download PDF

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CN115286684A
CN115286684A CN202210553492.1A CN202210553492A CN115286684A CN 115286684 A CN115286684 A CN 115286684A CN 202210553492 A CN202210553492 A CN 202210553492A CN 115286684 A CN115286684 A CN 115286684A
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triptolide
cancer
conjugate
derivative
sugar
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许建华
张勇民
刘艳
黄家庆
欧阳宇华
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Fujian Medical University
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Abstract

The invention discloses a conjugate of sugar and triptolide or derivatives thereof, and a preparation method and application thereof. The conjugate is obtained by connecting triptolide and hydroxyl at different positions of sugar through a linker C. The preparation method comprises the following steps: (1) Exposing sugars at different hydroxyl positions to be condensed with succinic anhydride to form an intermediate M1 of a carboxyl joint, (2) reacting the intermediate M1 with triptolide or a derivative thereof under the action of a dehydrating agent EDCI and a catalyst DMAP to form an intermediate M2; (3) Intermediate M2 in H 2 Pd/C and Pd (OH) 2 Removing all benzyl and benzylidene groups under the catalysis to obtain the product. Compared with parent compounds, the conjugate has improved water solubility, can be transported into tumor cells via glucose transporter highly expressed by tumor cell membrane, and hydrolyzed under the action of cellular esterase to release parent drug triptolide, thereby improving targeting and antitumor activity of triptolide on tumor tissue.

Description

Conjugate of sugar and triptolide or derivatives thereof, and preparation method and application thereof
Technical Field
The invention relates to the field of preparation of antitumor drugs, and particularly relates to a conjugate of sugar and triptolide or a derivative thereof, and a preparation method and application thereof.
Background
Triptolide is an important effective component of tripterygium wilfordii of Celastraceae, is obtained by first separation of Kupchan and the like in 1972, and is reported to have strong in-vivo and in-vitro antitumor activity on human nasopharyngeal carcinoma KB cell strains and mouse leukemia L1210 and P388 in-vivo models, and then scholars at home and abroad successively study the antitumor activity. It has been found that it has a wide range of unique biological activities, such as anti-cancer, anti-inflammatory, anti-rheumatoid, anti-alzheimer, anti-chronic asthma, anti-osteoporosis, immunosuppressive and anti-fertility. Triptolide shows good antitumor activity in vitro and in vivo against various cancers, and can be used as a clinical candidate drug.
Recent research finds that one of the important anti-tumor targets of triptolide is covalent binding with the core subunit XPB of the universal transcription factor TFIIH and inhibiting the DNA-dependent ATPase activity of TFIIH. The triptolide can also induce ubiquitination of the largest subunit RPB1 of RNAPII and proteasome-mediated degradation of RPB1, and inhibit RNA synthesis of RNAPII.
Although triptolide has significant antitumor effects on solid tumors such as colon cancer, the main reasons limiting the clinical application are narrow therapeutic window (the maximum tolerated dose is 4-7 times of the effective dose), poor water solubility, short half-life and severe multi-organ toxicity (particularly gastrointestinal tract, male reproductive system and bone marrow toxicity).
The main strategy to improve triptolide application in short plates is to deliver it selectively to tumor cells. According to the characteristics that tumor cells mainly depend on glucose in energy metabolism and glucose transport carriers of tumor cell membranes are obviously higher than those of normal cells, the glucose transport carriers are used by people 18 F-FDG (2-fluoro-2-deoxyglucose) is used as a radiotracer in Positron Emission Tomography (PET) for tumor imaging. In the case of a healthy patient, the patient will, 18 F-FDG is taken up only by tissues that constitutively consume glucose (e.g., brain and bladder). In cancer patients, tumor cells take up preferentially 18 F-FDG, allows clinicians to identify tumor sites and metastases and is used for staging of cancer and monitoring of treatment. Thus, chemotherapeutic drugs can be selectively delivered to cancer cells by tumor cell glucose transport carrier-mediated targeting using glucose derivatives as carriers of the active drug. The first anticancer prodrug that utilizes high levels of glycolysis in tumor cells and has been clinically tested is Glufosfamide (ifosfamide in combination with glucose), which has lower myelotoxicity and better antitumor activity than the parent drug.
In recent years, the idea that a glucose derivative is combined with a chemotherapeutic drug to form a prodrug to target tumor cells is hot, for example, bastien Reux synthesizes a series of compounds by coupling fluorodeoxyglucose derivative with chlorambucil, and compared with a parent drug, the compounds show obviously increased cytotoxicity in vitro. Lin binds paclitaxel to glucose derivatives to form conjugates, which have been found to act by a similar mechanism to the parent drug paclitaxel. Morphological changes in tubulin and chromosomes can be observed in the target cells, and the prodrug can be transported into the cells via Glut-1. Malay Patra rationally designed three glu-Pts by coupling glucose to platinum compounds, found to have high levels of cytotoxicity against cancer cells and cellular uptake mainly through Glut-1. He et al (references to Targeted delivery and sustained activity of triple through glucose conjugation, angew. Chem. Int. Ed. Engl.55 (2016) 12035-12039) use triptolide and a glucose derivative to form the prodrug Glutriptolide. Glutriptolide is more water soluble than the parent drug. It can gradually release triptolide in vivo, has better tumor distribution selectivity, and remarkably improves the therapeutic index in vivo, but has the defects of relatively weaker targeting and relatively poorer tumor selectivity.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a conjugate of sugar and triptolide or derivatives thereof, and a preparation method and application thereof. The design idea of the conjugate obtained by the application is different from that of He, the C1, C2, C3, C4 and C6 hydroxyls of D-glucose and the C2 hydroxyl of methyl glucose are structurally modified to be connected with the C-14 hydroxyl of triptolide through ester bonds, a series of triptolide-glucose conjugates are synthesized, and the influence of the difference of D-glucose substitution positions on the bioactivity of the triptolide-glucose conjugate is discussed.
Specifically, the sugar derivative similar to a PET tracer agent is synthesized and combined with triptolide or the derivative thereof, and the synthesized triptolide or the derivative thereof, namely the C sugar conjugate, has higher water solubility compared with a parent compound, can be transported into tumor cells through a glucose transporter highly expressed by tumor cell membranes, is hydrolyzed under the action of cell esterase to release the parent drug triptolide, so that the uptake of the triptolide or the derivative thereof by the tumor cells is promoted, and the targeting property and the antitumor activity of the triptolide or the derivative thereof to the tumor cells are improved. Solves the problems of narrow therapeutic window, multi-organ toxicity, low selectivity, poor water solubility and the like which limit the clinical application of the triptolide or the triptolide derivatives.
