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2,3,6-trideoxyglycosyl demethylepipodophyllotoxin compound as well as preparation method and application thereof

A technology for removing epipodophyllin and trideoxyglycosyl, which is applied in the fields of medicinal chemistry and pharmacology, and can solve the problems of easy metabolic inactivation, unsatisfactory therapeutic effect, and poor water solubility

Active Publication Date: 2019-02-22
南通大学技术转移中心有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Etoposide and teniposide are podophyllotoxin derivatives developed by Sandoz in the 1860s and 1970s. Although they have good curative effects on various cancers, they still have limitations, such as unsatisfactory therapeutic effect and poor water solubility. , easy metabolic inactivation, multi-drug resistance and other disadvantages

Method used

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  • 2,3,6-trideoxyglycosyl demethylepipodophyllotoxin compound as well as preparation method and application thereof
  • 2,3,6-trideoxyglycosyl demethylepipodophyllotoxin compound as well as preparation method and application thereof
  • 2,3,6-trideoxyglycosyl demethylepipodophyllotoxin compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 (2R, 3R, 6R)-3,6-dihydro-2-methyl-6-norepipodophyllotoxin-2H-pyran-3-ol (Ia)

[0034] Add n-butyl ((2S,6R)-6-methyl-5-oxo-5,6-dihydro-2H-pyran-2-yl)carbonate (912mg, 4mmol) in a 50mL round bottom flask and norepipodophyllotoxin (2.2g, 4.4mmol) were dissolved in 20mL of dichloromethane, and then Pd 2 (dba) 3 (91.6mg, 0.1mmol) and PPh 3 (105.0mg, 0.4mmol), nitrogen protection under ice bath for 12h. The end of the reaction was detected by TLC, concentrated, and column chromatography (prtroleum ether:EtOAc=1:1) gave a slightly yellow solid IIIa (1.4g), with a yield of 60%.

[0035] In a 50mL round bottom flask, add IIIa (600mg, 1mmol), CeCl 3 • MeOH (5mL, 0.4eq), sodium borohydride (42mg, 1.1mmol) and 5mL of dichloromethane were mixed and stirred at -78°C for 2.5h. The end of the reaction was detected by TLC, quenched with deionized water, extracted with dichloromethane (50mL×3), dried over anhydrous sodium sulfate, filtered, concentrated, column chromatogra...

Embodiment 2

[0038] The method for reference example 1 prepares Ib-If compound, and the physicochemical data of each compound Ib-If is as follows:

[0039] (2R,3R,6R)-3,6-Dihydro-2-isopropyl-6-norepipodophyllotoxinyl-2H-pyran-3-ol (Ib)

[0040] 1 H NMR (400MHz, DMSO-d 6 ):δ8.24(s,1H,Ar-OH),6.93(s,1H,ArH),6.52(s,1H,ArH),6.21(s,2H,ArH),6.02(d,2H,J= 4.8Hz,CH 2 ), 4.85 (m, 2H, H2, CH), 4.64 (d, 1H, J = 5.6 Hz, CH 2 ),4.52(d,1H,J=5.2Hz,CH 2 ),4.46(m,1H,CH),4.03(m,1H,H6),3.95(m,1H,OH),3.63(s,6H,OCH 3 ),3.33(m,1H,H5),3.20(dd,1H,J 1 =14Hz,J 2 =4.8Hz,CH),2.85(m,1H,CH),2.14(m,1H,CH),1.85(d,1H,J=12.4Hz,H3),1.89(m,3H,H3,H4), 1.08(d, 3H, J=6.8Hz, CH 3 ),0.92(d,3H,J=6.4Hz,CH 3 ). 13 C NMR (100MHz, DMSO-d 6 ): δ 175.0, 147.9, 147.6, 146.8, 135.2, 132.9, 130.6, 130.6, 110.6, 109.9, 109.0, 101.8, 97.3, 77.6, 73.1, 68.2, 66.4, 56.5, 49.1, 483.2, 41.1, 293.4, 38. , 27.7, 20.4, 16.6. HRMS (ESI): m / z calcd for C 29 h 34 o 10 :542.2140; found: 542.2146[M].

[0041] (2R,3R,6R)-3,6-Dihydro-2-meth...

Embodiment 3

[0049] In order to better understand the essence of the present invention, the pharmacological experiment results of the growth inhibitory effect of the 2,3,6-trideoxyglycosyl norepipodophyllotoxin compound of the present invention on five tumor cell lines are as follows: Describe its new application in the field of antitumor drug research. The Pharmacological Examples present partial activity data for representative compounds. It must be noted that the pharmacological examples of the present invention are used to illustrate the present invention rather than limit the present invention. The simple improvements made to the present invention according to the essence of the present invention all belong to the protection scope of the present invention.

[0050] Compounds Ia-If are effective against human lung cancer cells (A549), human liver cancer cells (HepG2), human cervical cancer cells (Hela), human neuroblastoma cells (SH-SY5Y), oral cancer resistant vincristine cells (KB / ...

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Abstract

The invention discloses 2,3,6-trideoxyglycosyl demethylepipodophyllotoxin compound or pharmaceutically acceptable ester thereof. The chemical structural formula of the 2,3,6-trideoxyglycosyl demethylepipodophyllotoxin compound is as shown in the figure I in the specification, wherein R represents C1-C6 alkyl, -OH, -NH2, NO2 and halogen groups. The compound has the advantage of being capable of remarkably improving the cytotoxic activity on human lung cancer cells (A549), human hepatoma cells (HepG2), human cervical cancer cells (HeLa), human neuroblastoma cells (SH-SY5Y) and oral cancer vinblastine-resistant cells (KB-VCR) compared with clinical medication of etoposide and has the potential of being developed into anti-tumor drugs.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and pharmacology. Specifically, the present invention relates to a novel podophyllotoxin derivative 2,3,6-trideoxyglycosyl norepipodophyllotoxin compound, its preparation method and application. Background technique [0002] With the advancement of medicine, common infectious diseases are gradually being controlled, and malignant tumor-cancer has become one of the main diseases that are common and seriously threaten human life and quality of life. The cytotoxic antitumor drugs currently used in clinical practice are not highly selective, resulting in relatively large side effects. Therefore, finding and discovering new antitumor drugs with high efficiency and low toxicity is a current research hotspot. [0003] Podophyllotoxin is derived from the rhizome extract of podophyllum, which has anti-mitotic activity. Due to its serious side effects, podophyllotoxin has been greatly restrict...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61P35/00A61K31/365
CPCA61P35/00C07B2200/07C07D493/04
Inventor 赵芮涵赵育陆亚鹏
Owner 南通大学技术转移中心有限公司
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