CN116265455A - Sesquiterpene-alkaloid heteropolymer, preparation method and pharmaceutical application thereof - Google Patents

Sesquiterpene-alkaloid heteropolymer, preparation method and pharmaceutical application thereof Download PDF

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CN116265455A
CN116265455A CN202111585331.2A CN202111585331A CN116265455A CN 116265455 A CN116265455 A CN 116265455A CN 202111585331 A CN202111585331 A CN 202111585331A CN 116265455 A CN116265455 A CN 116265455A
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alkaloid
sesquiterpene
leukemia
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熊娟
何宇航
胡金锋
茅以诚
李启秀
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Fudan University
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract

The invention belongs to the technical field of medicines, and relates to a sesquiterpene-alkaloid heteromer with a skeleton structure shown in formulas 1-4, a preparation method thereof and application thereof in anti-leukemia medicines. The compound is extracted and separated from the leaves and stems of tulip tree (Liriodendron chinenese) which is a magnoliaceae medicinal plant, and pharmacological experiments prove that the compound can obviously inhibit proliferation and induce apoptosis of four leukemia cells of Raji, jeko-1, daudi and Jurkat, and can be singly used or combined with a proper excipient to prepare oral or non-oral medicament formulations for treating or assisting in treating leukemia according to a conventional method.

Description

Sesquiterpene-alkaloid heteropolymer, preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to a sesquiterpene-alkaloid heteromer with a skeleton structure shown in formulas 1-4, a preparation method thereof and application thereof in preparing anti-leukemia medicines. In particular to a sesquiterpene-alkaloid heteromer obtained from tulip tree extract, a preparation method thereof and application thereof in preparing anti-leukemia drugs. .
Background
Leukemia (leukemia) is a collective term for several malignant diseases and is described by research data as manifested by abnormal proliferation of leukocytes in blood and/or bone marrow. In clinical practice, there are mainly 5 clinical types of leukemias, including Acute Myeloid Leukemia (AML), acute Lymphoblastic Leukemia (ALL), chronic Myeloid Leukemia (CML), chronic Lymphocytic Leukemia (CLL) and Acute Promyelocytic Leukemia (APL), classified according to acute or chronic onset and the type of blood cells affected. Studies have shown that radiation, viruses, parasites, bacteria and chemicals may all contribute to the occurrence of leukemia. Leukemia is currently the sixth malignancy in our country and is the leading cause of cancer death in children or teenagers aged 0-19 years, but leukemia remains a public health problem worldwide despite its decreased mortality in recent years.
Natural products have been an important source of novel antitumor drugs, such as vincristine and vinblastine, the first plant antitumor drugs approved by the FDA in the united states, useful for the treatment of acute lymphoblastic leukemia; semisynthetic teniposide derived from plants can be used in combination with chemotherapeutic agents for various leukemia. The acquisition of compounds with good activity from nature to develop new drugs for the treatment of leukemia remains the subject of search by those skilled in the art.
The tulip tree (Liriodendron chinenese) is a plant of the genus tulip tree of the family Magnoliaceae (Magnoliaceae), the wild species of which is a national secondary important rare endangered protection plant, and is mainly distributed in the eastern China, the Yunnan and the adjacent southwest regions of Anhui and Zhejiang, and sporadically grows in the mountain broadleaf forest with the altitude of 900-1800 m. The tree trunk is straight, the crown is umbrella-shaped, the leaf shape is peculiar, and the tree is a beautiful tree species of the court and the street, and is called as five street species of the world together with sycamore, basswood, ginkgo and horse chestnut, and is called as tulip because the flower shape is exactly like tulip, so the tree is called as tulip tree (Chinese Tulip Tree) in China, and the tree is widely planted and cultivated in all regions of China. Besides high garden value, tulip tree has high medicinal value, and roots and barks of tulip tree can be used as medicines, have the effects of dispelling wind, removing dampness and relieving cough, and are used for treating rheumatic arthralgia and wind-cold cough. No report on the inhibiting activity of tulip trees on leukemia cells is yet seen.
