CN109761995B - Plectranthin diterpene amino acid ester derivative and preparation method and application thereof - Google Patents
Plectranthin diterpene amino acid ester derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of natural medicines and medicinal chemistry, and relates to plectranthin diterpene amino acid ester derivatives, and a preparation method and application thereof. In particular to a 14-hydroxy split amino acid derivative of plectranthin diterpene, a preparation method thereof and application thereof in preparing anti-tumor drugs. The plectranthin diterpene derivative and the pharmaceutically acceptable salt thereof are shown in a general formula I. Wherein R is as described in the claims and specification.
Description
Technical Field
The invention relates to the field of natural medicines and medicinal chemistry, and relates to plectranthin diterpene amino acid ester derivatives, and a preparation method and application thereof. In particular to a derivative of 14-position hydroxyl of plectranthin diterpene and amino acid in ester. Also relates to a preparation method of the 14-hydroxy-spliced amino acid derivatives of the plectranthin diterpene and application of the plectranthin diterpene in preparation of antitumor drugs.
Background
Enmeicin (enmein) is a natural organic compound of kaurane diterpenoid (ent-kaurane diterpenoid) separated from a plant of Rabdosia (Rabdosia) in Labiatae, in 1958, Takshashi and the like firstly obtain enmein from Rabdosia japonica (Rabdosia japonica), in 1966, Natsume and the like determine the three-dimensional structure of enmein by using an X-ray diffraction method, and the complex structure attracts the eyes of chemists and pharmacologists.
Amino acids play an irreplaceable role due to structural diversity, unique acidity and basicity and optical activity.
The invention takes plectranthin diterpene as a lead compound, utilizes the splicing principle to connect different types of amino acids to 14-hydroxy of the molecular structure of the plectranthin diterpene, and designs and synthesizes the plectranthin diterpene amino acid ester derivative with the general formula I.
Disclosure of Invention
The invention aims to solve the technical problem of finding plectranthin diterpene amino acid ester derivatives with good antitumor activity and further providing a pharmaceutical composition containing the derivatives, wherein the plectranthin diterpene amino acid ester derivatives or the composition thereof have antitumor effect.
In order to solve the technical problems, the invention provides the following technical scheme:
plectranthin diterpene amino acid ester derivatives and isomers shown in a general formula I and pharmaceutically acceptable salts thereof:
wherein R is H, substituted or unsubstituted C1-C4An alkyl group, the substituent being a 5-6 membered heteroaryl group, a 5-6 membered aryl group, or a 5-6 membered aromatic or heteroaromatic ring and a 5-6 membered aromatic or heteroaromatic ring,
the heteroaryl group contains 1-3 heteroatoms of N, O or S.
The invention preferably selects plectranthin diterpene amino acid ester derivatives, isomers and pharmaceutically acceptable salts thereof shown in the general formula I:
wherein R is H, substituted or unsubstituted C1-C4An alkyl group, the substituent being a 5-6 membered heteroaryl, phenyl or indolyl group,
said heteroaryl group containing2N atoms.
The invention preferably selects plectranthin diterpene amino acid ester derivatives, isomers and pharmaceutically acceptable salts thereof shown in the general formula I:
wherein R is
The invention preferably selects plectranthin diterpene amino acid ester derivatives, isomers and pharmaceutically acceptable salts thereof shown in the general formula I:
wherein R is
The invention preferably selects plectranthin diterpene amino acid ester derivatives, isomers and pharmaceutically acceptable salts thereof shown in the general formula I:
wherein R is
The following derivatives, isomers and pharmaceutically acceptable salts thereof are preferred in the present invention:
the derivative of the general formula I can be prepared by the following method:
dissolving rubescensine A1 in water, reacting with sodium periodate at room temperature to obtain plectranthin type derivative 2, dissolving 2 in acetone, and reacting with Jones reagent to obtain 6-position oxidized derivative 3.
Dissolving the 6-position oxidized derivative 3 in Dichloromethane (DCM), and reacting with tert-butyloxycarbonyl (Boc) -L-amino acid or Boc-D-amino acid 4 respectively under EDCI/DMAP condition at room temperature to obtain plectranthin diterpene-Boc-amino acid ester derivative 5.