A conjugate of a saccharide and triptolide or a derivative thereof has the following structural formula:
triptolide or its derivative-C-sugar derivative.
Wherein the triptolide or its derivative is selected from the following compounds 1 to 13, wherein the compound 1 is triptolide:
Figure BDA0003653942240000031
wherein C may be selected from-X-Y-Z-, wherein X and Z may be used as independent direct links, -O-, -CH 2 -, -C (O) -, -O (CO) -, where Y is a direct bond and may be a substituted or unsubstituted- (C) 1 -C 6 ) Alkyl, substituted or unsubstituted- (CH) 2 ) n O(C 1 -C 6 ) Alkyl, wherein each alkyl may be optionally substituted with alkoxy, hydroxy, oxy, aryl, heteroaryl, or carboxy.
Wherein the sugar derivative is selected from compound 14 to compound 27:
Figure BDA0003653942240000041
in the above general formula, triptolide or its derivative and hydroxyl groups at different positions of sugar derivative are connected via linker C to obtain conjugate (Glu-tpls) such as glucose (compounds 14-18) and mannose (compounds 19-27).
(5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"':8a,9]Phenanthrene [1,2-c]Furan-8-yl ((2R, 3R,4S,5S, 6R) -2,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) succinate (Compound G2) in which C is-C (O) CH 2 CH 2 C(O)-
Figure BDA0003653942240000051
(5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1,2, 3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxireno) [2',3':4b,5;2",3":6,7;2"',3"':8a,9]Phenanthrene [1,2-c]Furan-8-yl ((2R, 3R,4S,5R, 6R) -2,3,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) succinate (Compound G3) in which C is-C (O) CH 2 CH 2 C(O)-
Figure BDA0003653942240000052
(5bS, 6aS,7aR,8aS,9aS, 10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyl tris (oxireno) [2',3':4b,5;2",3":6,7;2"',3"':8a,9]Phenanthrene [1,2-c]Furan-8-yl ((2R, 3S,4R,5R, 6R) -4,5,6-trihydroxy-2- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) succinate (Compound G4) in which C is-C (O) CH 2 CH 2 C(O)-
Figure BDA0003653942240000053
(5bS, 6aS,7aR,8aS,9aS, 10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyl tris (oxireno) [2',3':4b,5;2",3":6,7;2"',3"':8a,9]Phenanthrene [1,2-c]Furan-8-yl (succinic acid (((2R, 3S,4S, 5R) -3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl) methyl) (Compound G6) in which C is-C (O) CH 2 CH 2 C(O)-
Figure BDA0003653942240000061
(2S, 3R,4S,5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3-yl ((5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a, 10b-dodecyltrihydroxymethyl (oxiro) [2',3':4b,5, 3', 6,7 ',3': 8a,9]Phenanthrene [ [1,2-c]Furan-8-yl) succinate (Compound alpha-6) in which C is-C (O) CH 2 CH 2 C(O)-
Figure BDA0003653942240000062
(2R, 3R,4S,5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3-yl ((5 bS,6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltrihydroxymethyl (oxiro) [2',3':4b,5 ", 2",3":6,7 2" ',3': 8a,9]Phenanthrene [ [1,2-c]Furan-8-yl) succinate (Compound beta-6) in which C is-C (O) CH 2 CH 2 C(O)-
Figure BDA0003653942240000071
As an improvement (by changing the connecting bond C, when C is-X-Y-Z-, wherein X is-O-, -C (O) -, Y is a substituted or unsubstituted- (C1-C6) alkyl, substituted or unsubstituted- (CH 2) nO (C1-C6) alkyl, and Z is-O-, -C (O) -), the conjugate obtained by the application also comprises the following compounds T1-T8:
Figure BDA0003653942240000072
the preparation method of the conjugate of the sugar and the triptolide or the derivative thereof comprises the following steps:
(1) Condensing the sugar with exposed hydroxyl groups at different positions with succinic anhydride to form an intermediate M1 of a carboxyl joint;
(2) The intermediate M1 and triptolide form an intermediate M2 under the action of a dehydrating agent and a catalyst.
The dehydrating agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI); the catalyst is 4-dimethylamino pyridine (DMAP);
(3) Intermediate M2 in H at room temperature in MeOH 2 Removing all benzyl and benzylidene groups under the action of a catalyst, wherein the catalyst is Pd/C and Pd (OH) with equal mass 2 Can be used in combination.
A pharmaceutical composition comprises a conjugate of the above saccharide and triptolide or its derivative, and a pharmaceutically acceptable excipient.
The conjugate of the above saccharide and triptolide or its derivatives can be used for preventing or treating tumor and immune related diseases. The tumor includes but is not limited to bladder cancer, breast cancer, nasopharyngeal cancer, pancreatic cancer, gastric cancer, cervical cancer, colon cancer, lung cancer, prostate cancer, rectal cancer, liver cancer, kidney cancer, and testicular cancer.
The immune related diseases include, but are not limited to, acute Disseminated Encephalomyelitis (ADEM), ankylosing spondylitis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune lymphoproliferative syndrome (ALPS), rheumatoid arthritis, rheumatoid psoriasis, lupus including Systemic Lupus Erythematosus (SLE), autoimmune immunodeficiency, autoimmune urticaria.
Has the advantages that: compared with the prior art, the invention has the following advantages:
(1) The obtained sugar and triptolide or the derivative thereof are conjugated to form a novel prodrug compound, the water solubility of the prodrug compound is obviously higher than that of triptolide, the prodrug compound has strong cancer inhibition activity in vitro, shows strong nude mouse transplanted tumor proliferation inhibition activity in vivo, the tumor inhibition rate is obviously higher than that of taxol and parent drug triptolide, and the toxicity of the prodrug compound is lower than that of the parent drug.
(2) The preparation method is characterized in that: compared with a synthetic route such as He, the synthetic route of the method is simpler, the steps are simpler, the synthetic requirement can be met, and the method can also be used for synthesizingThe operability of the experiment can be increased, and the pollution to the environment can be reduced. In the esterification reaction process of triptolide and glucose derivatives, the 14-hydroxyl of the triptolide has great steric hindrance, and the reaction conditions are strictly anaerobic and anhydrous. By strictly controlling the reaction conditions and screening the proportion of the EDCI and the DMAP, the yield of the esterification reaction can be obviously improved and can reach more than 60 percent. In the aspect of hydroxyl deprotection, because the benzyl group of the protective group of the glucose hydroxyl and the double bond of the five-membered unsaturated lactone ring of the triptolide can generate addition reaction with hydrogen, pd/C and Pd (OH) are adjusted 2 The proportion can reduce the reaction time and improve the reaction yield by more than 90 percent.
