Diosgenin combined nitrogen mustard derivative with antitumor activity and its preparation method and use

A technology of diosgenin and derivatives, which is applied in the field of natural medicine and medicinal chemistry, can solve problems such as limited successful cases, and achieve the effects of high research value, good cytotoxicity, and high clinical application prospects

Active Publication Date: 2022-02-15
QIQIHAR MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, melphalan (melphalan), developed using phenylalanine as a carrier, has good curative effects on malignant tumors such as ovarian cancer, breast cancer, lymphoma and multiple myeloma, but the disadvantage of this drug is that it must be injected medication
[0004] It can be seen that combining natural products with nitrogen mustards is a good strategy to modify nitrogen mustards to increase their efficacy and reduce their toxic side effects, although many pharmacists follow this strategy to treat nitrogen mustards. Research has been conducted, but currently known success stories are extremely limited
That is to say, the transformation of classic chemotherapy drugs such as nitrogen mustards in this way has not met the current huge clinical needs, and it is still necessary to find more natural compounds suitable for the transformation of nitrogen mustards through splicing. product

Method used

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  • Diosgenin combined nitrogen mustard derivative with antitumor activity and its preparation method and use
  • Diosgenin combined nitrogen mustard derivative with antitumor activity and its preparation method and use
  • Diosgenin combined nitrogen mustard derivative with antitumor activity and its preparation method and use

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]

[0050] Add intermediate 6a (60mg, 0.12mmol) and 5mL CH 2 Cl 2 , after stirring and dissolving, add DMAP (22.0mg, 0.18mmol), EDCI (33.4mg, 0.18mmol) and benzoen mustard 4 (36.5mg, 0.14mmol), stir at room temperature for 8h, thin layer chromatography (petroleum ether: ethyl acetate volume ratio=1.5:1) to monitor the reaction, the basic reaction of raw materials is complete, add 10mL water to the reaction solution, extract three times with 5mL dichloromethane, wash with saturated brine, anhydrous Na 2 SO 4 After drying, filtering, concentrating, and separating and purifying by silica gel column chromatography, the target compound 7a was obtained as a white powder with a yield of 81.2%.

[0051] 1 H NMR (600MHz, CDCl 3 ,δ):7.74(d,J=8.5Hz,2H,Ph-H),6.68(d,J=8.5Hz,2H,Ph-H),5.38(d,J=4.3Hz,1H,H-6 ),4.70(m,1H,H-3),4.41(dd,J=14.9,7.3Hz,1H,H-16),4.19(d,J=4.1Hz,2H,Gly-α-CH 2 ), 3.79(t, J=6.9Hz, 4H, NCH 2 CH 2 Cl,×2),3.65(t,J=6.9Hz,4H,NCH 2 CH 2 Cl,×2),3.47(dd,J=11.0,3...

Embodiment 2

[0055]

[0056] The target compound 7f was prepared according to the synthesis method of Example 1. White powder, yield 79.3%.

[0057] 1 H NMR (600MHz, CDCl 3 ,δ):8.22(br s,1H,Try-NH),7.61(d,J=8.7Hz,2H,Ph-H),7.59(d,J=8.3Hz,1H,Try-Ph),7.35( d,J=8.3Hz,1H,Try-Ph),7.18(t,J=7.7Hz,1H,Try-Ph),7.08(t,J=7.7Hz,1H,Try-Ph),7.03(s, 1H, Try-δ-CH), 6.61 (d, J=8.7Hz, 2H, Ph-H), 5.33 (d, J=4.4Hz, 1H, H-6), 5.08 (dd, J=12.8, 5.6 Hz, 1H, Try-α-CH), 4.59(m, 1H, H-3), 4.41(dd, J=15.0, 7.5Hz, 1H, H-16), 3.76(t, J=7.2Hz, 4H , NCH 2 CH 2 Cl,×2),3.62(t,J=7.2Hz,4H,NCH 2 CH 2 Cl,×2),3.47(dd,J=11.1,3.4Hz,1H,H-26),3.41(d,J=5.3Hz,2H,Try-β-CH 2 ), 3.38(t, J=11.1Hz, 1H, H-26), 1.00(s, 3H, 19-CH 3 ), 0.97 (d, J=7.1Hz, 3H, 21-CH 3 ),0.79(s,3H,18-CH 3 ),0.78(d,J=1.8Hz,3H,27-CH 3 ).