Based on the current state of the art, the inventors of the present application intend to provide sesquiterpene-alkaloid heteromers of novel framework structures, a preparation method thereof and use thereof in preparing anti-leukemia drugs.
Disclosure of Invention
The invention aims to provide a sesquiterpene-alkaloid heteromer with a novel framework structure, a preparation method thereof and application thereof in preparing anti-leukemia drugs based on the current state of the art.
The invention separates four novel sesquiterpene-alkaloid heteromers with brand new skeleton structures as shown in the formulas 1-4 from plant tulip tree, and the in vitro activity screening shows that the sesquiterpene-alkaloid heteromers have different degrees of inhibition activities on 4 leukemia cells.
The invention further provides a novel application of the novel sesquiterpene-alkaloid heteropolymer in preparation of medicines for treating leukemia.
The compound has the following chemical structural formula:
Figure BDA0003415601510000021
the invention provides a process method for extracting and separating the compounds 1-4 from tulip trees, which comprises the following steps:
the novel compound is prepared from the leaf and the bark of tulip tree by a conventional method in the field, and comprises the following steps: firstly taking two parts of tulip tree leaves and stems and barks as raw materials, crushing, soaking and extracting for 5 times at room temperature by using 90% methanol, concentrating an extracting solution, dispersing by using 3% tartaric acid aqueous solution, extracting for 5 times by using ethyl acetate with the same volume, and using Na as a water layer 2 CO 3 Regulating pH to about 9, extracting with chloroform for 5 times, wherein chloroform layer is total alkaloid fraction, and purifying chloroform extract with MCI resin, ODS reversed phase column, sephAnd performing dex LH-20 gel column chromatography and reversed-phase semi-preparative HPLC chromatographic separation to obtain 4 heteromer compounds shown in the formulas 1-4.
The anti-leukemia activity of the compounds 1-4 is tested, and the results show that the compounds have different degrees of inhibitory activity on four leukemia cells (leukemia Raji, jeko-1, daudi and Jurkat cells), so that the compounds can be applied to the preparation of medicines for treating or assisting in treating leukemia. In the present invention, the types of leukemias are especially Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphoblastic Leukemia (CLL)
The compounds 1-4 can be respectively and independently used or combined, or combined with a proper excipient, and prepared into oral or non-oral dosage forms according to a conventional method to be applied to preparing medicines for treating leukemia.
The invention has the following advantages: the present invention provides compounds 1-4 having novel chemical structures; the compounds 1-4 have remarkable anti-leukemia activity, can be used for further preparing medicines for treating leukemia, and have wide application prospects in the aspect of leukemia treatment.
Detailed Description
The invention is further illustrated by the following examples, which are in no way limiting. Any alterations in the practice of this invention that come within the scope of the claims will be within the purview of those skilled in the art in light of the present description.