Drawings
FIG. 1 is a graph showing that G2 obtained in example 11 promotes the degradation of RNA Pol II; wherein: (A) Degradation of H460 cell RNA pol II by G2 and tpl (triptolide) for 48H; (B) Degradation of H460 cell RNA pol II by G2 and tpl for 72H;
FIG. 2 is a graph showing the antitumor activity of G2 against human lung cancer H1975 xenograft tumor in nude mouse of example 12;
FIG. 3 is a graph showing the effect of G2 on the expression of RNA pol II in the H1975 tumor tissue in example 13.
Detailed Description
The following detailed description and the accompanying drawings illustrate the embodiments of the present invention. The content is to explain the invention and not to limit the scope of protection of the invention.
The following examples illustrate the apparatus used: 1 H-NMR and 13 C-NMR was measured using a Bruker Advance type III nuclear magnetic resonance apparatus; MS and HRMS were measured using Agilent S3 Technologies 1100 and Bruker micro TOF spectrometer.
Example 1
(5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthreneanthracene [1,2-c ] furan-8-yl ((2R, 3R,4S,5S, 6R) -2,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) succinate (Compound G3)
Figure BDA0003653942240000091
(1) Preparation of Mono- (((2R, 4aR,7R,8R, 8aR) -6,8-bis (benzyloxy) -2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-yl) succinate or Mono- (((2R, 4aR,7R, 8S) -6,7-bis (benzyloxy) -2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-8-yl) succinate (intermediate M1)
The raw material 4,6-O-benzylidene-1,3-tri-O-benzyl-3-beta-D-glucopyranoside is synthesized by the subject group. Synthetic reference Synthesis of equivalent 2,2-Linked manuose deviations by Homodimerization.
Figure BDA0003653942240000101
4,6-O-benzylidene-1,3-tri-O-benzyl-3- β -D-glucopyranoside or 4,6-O-benzyl-1,2-tri-O-benzyl-3- β -D-glucopyranoside (1.71g, 3.82mmol) and succinic anhydride (4eq, 0.682g) were weighed into a round bottom flask, and dichloromethane-N, N-diisopropylethylamine (10). Stirring at room temperature for 24h, extracting and washing the reaction solution with water and brine, and reacting with anhydrous Na 2 SO 4 Drying and concentrating. The concentrate was separated and purified by silica gel column chromatography (dichloromethane-methanol, 50. The yield thereof was found to be 80%. 1 H NMR(400MHz, Chloroform-d)δ7.51(dd,J＝7.2,2.5Hz,2H),7.47–7.17(m,28H),5.60(s,1H),5.48(s, 1H),5.33(t,J＝9.4Hz,1H),5.12(t,J＝8.4Hz,1H),4.98(d,J＝11.7Hz,1H),4.87(dd,J＝ 12.0,6.9Hz,3H),4.73(d,J＝7.1Hz,2H),4.66(dd,J＝12.6,5.7Hz,2H),4.60(d,J＝12.3 Hz,1H),4.54(d,J＝7.9Hz,1H),4.40(dt,J＝10.1,4.7Hz,2H),3.90–3.76(m,3H),3.72(t, J＝9.1Hz,1H),3.62(t,J＝9.5Hz,1H),3.56–3.50(m,2H),3.46(ddd,J＝14.6,9.8,5.0Hz, 1H),2.67–2.41(m,8H). 13 C NMR(300MHz,Chloroform)δ177.32,170.97,170.50,138.14, 137.94,137.15,136.91,136.86,129.01,128.95,128.50,128.41,128.30,128.26,128.18, 128.12,128.02,127.96,127.92,127.89,127.75,127.72,127.67,126.06,126.00,103.00, 101.25,100.15,81.50,79.59,78.66,78.34,74.50,74.10,73.29,73.09,71.72,70.77,68.66, 66.23,66.09,28.75,28.70,28.65,26.90.ESI-MS m/z calcd for C 31 H 32 O 9 Na[M+Na] + 571.1944,found 571.2245。
(2) Preparation of (2S, 6R,7R, 8S) -6,8-bis (benzyloxy) -2-phenylhexahydropyrano [3,2-d ] [1,3] dioxin-7-yl ((5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a, b, 10b-dodecyltrihydroxymethyl (oxiro) [2',3':4b,5;2",3":6,7, 2 '", 3'": 8a,9] phenanthrene [1,2-c ] furan-8-yl) succinate (intermediate M2)
Figure BDA0003653942240000102
Triptolide (0.1mmol, 36mg), intermediate M1 (1.54eq, 67.43mg), EDCI (1 eq,19.17 mg), DMAP (cat.) were weighed into a round bottom flask, dissolved with dichloromethane and stirred at room temperature for 20h, after which the resulting mixture was diluted with dichloromethane and washed with water, brine, respectively. The organic layer was washed with Na 2 SO 4 Dried, filtered and concentrated to give a residue. The residue was separated and purified by silica gel column chromatography (cyclohexane-ethyl acetate, 4:1) and dried in vacuo to give 62.32mg as a white solid. The yield was 70%. ESI-MS m/z calcd for C 51 H 54 O 14 Na[M+Na] + 913.3411,found 913.3547。
(3) (5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthreneanthracene [1,2-c ] furan-8-yl ((2R, 3R,4S,5S, 6R) -2,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) succinate
Figure BDA0003653942240000111
Intermediate M2 (10mg, 0.010mmol), pd/C (5%, 5 mg) and Pd (OH) were weighed 2 (10%, 5 mg) in a round bottom flask, dissolved by adding 1mL MeOH, the reaction was stirred at room temperature for 4h under hydrogen, and after removing palladium on carbon by filtration, the residue was concentrated and purified by silica gel column chromatography (dichloromethane-methanol, 15, 1) to obtain 5.91mg of a white solid. The yield thereof was found to be 95%. ESI-MS m/z calcd for C 30 H 38 O 14 Na[M+Na] + 645.3.2154,found 645.3.2169。
Example 2
(5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthrene [1,2-c ] furan-8-yl ((2R, 3R,4S,5R, 6R) -2,3,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) succinate (Compound G2)
Figure BDA0003653942240000112
(1) Preparation of Mono- (((2R, 4aR,7R,8R, 8aR) -6,8-bis (benzyloxy) -2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-yl) succinate or Mono- (((2R, 4aR,7R, 8S) -6,7-bis (benzyloxy) -2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-8-yl) succinate (intermediate M1)
The starting material 4,6-O-benzylidene-1,3-tri-O-benzyl-3-beta-D-glucopyranoside or 4,6-O-benzyl-1,2-tri-O-benzyl-3-beta-D-glucopyranoside was synthesized by the subject group. Synthetic reference Synthesis of equivalent 2,2' -Linked manuse Derivatives by Homodimerization.
