Rhamnoside compound and application thereof as medicament for anti-multidrug resistant tumor

An anti-tumor drug, rhamnoside technology, applied in the direction of anti-tumor drugs, steroids, sugar derivatives, etc., can solve the problems of limited drug delivery and low water solubility

Active Publication Date: 2015-11-25
YANGZHOU BLUE BIOMEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, with the continuous use of antitumor drugs, tumor cells have begun to develop drug resistance. Currently, paclitaxel and docetaxel are still effective for tumor cells resistant to cisplatin and other drugs, but they have their own shortcomings such as low water solubility. the way of administration

Method used

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  • Rhamnoside compound and application thereof as medicament for anti-multidrug resistant tumor
  • Rhamnoside compound and application thereof as medicament for anti-multidrug resistant tumor
  • Rhamnoside compound and application thereof as medicament for anti-multidrug resistant tumor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1 Preparation of monosaccharide glucosinolate donors 71-78

[0059] (1):

[0060] Weigh 3-methyl-2-butenoic acid (645mg, 6.44mmol) dissolved in dry CH 2 Cl 2 (30mL), add DCC (499mg, 2.42mmol), DMAP (39mg, 0.322mmol), stir at room temperature for 5 minutes, add compound 101 (500mg, 1.61mmol), stir the reaction at room temperature until TLC detects that compound 101 disappears, filter , After concentration under reduced pressure, through silica gel column chromatography (petroleum ether / EtOAc=10 / 1), compound 71 (531 mg; 84%) and its β-isomer were obtained;

[0061] Compound 71: 1 HNMR (400MHz, CDCl 3 ):δ7.38-7.34(m,2H),7.13(d,J=7.9Hz,2H,),5.71(s,1H),5.69(s,1H),4.96(dd,J=9.9,7.8Hz ,1H),4.35(dd,J=5.3,0.5Hz,1H),4.23(dd,J=8.0,5.5Hz,1H),4.21–4.17(m,1H),2.33(s,3H),1.93( s,3H),1.91(d,J=1.0Hz,3H),1.58(s,3H),1.35(s,3H),1.13(d,J=6.3Hz,3H).

[0062] Monosaccharide glucosinolate donors 72 and 73 can be prepared according to the above-mentioned similar method or the m...

Embodiment 2

[0078] Example 2 Preparation of Monosaccharide Acceptors 81-90

[0079]

[0080] Weigh L-rhamnose (2.0g, 10.98mmol) and n-hexadecanol (13.31g, 54.89mmol) with 1 crystal water and heat to 80°C, add TfOH–SiO 2 (274mg, 2mmol / g), after stirring and reacting for 5-8h, pour the reaction mixture into a (8cm×2cm) silica gel column while hot, and first use CH 2 Cl 2 Methane elution reclaims unreacted n-hexadecanol, and then elutes with EtOAc to obtain hexadecyl rhamnoside, which is dissolved in 50 mL of acetone, and 2,2-dimethoxypropane (2.1 mL, 16.47 mmol ), a catalytic amount of p-toluenesulfonic acid, stirred and reacted at room temperature for 0.5 h, concentrated, and subjected to silica gel column chromatography (petroleum ether / EtOAc=5 / 1) to obtain compound 89 (3.76 g, 80%) and its β-isomer;

[0081] Compound 89: 1 HNMR (400MHz, CDCl 3 ):δ4.94(s,1H),4.14–4.08(m,2H),3.69(dt,J=9.2,6.7Hz,2H),3.45–3.38(m,2H),2.47(broads,1H), 1.68–1.52(m,4H),1.53(s,3H),1.36(s,3H),1.31–1.24(m,2...

Embodiment 3

[0093] The preparation of embodiment 3 intermediate compound 111-134

[0094] (1): Weigh compound 85 (100mg, 0.268mmol) and compound 73 (138mg, 0.349mmol) and dissolve in 5mL dry dichloromethane, add appropriate amount MS, under the protection of argon, under ice bath, add NIS (90mg, 0.402mmol), TfOH (5μL), stir the reaction for 0.5 ~ 1h, filter, wash with 20mLCH 2 Cl 2 Diluted sequentially with 5% Na 2 S 2 o 3 , saturated NaHCO 3 , washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography (petroleum ether / EtOAc=8 / 1) to obtain compound 111 (155 mg, 90%);

[0095] Compound 111: 1 HNMR (400MHz, CDCl 3 ):δ5.64(s,1H),4.98–4.93(m,2H),4.21(dd,J=7.1,5.7Hz,1H),4.18–4.13(m,2H),4.10(d,J=5.6 Hz,1H),3.77(dq,J=12.7,6.3Hz,1H),3.70–3.62(m,2H),3.57(dd,J=9.9,7.3Hz,1H),3.42(dt,J=9.6, 6.5Hz, 1H), 3.27(d, J=16.4Hz, 1H), 3.17(d, J=16.4Hz, 1H), 2.36(s, 6H), 1.61–1.56(m, 5H), 1.54(s, 3H), 1.34(s, 3H), 1.33(s, 3H), 1....

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Abstract

The present invention relates to a rhamnoside compound and application thereof as a medicament for anti-multidrug resistant tumor. The compound of the invention has cytotoxic activity to sensitive tumor cell lines KB, MCF-7 similar to the activity of a positive control drug (doxorubicin, vincristine, paclitaxel), and has cytotoxic activity to resistant tumor cell lines KB / VCR, MCF-7 / ADR stronger than the positive control; and the compound of the invention has better water solubility. The compound provided by the invention is expected to be developed into a novel antitumor medicament.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to the application of a rhamnoside compound in the preparation of antitumor drugs. In particular, it relates to a human oral squamous cell carcinoma KB cell line, a vincristine-resistant human oral squamous cell carcinoma KB / VCR cell line, a human breast cancer MCF-7 cell line, and a doxorubicin-resistant human breast cancer MCF-7 / VCR cell line. All ADR cell lines have rhamnoside compounds with strong cytotoxic activity. Background technique [0002] Tumor is one of the most common and serious diseases threatening human life in the world today. In recent years, with the continuous use of antitumor drugs, tumor cells have begun to develop drug resistance. Currently, paclitaxel and docetaxel are still effective for tumor cells resistant to cisplatin and other drugs, but they have their own shortcomings such as low water solubility. its mode of administration. Therefore, the developm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04C07H15/14C07H1/00C07J17/00A61K31/704A61K31/7028A61K31/706A61P35/00
CPCY02P20/55
Inventor 于跃陈敏
Owner YANGZHOU BLUE BIOMEDICAL TECH CO LTD
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