Example 1:
6.3kg of tulip tree leaves and 3.2kg of bark are respectively soaked with 12L and 4L of 90% methanol for 24 hours at room temperature for 5 times. And combining the extracting solutions, and concentrating under reduced pressure to obtain 824.5g and 550.0g of total extract respectively. The obtained extract was dispersed in 1L of a 3% aqueous solution of tartaric acid, and the alkaloid component was dissolved in water, followed by extraction with ethyl acetate 5 times, to separate the non-alkaloid component (ethyl acetate layer). Then the aqueous layer is treated with Na 2 CO 3 The pH was adjusted to about 9, extraction was performed with chloroform for 5 times, the chloroform layers were combined, and concentrated under reduced pressure to give total alkaloid fraction A-L (15.7 g) and A-S (43.8 g), respectively. Preliminary segmentation and washing of alkaloid fraction with microporous resin (MCI)The stripping agent is methanol: water (from 3:10 to 1:0, v/v), A-L gives 10 components Fr.1-Fr.10, A-S gives 6 components Fr.1B-Fr.6B. Fr.6 was separated several times by a gel column (Sephadex LH-20) and an ODS reverse phase column (RP-C18) in this order, and then purified by semi-preparative HPLC to give Compound 3 (1.0 mg, t) R =22.8 min). Fr.3B and Fr.5B were separated by gel column and finally purified by semi-preparative HPLC. From the former, compound 4 (3.7 mg, t R =10.4 min), from which compound 2 (1.6 mg, t R =17.2 min) and compound 1 (0.8 mg, t R ＝14.6min)。
The compounds 1-4 are novel compounds, and the spectrum and physicochemical data are as follows:
compound 1: yellow amorphous powder;
Figure BDA0003415601510000031
(c 0.14,MeOH)；UV(MeOH)λ max (logε)232(4.38),286(3.57)nm；CD(MeOH)λ max (Δε)220(+25.2),270(+7.15)nm； 1 H NMR data(600MHz，CDCl 3 )：δ6.66(s,H-3),2.76(br dd,J＝16.7,4.7Hz,H-4α),2.85(ddd,J＝16.7,11.9,6.3Hz,H-4β),2.50(ddd,J＝12.3,11.9,4.7Hz,H-5α),3.11(br dd,J＝12.3,6.3Hz,H-5β),3.85(dd,J＝11.0,5.8Hz,H-6a),2.36(dd,J＝11.4,5.8Hz,H-7α),2.26(dd,J＝11.4,11.0Hz,H-7β),6.91(dd,J＝10.0,2.9Hz,H-8),6.43(dd,J＝10.0,1.6Hz,H-9),6.32(dd,J＝10.0,1.6Hz,H-11),7.07(dd,J＝10.0,2.9Hz,H-12),4.86(dd,J＝11.7,4.3Hz,H-1′),2.16(m,H-2′α),2.27(m,H-2′β),2.03(m,H-3′α),2.29(m,H-3′β),4.64(d,J＝9.4Hz,H-5′),4.76(dd,J＝9.4,9.3Hz,H-6′),2.94(ddd,J＝11.3,9.7,9.3Hz,H-7′),5.10(br dd,J＝9.8,9.7Hz,H-8′),2.32(dd,J＝12.3,9.8Hz,H-9′α),2.40(br d,J＝12.3Hz,H-9′β),2.57(br dd,J＝11.3,6.0Hz,H-11′),3.02(dd,J＝12.7,6.0Hz,H-13′),2.98(dd,J＝12.7Hz,H-13′),1.54(br s,Me-14′),1.70(br s,Me-15′),2.06(s,8′-OCOMe),3.63(s,OMe-1),3.83(s,OMe-2)ppm； 13 C NMR(150MHz,CDCl 3 ):δ144.3(C-1),132.7(C-1a),134.5(C-1b),153.4(C-2),111.5(C-3),128.1(C-3a),27.8(C-4),52.4(C-5),64.5(C-6a),48.3(C-7),50.9(C-7a),153.2(C-8),128.5(C-9),186.1(C-10),127.7(C-11),149.8(C-12),129.9(C-1′),25.3(C-2′),38.6(C-3′),141.6(C-4′),127.7(C-5′),78.4(C-6′),49.8(C-7′),73.8(C-8′),49.1(C-9′),132.1(C-10′),45.0(C-11′),177.8(C-12′),53.1(C-13′),16.7(C-14′),17.4(C-15′),21.4(C-8′-OCOMe),169.7(C-8′-OCOMe),61.1(C-1-OMe),56.3(C-2-OMe)ppm；(+)-HRESIMS:m/z 588.2950[M+H] + (calcd for C 35 H 42 NO 7 ,588.2956,Δ＝-1.0ppm).