4,6-O-benzyl-1,2-tri-O-benzyl-3-beta-D-glucopyranoside (1.71g, 3.82mmol) and succinic anhydride (4 eq, 0.682g) were prepared in the same manner as example 1 to give 1.675g of a colorless liquid. The yield thereof was found to be 80%. 1 H NMR(400 MHz,Chloroform-d)δ7.51(dd,J＝7.2,2.5Hz,2H),7.47–7.17(m,28H),5.60(s,1H),5.48 (s,1H),5.33(t,J＝9.4Hz,1H),5.12(t,J＝8.4Hz,1H),4.98(d,J＝11.7Hz,1H),4.87(dd,J ＝12.0,6.9Hz,3H),4.73(d,J＝7.1Hz,2H),4.66(dd,J＝12.6,5.7Hz,2H),4.60(d,J＝12.3 Hz,1H),4.54(d,J＝7.9Hz,1H),4.40(dt,J＝10.1,4.7Hz,2H),3.90–3.76(m,3H),3.72(t, J＝9.1Hz,1H),3.62(t,J＝9.5Hz,1H),3.56–3.50(m,2H),3.46(ddd,J＝14.6,9.8,5.0Hz, 1H),2.67–2.41(m,8H). 13 C NMR(300MHz,Chloroform)δ177.32,170.97,170.50,138.14, 137.94,137.15,136.91,136.86,129.01,128.95,128.50,128.41,128.30,128.26,128.18, 128.12,128.02,127.96,127.92,127.89,127.75,127.72,127.67,126.06,126.00,103.00, 101.25,100.15,81.50,79.59,78.66,78.34,74.50,74.10,73.29,73.09,71.72,70.77,68.66, 66.23,66.09,28.75,28.70,28.65,26.90.ESI-MS m/z calcd for C 31 H 32 O 9 Na[M+Na] + 571.1944,found 571.2245。
(2) Preparation of (2S, 6R,7R, 8S) -6,8-bis (benzyloxy) -2-phenylhexahydropyrano [3,2-d ] [1,3] dioxin-7-yl ((5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a, b, 10b-dodecyltrihydroxymethyl (oxiro) [2',3':4b,5;2",3":6,7, 2 '", 3'": 8a,9] phenanthrene [1,2-c ] furan-8-yl) succinate (intermediate M2)
Prepared from triptolide (0.1mmol, 36mg), intermediate M1 (1.23eq, 67.43mg), EDCI (1 eq,19.17 mg) and DMAP (cat.), and prepared by the same method as example 1 to obtain 62.32mg as a white solid. The yield was 70%. ESI-MS m/z calcd for C 51 H 54 O 14 Na[M+Na] + 913.3411,found 913.3547。
(3) (5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthrene [1,2-c ] furan-8-yl ((2R, 3R,4S,5R, 6R) -2,3,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-4-yl) succinate
Intermediate M2 (10mg, 0.010mmol), pd/C (5%, 5 mg) and Pd (OH) were weighed 2 (10%, 5 mg) in a round-bottom flask, 1mL of MeOH was added and dissolved, and the reaction was stirred under hydrogen at room temperatureAfter stirring for 4h, the palladium on carbon was removed by filtration, and the residue was concentrated and purified by silica gel column chromatography (dichloromethane-methanol, 15). The yield thereof was found to be 95%. ESI-MS m/z calcd for C 30 H 38 O 14 Na[M+Na] + 645.3.2154,found 645.3.2169。
Example 3
(5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltrihydroxymethyl (oxireno) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthroline [1,2-c ] furan-8-yl ((2R, 3S,4R,5R, 6R) -4,5,6-trihydroxy-2- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) succinate (Compound G4)
Figure BDA0003653942240000131
The raw material 1,2,3,6-tetra-O-benzyl-3-beta-D-glucopyranoside is synthesized by the subject group. Synthetic references Fast Pyrolysis of 13C-laboratory cells gaming organization of training instruments of Fast Pyrolysis of carbohydrate [ J ]. The Journal of Organic Chemistry 2015.
(1) Preparation of mono- (((2R, 3R,4S,5R, 6R) -4,5,6-tris (benzyloxy) -2- ((benzyloxy) methyl) tetrahydro-2H-pyran-3-yl) succinate (intermediate M1)
Prepared from 1,2,3,6-tetra-O-benzyl-3- β -D-glucopyranoside (0.697 g, 1.291mmol) and succinic anhydride (4 eq, 0.558 g) by the same method as example 1 to give 715.8mg as a pale white solid. The yield was 86.6%. 1 H NMR (400MHz,Chloroform-d)δ7.41–7.21(m,20H,Ar-H),5.05–4.91(m,3H),4.81(d,J＝ 11.6Hz,1H),4.70(dd,J＝11.4,7.4Hz,2H),4.61(d,J＝11.6Hz,1H),4.58–4.50(m,3H), 3.65–3.51(m,5H),2.55–2.25(m,4H). 13 C NMR(400MHz,Chloroform-d):δ(ppm) 171.45,170.91,138.38,138.18,137.97,137.17,128.42,128.33,128.32,128.29,128.16, 128.00,127.83,127.81,127.77,127.70,127.66,127.59,102.23,81.98,81.69,75.00,74.93, 73.51,73.31,71.35,71.14,69.68,28.63,28.51.ESI-MS m/z calcd for C 38 H 40 O 9 Na[M+Na] + 663.2570,found 663.3141。
(2) (5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltrihydroxymethyl (oxireno) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthroline [1,2-c ] furan-8-yl ((2R, 3R,4S,5R, 6R) -4,5,6-tris (benzyloxy) -2- ((benzyloxy) methyl) tetrahydro-2H-pyran-3-yl) succinate (intermediate M2)
Prepared from triptolide (0.1mmol, 36mg), intermediate M1 (1.4eq, 89.64mg), EDCI (1eq, 19.14mg) and DMAP (cat.) by the same method as example 1 to give a white solid (66.8 mg. Yield 68%. 1 H NMR (400MHz,Chloroform-d)δ7.40–7.18(m,20H),5.03(s,1H),5.00–4.88(m,3H),4.80(d, J＝11.7Hz,1H),4.67(dd,J＝11.4,4.5Hz,2H),4.61(d,J＝3.2Hz,3H),4.52(d,J＝5.1Hz, 2H),4.51–4.47(m,1H),3.78(d,J＝3.2Hz,1H),3.65–3.58(m,1H),3.58–3.51(m,3H), 3.49(d,J＝3.0Hz,1H),3.37(d,J＝5.6Hz,1H),2.63(d,J＝10.3Hz,1H),2.58–2.52(m, 2H),2.51–2.42(m,1H),2.34–2.23(m,2H),2.05(dt,J＝14.8,5.8Hz,2H),1.87(p,J＝6.9 Hz,1H),1.83–1.74(m,1H),1.63(s,1H),1.53(dd,J＝12.4,5.0Hz,1H),1.17(td,J＝12.0, 5.7Hz,1H),1.00(s,3H),0.90(d,J＝7.0Hz,3H),0.79(d,J＝6.9Hz,3H). 13 C NMR(400 MHz,Chloroform-d):δ(ppm)173.15,171.69,170.84,159.85,138.54,138.21,137.19, 128.40,128.32,128.30,128.16,127.98,127.81,127.77,127.72,127.61,127.59,102.14, 82.04,81.91,75.14,74.91,73.59,73.53,71.15,71.06,70.98,69.89,69.58,64.05,63.29, 61.17,59.63,55.35,54.94,40.30,35.63,29.80,28.86,27.93,23.36,17.44,17.02,16.63, 13.74.ESI-MS m/z calcd for C 58 H 62 O 14 Na[M+Na] + 1005.4032,found 1005.4018。
(3) (5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltrihydroxymethyl (oxireno) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthroline [1,2-c ] furan-8-yl ((2R, 3S,4R,5R, 6R) -4,5,6-trihydroxy-2- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) succinate
From intermediate M2 (10mg, 0.010mmol), pd/C (5%, 5 mg) and Pd (OH) 2 (10%, 5 mg) was obtained in the same manner as in example 1 to give 5.72mg of a white solid. The yield was 92%.
