Rubescensin A derivatives and preparation method and applications thereof

A technology of oridonin A and its derivatives, which is applied in the direction of drug combinations, pharmaceutical formulas, and medical preparations containing active ingredients, etc., and can solve the problem of not greatly improving antitumor activity, water solubility, and reducing toxicity. Comparing the selectivity difference of derivatives and restricting the development of Rubescensine A to achieve the effects of increasing bioavailability, reducing drug dosage and improving anti-tumor activity

Active Publication Date: 2018-07-20
MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD +1
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Problems solved by technology

[0004] Although Xu et al. introduced an aromatic ring side chain at the 14th position of oridonin to improve its antitumor activity, they did not evaluate the activity of the different linking chains between the benzene ring and the C-14th position of oridonin. and toxicity effects are studied
In addition, amino acid side chains are also introduced at the C-14 position to improve its activity, but there are only two amino acids, alanine and phenylalanine, and no in-depth research has been done on the introduction of other amino acid structures, and different amino acid structures (hydrophobicity and The introduction of hydrophilicity) also has a great difference in the improvement of its activity and water solubility, and after the amino group is connected with a large group, its activity, selectivity, toxicity, fat solubility and water solubility are also due to steric hindrance and other reasons. will change a lot
Moreover, the compounds obtained in this field have not been greatly improved in terms of antitumor activity, water solubility and reduced toxicity.
Especially for the three cell lines of human lung cancer cell A549 cell, human multiple myeloma cell RPMI-8226 cell and human liver cancer cell HepG2 cell, they were not tested, and the selectivity of the derivatives among different cancer cells was not compared difference, and it has not been structurally modified from the perspective of reducing the dosage and thus reducing its toxicity
These shortcomings all greatly limit the development of oridonin into new antitumor drugs

Method used

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  • Rubescensin A derivatives and preparation method and applications thereof
  • Rubescensin A derivatives and preparation method and applications thereof
  • Rubescensin A derivatives and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117]

[0118] Oridonin (100mg, 0.27mmol), N-Boc-glycine (48mg, 0.27mmol), EDCI (157mg, 0.82mmol) and DMAP (101mg, 0.82mmol) were added to a 50ml eggplant-type bottle, under nitrogen Under protective conditions, 10 ml of dried dichloromethane was added, reacted in an ice bath for 1 h, then stirred and reacted overnight at room temperature, and TLC detected that the reaction was complete. The reaction solution was transferred to a separatory funnel, washed twice with 1M dilute hydrochloric acid, and the organic phase was taken, dried over anhydrous magnesium sulfate, and silica gel column chromatography to obtain a white solid.

[0119] ent-1α-hydroxy-6β,7β-dihydroxy-[14β-O-(Boc-L-glycine)]-15-oxo-7,20-oxo-16-kaurene 1 HNMR (500MHz, CDCl 3 )δ6.20(d, J=10.7Hz, 1H), 6.12(s, 1H), 5.95(s, 1H), 5.50(s, 1H), 5.37(t, J=5.2Hz, 1H), 4.52( s,1H),4.27(d,J=10.3Hz,1H),4.02(d,J=10.3Hz,1H),3.79(ddd,J=23.2,18.2,5.7Hz,2H),3.69(dd,J =10.8,7.0Hz,1H),3.44(dd,J=11.3,5.5Hz,1H),3.11(d,J=9.7Hz,...

Embodiment 2

[0121]

[0122] ent-1α-hydroxy-6β,7β-dihydroxy-[14β-O-(Boc-L-leucine)]-15-oxo-7,20-oxo-16-kaurene. Referring to the synthetic method of Example 1. 1 H NMR (500MHz, CDCl 3 )δ6.10(d, J=12.4Hz, 1H), 5.87(s, 1H), 5.47(s, 1H), 4.90(d, J=7.6Hz, 1H), 4.28(d, J=10.4Hz, 1H), 4.23(s, 1H), 4.18(s, 1H), 4.05(d, J=10.4Hz, 1H), 3.73(dd, J=10.6, 6.9Hz, 1H), 3.51–3.44(m, 1H ),3.12(d,J=9.8Hz,1H),2.63–2.54(m,1H),2.31–2.18(m,1H),1.99–1.90(m,1H),1.75(dt,J=20.2,6.4 Hz,1H),1.72–1.63(m,1H),1.63–1.52(m,2H),1.48–1.42(m,1H),1.38(s,4H),1.29–1.22(m,1H),1.10( s,3H),0.87(t,J=5.9Hz,3H). 13 C NMR (126MHz, CDCl 3 )δ206.25,171.84,155.28,149.89,119.99,96.01,79.96,77.24,76.52,74.40,73.37,63.38,62.01,59.51,54.71,52.52,41.30,40.89,38.70,33.70,32.62,30.49,29.89,28.23,24.77 ,22.71,21.94,21.73,19.84.HRESIMS m / z 578.3324[M+H] + .