The plectranthin diterpene-Boc-amino acid ester derivative 5 is reacted under the condition of DCM/trifluoroacetic acid (TFA), and the Boc protecting group is removed to obtain the target compound 6.
The plectranthin diterpene base acid ester derivative or the composition thereof has obvious antitumor activity and can be used for preparing antitumor drugs, and the tumor can be breast cancer, liver cancer, gastric cancer, prostatic cancer, lung cancer or leukemia.
Detailed Description
Example 1
Isomeicine type mother nucleus 3(52mg, 0.14mmol) was weighed, dissolved in DCM (5mL), and N-Boc-glycine (40mg, 0.23mmol), EDCI (62mg, 0.32mmol), DMAP (9mg, 0.07mmol) were sequentially added thereto, the reaction was stirred at room temperature, the progress of the reaction was monitored by TCL, and the reaction was terminated after 8 hours. The reaction was poured into 20mL of ice-water mixture, extracted with DCM (30 mL. times.3), washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product 5, which was taken directly as intermediate 5(70 mg) without purification0.14mmol) was dissolved in DCM (3mL), 100. mu.L of TFA was added under ice-bath conditions, the reaction was stirred at room temperature, the progress of the reaction was monitored by TCL, and the reaction was terminated after 8 h. The reaction solution was poured into an ice-water mixture, and then a saturated sodium bicarbonate solution was added to adjust the pH to 8 to 9, and the mixture was extracted with DCM (30mL × 3), washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated by silica gel column chromatography (dichloromethane: methanol ═ 60: 1) to obtain compound 6 as a yellow powder with a yield of 17%. HRMS (ESI) m/z calcd for C22H28NO7[M+H]+418.1860,found 418.1821.1H NMR(CD3OD,400MHz)δ6.21(s,1H,14-CH),6.04(s,1H,17-CH2),5.73(s,1H,17-CH2),4.85(m,1H,1-CH),4.48(d,J＝10.11Hz,1H,20-CH2),3.89(d,J＝10.11Hz,1H,20-CH2),3.84(d,J＝17.50Hz,1H,-CH2NH2),3.71(d,J＝17.50Hz，1H,-CH2NH2),3.34(d，J＝7.78Hz,1H,13-CH),2.64(m,1H,-CH2),2.37(s,1H,10-CH),2.22(m,1H,8-CH),1.52-2.01(m,7H,-CH2),1.19(s，3H，18-CH3)，1.06(s，3H，19-CH3).13C NMR(CD3OD,100MHz)δ198.97,177.25,169.18,168.26，148.98,122.21,77.35,76.38,72.27,61.45,51.94,48.12,41.76,40.96,36.92，33.94,32.30,30.80,24.04，23.93，19.66,18.37。
Example 2
Prepared according to the synthesis method of example 1. Yellow powder, yield 37%. HRMS (ESI) m/z calcd for C23H30NO7[M+H]+432.2017,found 432.1945.1H NMR(CD3OD,400MHz)δ6.22(s,1H,14-CH),5.99(s,1H,17-CH2),5.74(s,1H,17-CH2),4.85(m,1H,1-CH),4.48(d,J＝10.08Hz,1H,20-CH2),4.00(q,1H,CH3CHNH2),3.90(d,J＝10.08Hz,1H,20-CH2),3.34(d,J＝9.53Hz,1H,13-CH),2.64(m,1H,-CH2),2.37(s,1H，10-CH),2.23(m,1H,8-CH),1.52-2.01(m,7H,-CH2),1.46(d,J＝7.24Hz,3H,CH3CHNH2),1.19(s,3H,18-CH3),1.06(s,3H,19-CH3).13C NMR(CD3OD,100MHz)δ199.01,177.25,170.39,169.07,148.94,122.22,77.39,76.40,72.27,61.38,51.93,49.73,48.12,41.73,36.91,33.94,32.30,30.75,27.71,24.03,23.94,19.66,15.93。