Example 4
(5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthrene [1,2-c ] furan-8-yl (succinic acid (((2R, 3S,4S, 5R) -3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl) methyl) (Compound G6)
Figure BDA0003653942240000151
The raw material benzyl 2,3,4-tri-O-benzyl-D-glucopyranoside is synthesized by the subject group. Synthetic references An experiential synthesis of benzyl 2,3,4-tri-O-benzyl-beta-D-glucopyranoside and benzyl 2,3,4-tri-O-benzyl-beta-D-mannopyranoside [ J ] Carbohydrate Research,2005,340 (6): 1213-1217.
(1) Preparation of mono- (((2R, 3R,4S, 5R) -3,4,5,6-tetrakis (benzyloxy) tetrahydro-2H-pyran-2-yl) methanol) ester (intermediate M1)
Prepared from benzyl 2,3,4-tri-O-benzyl-D-glucopyranoside (1.405g, 2.602mmol) and succinic anhydride (4 eq,1.04 g) by the same method as example 1 to give 715.8mg as an off-white solid. The yield was 86.6%. 1 H NMR(300 MHz,Chloroform-d)δ7.42–7.21(m,20H),5.02–4.89(m,2H),4.89–4.61(m,3H),4.60– 4.47(m,2H),4.41(dd,J＝11.8,1.9Hz,1H),4.27(dd,J＝11.8,4.2Hz,1H),4.14(dq,J＝ 10.3,7.2Hz,1H),3.73–3.61(m,1H),3.60–3.45(m,2H),2.67–2.60(m,4H),2.05(s,1H), 1.26(t,J＝7.1Hz,3H).ESI-MS m/z calcd for C 38 H 40 O 9 Na[M+Na] + 663.2570,found 663.2647。
(2) (5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthrene [1,2-c ] furan-8-yl (succinic acid (((2R, 3R,4S, 5R) -3,4,5,6-tetrakis (benzyloxy) tetrahydro-2H-pyran-2-yl) methyl)
Prepared from triptolide (0.1mmol, 36mg), intermediate M1 (1.4eq, 80.04mg), EDCI (1eq, 19.17mg) and DMAP (cat.) by the same method as example 1 to give 73.39mg as a white solid. The yield was 74.7%. 1 H NMR (400MHz,Chloroform-d)δ7.40–7.24(m,21H),5.06(d,J＝3.7Hz,1H),4.99–4.91(m, 2H),4.87(d,J＝10.8Hz,1H),4.80(d,J＝10.9Hz,1H),4.75–4.67(m,2H),4.67–4.59(m, 2H),4.57(s,1H),4.52(d,J＝7.7Hz,1H),4.40(dd,J＝11.8,2.1Hz,1H),4.31(dd,J＝11.8, 4.6Hz,1H),3.80(d,J＝3.1Hz,1H),3.66(t,J＝8.7Hz,1H),3.61–3.54(m,1H),3.54– 3.49(m,2H),3.39(d,J＝5.6Hz,1H),2.79–2.63(m,4H),2.31(d,J＝17.6Hz,1H),2.08(dt, J＝14.7,5.6Hz,2H),1.94–1.78(m,2H),1.65–1.50(m,4H),1.19(td,J＝12.1,5.7Hz, 1H),1.03(d,J＝4.4Hz,3H),0.93(d,J＝6.9Hz,3H),0.83(d,J＝6.9Hz,3H). 13 C NMR (400MHz,Chloroform-d)δ173.30,171.88,171.47,159.82,138.38,138.20,137.93,137.30, 128.42,128.38,128.34,128.11,128.00,127.85,127.68,127.66,126.04,102.66,84.93,82.44, 75.73,75.10,75.08,73.20,71.22,71.18,70.02,63.48,63.29,61.00,59.62,55.25,54.78, 40.32,35.62,29.65,29.07,28.86,28.09,23.56,17.45,17.03,16.68,13.74.ESI-MS m/z calcd for C 54 H 62 O 14 Na[M+Na] + 1005.4032,found 1005.4018。
(3) (5bS, 6aS,7aR,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltris (oxoro) [2',3':4b,5;2",3":6,7;2"',3"': preparation of 8a,9] phenanthrene [1,2-c ] furan-8-yl (succinic acid (((2R, 3S,4S, 5R) -3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yl) methyl)
From intermediate M2 (10mg, 0.010mmol), pd/C (5%, 5 mg) and Pd (OH) 2 (10%, 5 mg) was obtained in the same manner as in example 1 to give 5.54mg of a white solid. The yield thereof was found to be 89%.
Example 5
Preparation of (2S, 3R,4S,5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3-yl ((5 bS,6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxomercaptotris (oxireno) [2',3':4b,5 ', 2",3":6,7 "', 2" ',3"':8a,9] phenanthrene [ [1,2-c ] furan-8-yl) succinate (Compound α -6)
Figure BDA0003653942240000161
The starting material (2R, 4aR,6S,7R,8R, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-ol was synthesized by the subject group. Synthetic reference Chemoenzymatic synthesized glycosylated GM3 analogues with inhibited effects on the bulk cell growth and propagation [ J ]. European Journal of Medicinal Chemistry,2019.