Embodiment 3

[0124]

[0125] ent-1α-hydroxy-6β,7β-dihydroxy-[14β-O-(Fmoc-L-phenylalanine)]-15-oxo-7,20-oxo-16-kaurene. Referring to the synthetic method of Example 1. 1 H NMR (500MHz, CDCl 3 )δ7.76(d, J=7.4Hz, 2H), 7.55(d, J=7.3Hz, 2H), 7.40(t, J=7.4Hz, 2H), 7.32(t, J=7.4Hz, 2H) ,7.24(d,J=9.6Hz,2H),7.12(d,J=6.9Hz,2H),6.17(d,J=10.9Hz,1H),6.07(s,1H),5.95(s,1H) ,5.51–5.45(m,1H),5.40(s,1H),4.53(dd,J=13.4,6.6Hz,1H),4.37(dd,J=10.2,7.5Hz,1H),4.32(s,1H ),4.30–4.23(m,2H),4.17(t,J=7.0Hz,1H),4.03(d,J=10.3Hz,1H),3.72(dd,J=10.8,7.1Hz,1H),3.41 (d,J=5.9Hz,1H),3.12(dd,J=13.9,6.5Hz,1H),2.99(dd,J=13.8,6.3Hz,1H),2.93(d,J=9.7Hz,1H) ,2.52(dt,J=13.6,8.9Hz,1H),2.17(dt,J=21.5,13.4Hz,1H),1.92(s,1H),1.87(dd,J=12.9,5.3Hz,1H), 1.77–1.68(m,1H),1.63(d,J=3.5Hz,2H),1.60–1.48(m,2H),1.42(d,J=13.5Hz,1H),1.08(d,J=13.7Hz ,6H). 13 C NMR (126MHz, CDCl 3 )δ206.20,170.35,155.67,149.86,143.83,143.75,141.24,135.93,129.38,128.56,128.51,127.69,127.13,127.10,127.02,125.22,125.15,120.22,119.93,95.97,75.89,74.71,73.41,67.14,6...

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Abstract

The invention discloses rubescensin A derivatives and a preparation method and applications thereof. The rubescensin A derivatives have structures represented by formulas (I), (II), (III), or (IV). Onthe premise that the active center of rubescensin A is not destroyed, the hydroxyl groups on the 1st, 6th, and 14th positions or the hydroxyl groups on the 6th and 7th positions are subjected to ringchange modification; and obtained rubescensin A derivatives have higher antitumor activity, higher intercellular selectivity, lower dosage, and lower toxicity. Compared with that of rubescensin A, the performance of rubescensin A derivatives on killing cancer cells of human liver cancer, human multiple myeloma, human lung cancer, and the like, is enhanced by 3 to 5 times; the optimal performancecan be strengthened by 11 times; and the rubescensin A derivatives can be used to prepare antitumor drugs for treating liver cancer, rubescensin A derivatives, lung cancer, and the like.

Description

technical field [0001] The invention belongs to the field of natural products and medicinal chemistry, and specifically relates to oridonin derivatives simultaneously modified at the 14-position and 1, 6, 7, and 14-positions of oridonin, a preparation method thereof, and a method for preparing antitumor Drug use. Background technique [0002] As an important traditional Chinese herbal medicine, Donglingcao has been certified by the China Food and Drug Administration due to its remarkable curative effect on inflammation. Tonsillitis, esophagitis, stomatitis, gingivitis, etc. (see Chen, S; Liu, J; Zhang, H.J. Huazhong Univ. Sci. Technol. Med. Sci. 2009, 29, 659). Among the folks in Henan, Donglingcao is widely used as a traditional Chinese medicine to treat esophageal cancer and lung cancer. Studies on the mechanism of its treatment of diseases have shown that Rubescens can not only inhibit breast cancer cells by regulating MAPK and Akt signaling pathways (see M.R.Sartippour...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/10A61K31/352A61K31/422A61K31/4192A61K31/453A61K31/4025A61K31/4433A61K31/385A61P35/00
CPCC07D493/10
Inventor 万升标赵万洲彭凯敖磊罗栋栋
Owner MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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