Furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and preparation method and application thereof

A technology of dihydropyrazole hydroxamic acid and saponin aglycone, which is applied in the field of dihydropyrazole hydroxamic acid C21 steroidal saponin aglycon derivatives, can solve the problems of low biological activity and selectivity, and high toxicity, and achieve good Biological activity, low toxicity, low toxicity effect

Inactive Publication Date: 2015-08-26
JIANGSU NAIQUE BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the existing products still have disadvantages such as low biological activity and selectivity, and high toxicity.

Method used

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  • Furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and preparation method and application thereof
  • Furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and preparation method and application thereof
  • Furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: 4-(5-(2-furan)-3-((3aR,4aS,8S,10aS,11S,12S,12aS)-(8,11,12-trihydroxy)-(10a,12a- Dimethyl)-(1,2-cyclopentyl)-1,10a-b-epoxytetradecyl)-(4,5-dihydropyrazole))benzoylhydroxamic acid ( Compound 15) Preparation

[0053]

[0054] Under stirring at -20°C, add the corresponding intermediate 12 (10.0mmol) and dichloromethane (25mL) obtained in step 5 to a 50mL round bottom flask in turn, and gradually add boron tribromide (5mmol) dropwise to continue the reaction with stirring After 1 h, the reaction flask was transferred to room temperature, and the reaction was continued for 12 h. The reaction was tracked by TLC (developer VAcOEt:V n-hexane=1:2). After the reaction, it was filtered, the solid was washed with distilled water, and finally dried in vacuum. The obtained solid was dissolved in absolute ethanol for recrystallization and purification to obtain the crystalline target compound.

[0055] White crystals were obtained with a yield of 48.9%. m.p.195~197℃; 1...

Embodiment 2

[0056] Example 2: 4-(5-(2-(5-methyl-furan))-3-((3aR,4aS,8S,10aS,11S,12S,12aS)-(8,11,12-trihydroxy )-(10a,12a-dimethyl)-(1,2-cyclopentyl)-1,10a-b-epoxytetradecyl)-(4,5-dihydropyrazole)) Preparation of Benzoylhydroxamic Acid (Compound 16)

[0057]

[0058] The preparation method is the same as in Example 1 (using furan-2-carbaldehyde with different substituents from Example 1). White crystals were obtained with a yield of 44.2%. m.p.200~201℃; 1H NMR(DMSO-d6,300MHz)δ:10.54(s,1H,OH),8.03(d,J=7.5Hz,2H,ArH),7.73(d,J=7.6Hz,2H ,ArH),7.71(s,1H,NH),6.17(d,J=5.2Hz,1H,CH),6.02(d,J=5.6Hz,1H,CH),5.58(t,J=4.4Hz, 1H, CH), 5.39(s, 2H, OH), 4.48(s, 1H, OH), 3.54(dd, J1=4.7, J2=4.2Hz, 1H, CH), 3.44(t, J=8.1Hz, 1H, CH), 3.34(d, J=6.8Hz, 1H, CH), 2.79(dd, J1=4.8, J2=5.1Hz, 2H, CH2), 2.20(s, 3H, CH3), 2.01(t, J=7.1Hz, 1H, CH), 1.72~1.31(m, 15H, CH and CH2), 1.13(dd, J1=7.2Hz, J2=7.1Hz, 1H, CH), 0.84(s, 3H, CH3) ,0.80(s,3H,CH3).ESI-MS:606.7[M+H]+.Anal.Calcd for C34H43N3O7:C,H,N.

Embodiment 3

[0059] Example 3: 4-(5-(2-(5-fluoro-furan))-3-((3aR,4aS,8S,10aS,11S,12S,12aS)-(8,11,12-trihydroxy) -(10a,12a-dimethyl)-(1,2-cyclopentyl)-1,10a-b-epoxy tetradecyl)-(4,5-dihydropyrazole))benzene Preparation of Formylhydroxamic Acid (Compound 17)

[0060]

[0061]The preparation method is the same as in Example 1 (using furan-2-carbaldehyde with different substituents from Example 1). White crystals were obtained with a yield of 52.8%. m.p.213~214℃; 1H NMR(DMSO-d6,300MHz)δ:10.50(s,1H,OH),7.94(d,J=7.1Hz,2H,ArH),7.71(t,J=6.8Hz,3H , CH and NH), 7.68(d, J=7.9Hz, 2H, ArH), 6.50(t, J=5.5Hz, 1H, CH), 5.62(t, J=5.3Hz, 1H, CH), 5.34( s,2H,OH),4.44(s,1H,OH),3.58(dd,J1=4.5,J2=4.1Hz,1H,CH),3.44(t,J=8.1Hz,1H,CH),3.34( d, J=6.8Hz, 1H, CH), 2.79(dd, J1=3.7, J2=3.4Hz, 2H, CH2), 2.01(t, J=7.1Hz, 1H, CH), 1.79~1.21(m, 15H, CH2and CH), 1.14(dd, J1=7.2Hz, J2=7.1Hz, 1H, CH), 0.92(s, 3H, CH3), 0.85(s, 3H, CH3).ESI-MS: 610.7[M +H]+.Anal.Calcd for C33H40FN3O7:C,H,N.

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Abstract

The invention discloses a furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and a preparation method and an application thereof. The structure of the derivative is shown as the formula VIII (img file = 'DDA 000709386530000011. TIF' wi= '882' he= '498' / ), R1 is selected from H and CH3; R2 is selected from H and F. The derivative has an apparent inhibiting effect on human breast cancer cells (MCF-7), cervical cancer cells (HeLa), lung carcinoma cells (A549) and hepatoma carcinoma cells (HepG2), and cytotoxicity equivalent to or higher than positive control drugs Celecoxib is presented to human kidney epithelial cells (293T), and the derivative can be applied to preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to dihydropyrazole hydroxamic acid C containing furan skeleton 21 Steroidal saponin aglycone derivative, its preparation method and application. Background technique [0002] C 21 Steroidal saponin is a steroidal saponin component obtained by extraction, separation and purification from the Chinese medicine Tongguanteng. Its aglycon is a unique steroidal saponin structure composed of 21 C atoms, so it is called C 21 steroidal saponins. have C 21 Steroidal saponin core compounds have pharmacological activities such as immunoregulation and anti-asthma, and have been widely used clinically as the index active ingredients of drugs. [0003] After in-depth research by the applicant, it is found that there is a C 21 Steroidal saponin core compounds may have good antitumor activity. Currently for such C 21 The research content of steroidal saponins mainly includes: separation, pur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P35/00
CPCC07J71/0021
Inventor 魏元刚严晓强金显友钟慧杨永安
Owner JIANGSU NAIQUE BIOLOGICAL ENG
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