(1) Preparation of 4- (((((2R, 4aR,6S,7R,8S, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-yl ] oxy) -4-oxobutanoic acid (intermediate M1)
From (2R, 4aR,6S,7R,8R, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d] [1,3]Dioxin-7-ol (1.405g, 2.602mmol) and succinic anhydride (4 eq, 1.04g) were prepared as in example 1 to afford 715.8mg as a pale yellow solid. The yield thereof was found to be 86.6%. 1 H NMR(400MHz,Chloroform-d)δ7.53–7.28(m, 10H),5.60(s,1H),4.95–4.86(m,3H),4.71(d,J＝11.8Hz,1H),4.31(dd,J＝9.9,4.5Hz, 1H),4.05(tt,J＝9.0,1.7Hz,1H),3.88(td,J＝9.8,4.5Hz,1H),3.80(d,J＝10.1Hz,1H), 3.78–3.69(m,1H),3.39(s,3H),2.73–2.57(m,4H)。
(2) (2R, 4aR,6S,7R,8S, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-yl ((5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a, a,9b, 10b-dodecotritis (oxireno) [2',3':4b,5;2 ',3': 6, 72, 3': 8a,9] phenanthrene [ [1,2-c ] furan-8-yl) succinate (intermediate 2M 2
Is prepared from triptolide (0.1mmol, 36mg) and intermediate M1 (1.3 e)q,61.38 mg), EDCI (1eq, 19.17mg) and DMAP (cat.) prepared as in example 1 to give 16.28mg of a white solid. The yield thereof was found to be 42%. 1 H NMR (400MHz,Chloroform-d)δ7.49(d,J＝6.2Hz,2H),7.43–7.26(m,8H),5.58(s,1H),5.09 (s,1H),4.92(s,1H),4.91–4.83(m,1H),4.72(d,J＝11.9Hz,1H),4.66(s,2H),4.34–4.26 (m,1H),4.05(d,J＝8.2Hz,1H),3.84(d,J＝10.8Hz,1H),3.79(d,J＝9.8Hz,1H),3.71(q, J＝8.7Hz,1H),3.53(s,1H),3.44(d,J＝5.2Hz,1H),3.39(s,2H),2.79–2.64(m,4H),2.31 (d,J＝25.8Hz,1H),2.16(q,J＝7.2,6.4Hz,2H),1.89(dd,J＝17.0,11.8Hz,2H),1.57(d,J ＝10.8Hz,2H),1.46(s,2H),1.24(dd,J＝22.5,7.7Hz,2H),1.06(s,3H),0.95(d,J＝6.9Hz, 3H),0.85(d,J＝6.9Hz,3H). 13 C NMR(300MHz,Chloroform-d)δ173.14,171.47,171.42, 159.88,138.46,137.25,128.95,128.26,128.21,127.78,127.56,126.00,125.60,101.29, 97.70,83.00,76.00,74.76,73.28,71.25,69.91,68.91,63.51,63.30,62.27,61.12,59.63, 55.32,55.28,54.97,40.35,35.66,29.83,29.05,28.97,28.02,26.89,23.42,17.93,17.04, 16.73,13.74。
(3) Preparation of (2S, 3R,4S,5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3-yl ((5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxomercaptotris (oxireno) [2',3':4b,5, 2",3":6,7, ',3': 8a,9] phenanthrene [ [1,2-c ] furan-8-yl) succinate
From intermediate M2 (10mg, 0.010mmol), pd/C (5%, 5 mg) and Pd (OH) 2 (10%, 5 mg) was obtained in the same manner as in example 1 to give 6.95mg of a white solid. The yield was 89%.
Example 6
(2R, 3R,4S,5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3-yl ((5 bS,6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltrihydroxymethyl (oxiro) [2',3':4b,5 ",3":6,7 ",3": 8a,9] phenanthrene [ [1,2-c ] furan-8-yl) succinate (Compound beta-6)
Figure BDA0003653942240000181
The starting material (2R, 4aR,6R,7R,8R, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-ol was synthesized by the subject group. Synthetic reference Chemoenzymatical synthesized branched glycosides GM3 analogue with inhibiting effects on tire cell growth and migration [ J ]. European Journal of Medicinal Chemistry,2019.
(2) Preparation of 4- ((((2R, 4aR,6R,7R,8S, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-yl) oxy) -4-oxobutanoic acid (intermediate M1)
From (2R, 4aR,6R,7R,8R, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d] [1,3]Dioxin-7-ol (1.405g, 2.602mmol) and succinic anhydride (4 eq, 1.04g) were prepared in the same manner as in example 1 to give 0.964g of a pale yellow solid. The yield was 78.5%. 1 H NMR(400MHz,Chloroform-d)δ7.58–7.26(m, 10H),5.47(s,1H),5.38(dd,J＝10.0,8.0Hz,1H),4.66(q,J＝12.6Hz,2H),4.39–4.30(m, 2H),4.17(d,J＝3.4Hz,1H),4.04(dd,J＝12.3,1.5Hz,1H),3.61(dd,J＝10.1,3.5Hz,1H), 3.49(d,J＝0.7Hz,4H),3.39(s,1H),2.66(t,J＝4.3Hz,4H)。 13 C NMR(400MHz, Chloroform-d)δ177.50,172.14,138.05and 137.52(C,aromatic),129.77,129.02,128.57, 128.39,128.13,127.86,127.81,127.45and 126.45(C,aromatic),101.75,101.20,73.26, 72.84,71.26,70.46,69.10,66.60,56.18,29.01,28.93。
(2) (2R, 4aR,6R,7R,8S, 8aR) -8- (benzyloxy) -6-methoxy-2-phenylhexahydropyran [3,2-d ] [1,3] dioxin-7-yl ((5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a, a,9b, 10b-dodecotritis (oxireno) [2',3':4b,5;2 ',3': 6, 72, 3': 8a,9] phenanthrene [ [1,2-c ] furan 8-yl) succinate (intermediate 2M 2)
Prepared from triptolide (0.1mmol, 36mg), intermediate M1 (1.35eq, 63.74mg), EDCI (1 eq,19.17 mg) and DMAP (cat.) by the same method as example 1 to obtain white solid (48.86 mg, 60% yield. 1 H NMR(400MHz,Chloroform-d)δ7.53(dd,J＝7.3,2.3Hz,2H),7.39–7.24(m,8H),5.48 (s,1H),5.37(dd,J＝10.0,8.0Hz,1H),5.09(s,1H),4.66(d,J＝3.4Hz,3H),4.36(d,J＝8.0 Hz,1H),4.32(dd,J＝12.3,1.6Hz,1H),4.15(d,J＝3.8Hz,1H),4.12(d,J＝7.1Hz,1H), 4.03(dd,J＝12.4,1.8Hz,1H),3.82(d,J＝3.2Hz,1H),3.59(dd,J＝10.0,3.5Hz,1H),3.54 (s,1H),3.49(s,2H),3.44(d,J＝5.6Hz,1H),3.36(s,1H),2.79–2.65(m,4H),2.32(d,J＝ 17.6Hz,1H),2.18–2.11(m,1H),2.04(s,1H),1.98–1.83(m,2H),1.62–1.54(m,2H), 1.26(t,J＝7.1Hz,2H),1.06(s,3H),0.94(d,J＝6.9Hz,3H),0.83(d,J＝6.9Hz,3H)。 13 C NMR(300MHz,Chloroform-d)δ174.21,172.46,170.26,157.69,138.59,137.29,128.98, 128.34,128.26,127.80,127.79,126.47,126.00,100.89,98.74,84.01,76.20,74.69,73.61, 72.02,69.75,68.82,64.51,64.21,62.76,61.59,59.56,57.45,56.38,55.97,40.35,37.89, 30.83,29.95,29.07,28.02,27.67,24.67,18.39,17.54,15.68,13.37。
(3) Preparation of (2R, 3R,4S,5S, 6R) -4,5-dihydroxy-6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3-yl ((5bS, 6aS,7aR,8R,8aS,9aS,9bS,10aS, 10bS) -8 a-isopropyl-10 b-methyl-3-oxo-1, 2,3,5,5b,6,6a,8,8a,9a,9b, 10b-dodecyltrihydroxymethyl (oxiro) [2',3':4b,5 ], 2',3': 6,7 ' ″,2', 3': 8a,9] o-phenanthrene [1,2-c ] furan-8-yl) succinate
From intermediate M2 (10mg, 0.010mmol), pd/C (5%, 5 mg) and Pd (OH) 2 (10%, 5 mg) was obtained in the same manner as in example 1 to give 7.03mg of a white solid. The yield thereof was found to be 90%.