compound 2: yellow amorphous powder;
Figure BDA0003415601510000041
(c 0.14,MeOH)；UV(MeOH)λ max (logε)236(4.30),286(3.43)nm；CD(MeOH)λ max (Δε)222(+25.1),270(+8.10)nm； 1 H-NMR data(600MHz，CDCl 3 )：δ6.62(s,H-3),2.83(ddd,J＝16.4,3.8Hz,H-4α),3.05(ddd,J＝16.4,11.5,5.8Hz,H-4β),2.98(ddd,J＝11.6,11.5,3.8Hz,H-5α),3.17(br dd,J＝11.6,5.8Hz,H-5β),4.00(dd,J＝8.4,8.3Hz,H-6a),2.47(br d,J＝8.3Hz,H-7α),2.47(br d,J＝8.4Hz,H-7β),6.89(dd,J＝10.0,2.8Hz,H-8),6.42(dd,J＝10.0,1.7Hz,H-9),6.32(dd,J＝10.0,1.7Hz,H-11),7.01(dd,J＝10.0,2.8Hz,H-12),4.84(dd,J＝11.6,4.2Hz,H-1′),2.18(m,H-2′α),2.24(m,H-2′β),2.01(ddd,J＝12.0,11.7,5.6Hz H-3′α),2.32(br d,J＝12.0Hz,H-3′β),4.65(d,J＝9.4Hz,H-5′),4.73(dd,J＝9.4,9.3Hz,H-6′),2.22(ddd,J＝10.8,9.3,9.2Hz,H-7′),3.79(ddd,J＝9.6,9.2,1.8Hz,H-8′),2.25(dd,J＝13.2,9.6Hz,H-9′α),2.63(br d,J＝13.2Hz,H-9′β),2.93(ddd,J＝10.8,10.6,2.6Hz,H-11′),3.50(dd,J＝14.1,2.6Hz,H-13′),2.69(dd,J＝14.1,10.6Hz,H-13′),1.45(br s,Me-14′),1.67(br s,Me-15′),3.61(s,OMe-1),3.81(s,OMe-2)ppm； 13 C-NMR(150MHz,CDCl 3 ):δ144.7(C-1),132.5(C-1a),132.9(C-1b),153.8(C-2),111.7(C-3),126.8(C-3a),27.6(C-4),55.5(C-5),66.3(C-6a),47.4(C-7),51.0(C-7a),152.8(C-8),128.6(C-9),185.9(C-10),128.0(C-11),148.7(C-12),128.6(C-1′),25.3(C-2′),39.0(C-3′),141.2(C-4′),127.2(C-5′),78.3(C-6′),60.8(C-7′),70.7(C-8′),52.8(C-9′),134.2(C-10′),46.8(C-11′),175.5(C-12′),59.8(C-13′),17.1(C-14′),17.4(C-15′),61.0(C-1-OMe),56.3(C-2-OMe)ppm；(+)-HRESIMS:m/z 546.2851[M+H] + (calcd for C 33 H 40 NO 6 ,546.2850,Δ＝+0.2ppm).
compound 3: white amorphous powder;
Figure BDA0003415601510000042
(c 0.05,MeOH)；UV(MeOH)λ max (logε)216(4.78),278(4.30),300(4.25)nm；CD(MeOH)λ max (Δε)232(+17.6),266(-3.61)nm； 1 H-NMR data(600MHz，CD 3 OD)：δ6.69(s,H-3),3.13(m,H-4α),2.65(br d,J＝16.0Hz,H-4β),3.23(br dd,J＝11.6,5.1Hz,H-5α),2.33(ddd,J＝11.6,11.4,5.4Hz,H-5β),3.07(br d,J＝12.5Hz,H-6a),2.34(dd,J＝13.2,12.5Hz,H-7α),3.14(dd,J＝13.2,3.4Hz,H-7β),6.81(br s,H-8),7.95(br s,H-11),5.43(br d,J＝11.7Hz,H-1′),2.19(m,H-2′α),2.50(dddd,J＝13.2,12.6,11.7,5.6Hz,H-2′β),1.31(ddd,J＝13.0,12.6,6.6Hz,H-3′α),2.13(br dd,J＝13.0,5.6Hz,H-3′β),3.06(d,J＝9.1Hz,H-5′),4.38(dd,J＝9.1,9.1Hz,H-6′),2.78(br dd,J＝10.8,9.1Hz,H-7′),5.91(br d,J＝6.0Hz,H-8′),2.30(br d,J＝14.0Hz,H-9′α),2.53(dd,J＝14.0,6.0Hz,H-9′β),3.12(ddd,J＝10.8,10.8,3.7Hz,H-11′),3.26(dd,J＝12.8,10.8Hz,H-13′),2.77(dd,J＝12.8,3.7Hz,H-13′),1.75(br s,Me-14′),1.36(s,Me-15′),2.13(s,8′-OCOMe),3.64(s,OMe-1),3.87(s,OMe-2),3.88(s,OMe-10)ppm； 13 C-NMR(150MHz,CD 3 OD):δ145.3(C-1),128.6(C-1a),130.8(C-1b),153.3(C-2),111.6(C-3),128.7(C-3a),29.9(C-4),50.0(C-5),62.2(C-6a),36.0(C-7),131.6(C-7a),115.8(C-8),147.1(C-9),147.6(C-10),113.2(C-11),124.8(C-11a),129.0(C-1′),25.0(C-2′),37.3(C-3′),63.5(C-4′),68.3(C-5′),77.8(C-6′),53.6(C-7′),75.9(C-8′),44.3(C-9′),132.9(C-10′),43.0(C-11′),178.3(C-12′),57.2(C-13′),20.3(C-14′),17.2(C-15′),21.1(C-8′-OCOMe),172.1(C-8′-OCOMe),60.4(C-1-OMe),56.3(C-2-OMe),56.6(C-3-OMe)ppm；(+)-HRESIMS:m/z 634.3016[M+H] + (calcd for C 36 H 44 NO 9 ,634.3011,Δ＝+0.8ppm).