[0058] 13 C NMR (150MHz, CDCl 3 ,δ):171.8(Try-COO),166.5(-CONH),148.8(Ph-C),139.7(C-5),136.2(Try-Ph),129.3(Ph-C,×2),128.0( Try-Ph), 122.9(C-6), 122.7(Try-δ-C), 122.6(Ph-C), 122.3(Ph-C), 119.8(Try-Ph), 119.1(Try...

Embodiment 3

[0061]

[0062] The target compound 12a was prepared according to the synthesis method of Example 1. White powder, yield 84.7%.

[0063] 1 H NMR (600MHz, CDCl 3 ,δ):7.74(d,J=8.8Hz,2H,Ph-H),6.65(d,J=8.8Hz,2H,Ph-H),5.37(d,J=5.0Hz,1H,H-6 ), 4.59 (m, 1H, H-3), 4.30 (m, 1H, H-16), 4.23 (d, J=4.7Hz, 2H, Gly-α-CH 2 ), 4.09(dd, J=10.6, 5.7Hz, 1H, H-26), 3.99(dd, J=10.6, 6.8Hz, 1H, H-26), 3.79(t, J=7.0Hz, 4H, NCH 2 CH 2 Cl,×2),3.65(t,J=7.0Hz,4H,NCH 2 CH 2 Cl,×2),3.30(m,1H,H-22),2.03(s,3H,Ac-CH 3 ),1.03(s,3H,19-CH 3 ),0.99(d,J=6.8Hz,3H,21-CH 3 ), 0.95 (d, J=6.8Hz, 3H, 27-CH 3 ),0.80(s,3H,18-CH 3 ).

[0064] 13 C NMR (150MHz, CDCl 3 ,δ):170.7(Ac-COO),170.6(Gly-COO),166.9(-CONH),148.9(Ph-C),139.8(C-5),129.3(Ph-C,×2),122.5( C-6),111.3(Ph-C,×2),90.2(C-22),83.4(C-16),74.0(C-3),70.4(C-26),65.2(C-17), 57.0 (C-14), 53.5 (NCH 2 CH 2 Cl,×2),50.1(C-9),42.0(Gly-α-CH 2 ), 40.8 (C-12), 40.3 (NCH 2 CH 2 Cl,×2),39.5(C-13),38.2(C-4),38.1(C-20),37.1(C-1),36.8(C-10),32.9(C-24),32.4...

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Abstract

The invention belongs to the field of natural medicine and medicinal chemistry, and relates to a class of diosgenin combined nitrogen mustard derivatives and a preparation method and application thereof. It specifically relates to a preparation method for introducing a benzoic mustard derivative into the 3-OH or 26-OH site of the diosgenin core structure and its use in the preparation of antitumor drugs. The diosgenin and nitrogen mustard derivatives of the invention have good antitumor effects and can be used for further preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of natural medicine and medicinal chemistry, and relates to a class of diosgenin combined nitrogen mustard derivatives and a preparation method and application thereof. It specifically relates to a preparation method for introducing a benzoic acid mustard derivative into the 3-OH or 26-OH site of the diosgenin core structure and its use in the preparation of antitumor drugs. Background technique [0002] In recent years, the morbidity and mortality of cancer have continued to rise globally, and cancer has become the second leading cause of death after cardiovascular and cerebrovascular diseases. Although with the advancement of science and technology, a large number of new anti-tumor targets and anti-tumor drugs have emerged, but these new drugs are usually very expensive and cannot be afforded by the working class, and their drug safety is difficult to guarantee due to limited clinical data . The anti-tumor drugs c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J71/00A61P35/00A61P35/02A61K31/58
CPCC07J71/0005A61P35/00A61P35/02
Inventor 王文豹
Owner QIQIHAR MEDICAL UNIVERSITY
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