Example 7
The results of investigation of the oil-water distribution coefficient of the compound are shown in table 1:
table 1 shows the oil-water partition coefficients of the various compounds and triptolide obtained in examples 1-6
Figure BDA0003653942240000201
The oil-water distribution coefficient result shows that: the oil-water distribution coefficient lgP value is less than 0, and belongs to a hydrophilic compound, and the larger the absolute value of the value is, the stronger the hydrophilicity is. The absolute values of the oil-water distribution coefficients of the triptolide-glucose conjugate are all larger than that of the triptolide, so that the triptolide-glucose conjugate has good water solubility. Of these, G3 and G6 are the most water soluble.
Example 8
In vitro cell proliferation inhibition assay
Cell lines: human lung cancer cell lines NCI-H460 and NCI-H1975; human colon cancer cell lines SW620, HT29, HCT116; human breast cancer cell lines MCF-7 and MBA-MD-231; HUVEC (human umbilical vein vascular endothelial cells) and HaCaT (human immortalized keratinocyte cells); the normal human hepatocytes LO2 are all derived from the Shanghai cell bank.
The experimental method comprises the following steps: MTT method. Succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT into water-insoluble purple crystalline Formazan (Formazan) and deposit in the cells, while dead cells do not have the function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and the light absorption value of the formazan is measured at the wavelength of 570nm by using an enzyme-labeling instrument. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number. The number of living cells is judged according to the measured absorbance value (OD value), and the smaller the OD value, the weaker the cell activity, the higher the drug toxicity.
The specific method comprises the following steps: taking cells of logarithmic growth phase, adjusting cell number to 4000-5000 cells per well, inoculating to 96-well culture plate, culturing at 37 deg.C and 5% CO per well with volume of 180 μ L 2 Incubated under conditions overnight. The experimental groups were added with 20 μ L of each drug at different concentrations, the control group was not dosed with drugs, and a background control was added, each group was provided with 3 parallel wells, and cultured at 37 ℃ for 72h. Adding 20 mu L/well of 5mg/mL MTT solution, continuously culturing for 4h, discarding the supernatant, adding 100-150 mu L DMSO, shaking and dissolving by a micro-shaking instrument, and immediately measuring the absorbance (OD value) at the wavelength of 570nm by an enzyme-linked immunosorbent assay (ELISA) instrument.
The degree of inhibition of cell proliferation by the drug was calculated according to the following formula:
inhibition (%) = (OD control-OD administration well)/OD control well 100% and the concentration of the drug at which 50% inhibition is achieved, that is, IC is calculated according to the Logit method based on the inhibition (%) = (OD control-OD administration well)/OD control well X100% 50 The value is obtained. The experiment was repeated three times and the average was calculated. Compound IC 50 G2, G3, G4, G6, alpha-6 and beta-6 are arranged from high to low in sequence.
Table 2 shows the proliferation inhibition degree and therapeutic index of drugs prepared from different compounds on tumor cells with high Glut-1 expression
Figure BDA0003653942240000211
Table 3 shows the degree of inhibition of proliferation and therapeutic index of drugs prepared from different compounds on tumor cells with high expression of Glut-1 and normal cells with low expression of Glut-1
Figure BDA0003653942240000221
In vitro cell proliferation inhibition experiments show that: IC of cytotoxic drugs on normal and tumor cells 50 The ratio can reflect the selectivity of the drug to tumor cells, i.e. relative therapeutic index, the higher the ratio indicates the higher the selectivity of the drug to tumor cells, and as can be seen from Table 3, tpl (triptolide) has an average IC on normal cells and tumor cells 50 The ratio of (A) to (B) is 0.53; glucose-triptolide conjugates G2, G3, G4, G6, alpha-6, beta-6 mean IC against normal and tumor cells 50 The ratio of the values is 3.06, 1.33, 0.58, 0.71, 1.75, 0.87, respectively, all higher than the original drug tpl to different extents. Therefore, the glucose derivative of the triptolide can be transported to the tumor cells through Glut-1 highly expressed by the tumor cells, thereby showing higher tumor cell targeting and higher selective antitumor activity.
Example 9
NCI-H460 cells were treated with either Glut-1 inhibitor or sh-Glut-1 and the cytotoxicity of Glu-tpls was observed by MTT assay under the same genetic background.
TABLE 4 Effect of Glut-1 inhibitors and Glut-1 knockdown on Glu-tpls cytotoxicity
Figure BDA0003653942240000231
Knockdown in the presence of Glut-1 inhibitor (WZB 117 or Phloretin) or Glut-1(sh-39 or sh-40), IC of glucose-triptolide conjugates G2, G3, G4, G6, α -6, β -6 on H460 cells 50 Both increased to different extents, indicating that Glut-1 inhibitors and Glut-1 knockdown reduce the toxicity of the glucose-triptolide conjugate to H460 cells, where G2 had IC in the presence of 10. Mu.M WZB117 and Glut-1 knockdown 50 Increases by 10.62 and 14.37 times. The cytotoxicity of the original triptolide is unrelated to the activity of Glut-1. The above results confirm that the cytotoxicity of the synthesized triptolide-glucose conjugate is dependent on the Glut-1 activity to various degrees.