compound 4: yellow oily;
Figure BDA0003415601510000051
(c 0.42,MeOH)；UV(MeOH)λ max (logε)206(4.76),278(3.60)nm；CD(MeOH)λ max (Δε)207(-37.1),223(+27.3),279(+1.86)nm； 1 H-NMR data(600MHz，CDCl 3 )：δ6.75(d,J＝8.3Hz,H-2),6.66(d,J＝8.3Hz,H-3),3.10(m,H-4α),2.45(ddd,J＝16.3,6.6,2.9Hz,H-4β),3.51(ddd,J＝16.3,12.5,2.9Hz,H-5α),3.11(ddd,J＝16.3,6.6,6.3Hz,H-5β),4.19(dd,J＝11.3,2.6Hz,H-6a),2.91(dd,J＝14.0,2.6Hz,H-7),2.81(dd,J＝14.0,11.3Hz,H-7),7.30(br d,J＝8.3Hz,H-8),6.83(br d,J＝8.3Hz,H-9),6.83(br d,J＝8.3Hz,H-11),7.30(br d,J＝8.3Hz,H-12),4.77(dd,J＝11.1,5.0Hz,H-1′),2.19(m,H-2′α),2.14(m,H-2′β),2.14(m,H-3′α),2.24(m,H-3′β),4.11(d,J＝9.6Hz,H-5′),4.40(dd,J＝9.6,9.5Hz,H-6′),2.13(m,H-7′),4.89(ddd,J＝10.3,10.2,1.8Hz,H-8′),2.07(dd,J＝12.8,10.3Hz,H-9′α),2.29(br d,J＝12.8Hz,H-9′β),2.24(m,H-11′),3.35(dd,J＝14.4,1.6Hz,H-13′),2.64(dd,J＝14.4,3.7Hz,H-13′),1.40(br s,Me-14′),1.60(br s,Me-15′),1.79(s,8′-OCOMe),3.89(s,OMe-2)ppm； 13 C-NMR(150MHz,CDCl 3 ):δ143.7(C-1),142.5(C-1a),125.3(C-1b),109.0(C-2),119.9(C-3),128.0(C-3a),21.5(C-4),43.1(C-5),60.4(C-6a),38.8(C-7),133.3(C-7a),131.4(C-8),115.1(C-9),153.9(C-10),115.1(C-11),131.4(C-12),130.0(C-1′),25.6(C-2′),38.6(C-3′),140.5(C-4′),127.0(C-5′),77.7(C-6′),48.6(C-7′),74.2(C-8′),47.9(C-9′),132.6(C-10′),48.5(C-11′),177.8(C-12′),50.2(C-13′),16.4(C-14′),17.2(C-15′),20.8(C-8′-OCOMe),169.8(C-8′-OCOMe),56.1(C-1-OMe)ppm；(+)-HRESIMS:m/z 576.2951[M+H] + (calcd for C 34 H 42 NO 7 ,576.2956,Δ＝-0.8ppm).。
example 2: anti-leukemia Activity test
Leukemia Raji, jeko-1, daudi and Jurkat cells were purchased from the China academy of sciences cell bank; the culture medium was supplemented with 10% (v/v) Fetal Bovine Serum (FBS) (Jurkat cells were supplemented with 20% FBS),RMPI-1640 medium with 1% penicillin double antibody and 1% sodium pyruvate; at 37 ℃,5% CO 2 Incubating in the environment. Four cells were individually seeded in 96-well plates (seeding density: raji: 5X 10) 4 mu.L/80; daudi: 6.25X10 4 mu.L/80; jeko-1: 6.25X10 4 mu.L/80; jurkat: 6.25X10 4 mu.L/80. Mu.L) were cultured overnight. The next day, 10mM compound stock solution in DMSO was diluted 5 times the final concentration to 20. Mu.L of complete medium, and 20. Mu.L of drug-containing medium was added to 80. Mu.L of cell suspension and mixed well. After incubation for 24h and 48h in the cell incubator, 