Example 10
Cell lines: human lung cancer cell line a549; human breast cancer cell line MCF-7; hepatoma cell strains HepG2, QGY7703, SMMC7721, hep1-6 and SK-Hep1; human pancreatic cancer cell strains MIAPaCa-2, panc-1, asPC-1, capan-1 and BxPC-3; the human nasopharyngeal carcinoma cell strains CNE2 are all from Shanghai cell banks.
Table 5 shows the proliferation inhibition of G2 and triptolide on different types of tumor cells
Figure BDA0003653942240000241
TABLE 6 shows the proliferation inhibition effect of G2 and triptolide on different types of tumor cells
Figure BDA0003653942240000242
In vitro cell proliferation inhibition experiments show that: the compound G2 is used for treating a human lung cancer cell strain A549; human breast cancer cell line MCF-7; hepatoma cell strains HepG2, QGY7703, SMMC7721, hep1-6 and SK-Hep1; human pancreatic cancer cell strains MIAPaCa-2, panc-1, asPC-1, capan-1 and BxPC-3; the human nasopharyngeal carcinoma cell strains CNE2 have strong in-vitro anti-tumor activity.
Example 11
Western Blot to detect degradation of RNA Pol II, shown in FIG. 1, shows that: g2 And triptolide can both promote degradation of RNA PolII in a dose-dependent manner. G2 is used as the prodrug of triptolide, and under the action of intracellular esterase, a connecting ester bond in the molecule can be hydrolyzed and broken to release the triptolide, so that the triptolide acts on a target molecule of the triptolide.
Example 12
The result of the study on the antitumor effect of the human lung cancer H1975 nude mouse transplantation tumor is shown in figure 2. As can be seen, in the H1975 nude mouse transplantation tumor model of human lung cancer, PTX (15 mg/kg, q3 d), tpl (0.2 mg/kg, qd, d 1-5/w), G2 (1 mg/kg, qd, d 1-5/w), G2 (2 mg/kg, qd, d 1-4/w) were administered by intraperitoneal administration for 2 weeks.
The average tumor inhibition rates after two weeks of continuous administration were 56.92%, 28.65%, 75.44% and 90.42%, respectively. During the administration period, compared with the solvent control group, the difference has statistical significance, and in the whole experimental process, the nude mice have no toxic symptoms such as obvious weight reduction, diarrhea and the like.
Example 13
The expression of RNA pol II in H1975 nude mouse xenograft tumor tissues is detected by immunoblotting, and is shown in FIG. 3. As can be seen, by expression of RNA pol II, tpl and G2 were found to induce degradation of RNA pol II.
In examples 1 to 6, the inventors prepared compounds G2, G3, G4, G6, α -6, β -6 using triptolide (Compound 1) as a reactant, and obtained a triptolide derivative-based conjugate by changing Compound 1 to Compounds 2 to 13. By changing C, the inventor obtains compounds T1-T8, the water solubility is proved to be larger than that of triptolide per se, the tumor targeting is also greatly improved, and the results are not recorded based on space.
The above description is only a preferred embodiment of the present invention, and the scope of the present invention is not limited thereto, and any simple modifications or equivalent substitutions of the technical solutions that can be obviously obtained by those skilled in the art within the technical scope of the present invention are within the scope of the present invention.

Claims (8)

1. A conjugate of a saccharide and triptolide or a derivative thereof, having the formula: triptolide or its derivative-C-sugar derivative;
wherein the triptolide or a derivative thereof is selected from the following compounds 1 to 13:
Figure FDA0003653942230000011
Figure FDA0003653942230000021
wherein C is-X-Y-Z-;
wherein X and Z may be used as independent direct bonds selected from-O-, -CH 2 -、-C(O)-、-O(CO)-；
Wherein Y is a direct bond and may be a substituted or unsubstituted- (C) 1 -C 6 ) An alkyl group; substituted or unsubstituted- (CH) 2 ) n O(C 1 -C 6 ) Alkyl, wherein each alkyl may be optionally substituted with alkoxy, hydroxy, oxy, aryl, heteroaryl, or carboxy;
wherein the sugar is glucose or mannose, and the sugar derivative is selected from the following compounds 14 to 27:
Figure FDA0003653942230000022
Figure FDA0003653942230000031
。
2. the conjugate of a saccharide and triptolide or its derivatives according to claim 1, wherein: <xnotran> C -X-Y-Z-, X -C (O) -, Y - (C1-C6) , Z -C (O) - -O (CO) - , : </xnotran>
Figure FDA0003653942230000032
3. The conjugate of a saccharide and triptolide or its derivatives according to claim 1, wherein: the structural formula is as follows: when C is-X-Y-Z-, wherein X is-O-or-C (O) -, Y is a substituted or unsubstituted- (C1-C6) alkyl, substituted or unsubstituted- (CH 2) nO (C1-C6) alkyl, when Z is-O-or-C (O) -, the resulting conjugate is as follows:
Figure FDA0003653942230000041
4. the method of claim 1, wherein the steps of preparing the conjugate of a saccharide and triptolide or its derivative are as follows:
(1) Synthesizing sugar exposing different hydroxyl positions, and condensing with succinic anhydride to form an intermediate M1 of a carboxyl joint;
(2) The intermediate M1 reacts with triptolide or the triptolide derivative under the action of a dehydrating agent and a catalyst to form an intermediate M2; the dehydrating agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the catalyst is 4-dimethylaminopyridine;
(3) Intermediate M2 in H 2 Removing all benzyl and benzylidene groups under the action of a catalyst, wherein the catalyst is Pd/C and Pd (OH) 2 Can be used in combination.
5. A pharmaceutical composition comprising a conjugate of a saccharide of claim 1 and triptolide or a derivative thereof and a pharmaceutically acceptable excipient.
6. Use of the conjugate of a saccharide according to claim 1 and triptolide or a derivative thereof for the manufacture of a medicament for the treatment of a tumor or an immune-related disorder.
7. The use of claim 6, wherein the immune related diseases include, but are not limited to, acute disseminated encephalomyelitis, ankylosing spondylitis, autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus, polyarteritis.
8. The use according to claim 6, wherein said tumor includes, but is not limited to, bladder cancer, breast cancer, nasopharyngeal cancer, pancreatic cancer, gastric cancer, cervical cancer, colon cancer, lung cancer, prostate cancer, rectal cancer, liver cancer, kidney cancer, testicular cancer.
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