10. Mu.L of CCK-8 solution was added to each well, incubation was continued for 3h, and finally absorbance at 450nm was measured for each well. All experimental results were statistically analyzed using GraphPad Prism 7.00 software (IBM corporation). Mean ± standard deviation (Mean ± SD) represents quantitative data, the comparison of rates uses chi-square test, the comparison of Mean uses t-test, IC 50 Calculation use of "[ Inhibitor ]]vs normalized response-Variable slope "model, p<0.05 indicates that the difference is statistically significant. The positive controls, parthenolide and STS, were tested as shown in table 1:
TABLE 1 cytotoxic Effect of the tested compounds on four leukemia cells
Figure BDA0003415601510000061
a IC 50 value of each compound was defined as the concentrationμM of indicated compound that caused 50％inhibition of cell growth.
b positive controls.
The compounds 1-4 have remarkable anti-leukemia activity.

Claims (5)

1. The sesquiterpene-alkaloid heteropolymer is characterized in that the heteropolymer system is formed by combining germacrane sesquiterpene lactone and aporphine alkaloid, and the structure is shown as a formula 1-a formula 4;
Figure FDA0003415601500000011
2. the sesquiterpene-alkaloid oligomer according to claim 1, prepared by the following method:
pulverizing leaf and bark of tulip tree, soaking in 90% methanol at room temperature for 5 times, concentrating the extractive solution, dispersing with 3% tartaric acid aqueous solution, extracting with equal volume of ethyl acetate for 5 times, and collecting water layer with Na 2 CO 3 Adjusting pH to 9, extracting with chloroform for 5 times, wherein chloroform layer is total alkaloid fraction, and separating chloroform extract by MCI resin, ODS, sephadex LH-20 gel column chromatography and reversed phase semi-preparative HPLC chromatography to obtain 4 hetero polymers shown in formula 1-4.
3. Use of a sesquiterpene-alkaloid heteromer according to claim 1 for the preparation of a medicament for the treatment of leukemias, wherein the types of leukemias comprise Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphoblastic Leukemia (CLL).
4. The use according to claim 3, wherein the sesquiterpene-alkaloid heteromers are used individually or in combination for the preparation of an anti-leukemia drug.
5. The use according to claim 3 or 4, wherein the sesquiterpene-alkaloid oligomer is formulated into an oral or non-oral dosage form in combination with a pharmaceutically acceptable carrier or excipient.
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