Example 3
Prepared according to the synthesis method of example 1. Yellow powder, yield 15%. HRMS (ESI) m/z calcd for C31H35N2O7[M+H]+547.2439,found 547.2272.1H NMR(CD3OD,400MHz)δ7.48(m,1H,Ar-H),7.41(m,1H,Ar-H),7.19(s,1H,Ar-NH-CH),7.15(m,1H,Ar-H),7.08(m,1H,Ar-H),6.04(s,1H,14-CH),5.78(s,1H,17-CH2),5.43(s,1H,17-CH2),4.80(m,1H,1-CH)，4.44(d，J＝10.08Hz，1H，20-CH2),4.18(m,1H，-CHNH2),3.85(d,J＝10.08Hz,1H,20-CH2)，3.32(m，1H，-CH2),2.48(d,J＝9.46Hz,1H,13-CH),2.41(m,1H,-CH2),2.33(s,1H,10-CH),2.13(m,1H,8-CH),1.50-2.33(m,8H,-CH2),1.17(s,3H,18-CH3),1.03(s,3H,19-CH3).13C NMR(CD3OD,100MHz)δ198.89,177.23,170.18,169.18,148.56,138.14,128.36,125.48,122.95,122.03,120.34,118.77，112.73，107.75，77.24，76.40，72.23，61.38，54.61，51.89,48.04,41.26,36.86，33.91,32.27,30.55,27.81,27.70,23.99,23.91,19.51。
Example 4
Prepared according to the synthesis method of example 1. Yellow powder, yield 73%. HRMS (ESI) m/z calcd for C31H34N2O7Na[M+Na]+569.2258,found 569.2130.1H NMR(CD3OD,400MHz)δ7.51(m,1H,Ar-H),7.38(m,1H,Ar-H),7.19(s,1H,Ar-NH-CH),7.14(m,1H,Ar-H),7.05(m,1H,Ar-H),6.21(s,1H,14-CH)，5.94(s，1H，17-CH2)，5.64(s，1H,17-CH2),4.85(m，1H,1-CH),4.46(d,J＝10.08Hz,1H,20-CH2),4.26(m,1H,-CHNH2),3.92(d,J＝10.08Hz,1H,20-CH2),3.42(m,1H,-CH2),3.21(d,J＝9.45Hz,1H,13-CH),3.14(m，1H,-CH2),2.58(m,1H,-CH2),2.36(s,1H,10-CH),2.23(m,1H,8-CH),1.45-2.01(m,7H,-CH2),1.18(s,3H,18-CH3),1.04(s，3H,19-CH3).13C NMR(CD3OD，100MHz)δ199.29，177.30，169.95，168.70，148.74,138.33,127.91,125.93,122.89，122.39，120.27，118.73，112.70，107.78，77.40，76.32，72.33，61.31，54.38，51.91，48.19，41.74，36.87，33.92,32.30,30.65,27.70,27.59,24.05,23.94,19.62。
Example 5
Prepared according to the synthesis method of example 1. Yellow powder, yield 60%. HRMS (ESI) m/z calcd for C29H33NO7Na[M+Na]+530.2149,found 530.2085.1H NMR(CD3OD,400MHz)δ7.36(m,1H,Ar-H),7.32(m,2H,Ar-H),7.23(m,2H,Ar-H),6.12(s,1H,14-CH),5.93(s,1H,17-CH2),5.61(s,1H,17-CH2),4.83(m,1H,1-CH),4.45(d,J＝10.08Hz,1H,20-CH2),4.23(t,1H,-CHNH2),3.88(d,J＝10.08Hz,1H,20-CH2),3.14(d,J＝7.32Hz,2H,Ar-CH2),3.02(d,J＝9.39Hz,1H,13-CH),2.58(m,1H,-CH2),2.36(s,1H,10-CH),2.19(m,1H,8-CH),1.47-2.36(m,7H,-CH2),1.18(s,3H,18-CH3),1.05(s,3H,19-CH3).13C NMR(CD3OD,100MHz)δ198.91,177.22,169.57,169.14,148.60,135.31,130.39(×2),130.12(×2),128.94,122.39,77.37,76.41,72.25,61.36,54.88,51.89,48.05,41.55,37.38,36.85,33.92,32.29,30.63,27.70,23.99,23.94,19.58。
Example 6
Prepared according to the synthesis method of example 1. Yellow powder, yield 77%. HRMS (ESI) m/z calcd for C29H34NO7[M+H]+508.2330,found 508.2273.1H NMR(CD3OD,400MHz)δ7.25-7.34(m,5H,Ar-H),6.17(s,1H,14-CH),5.96(s,1H,17-CH2),5.65(s,1H,17-CH2),4.87(m,1H,1-CH),4.48(d,J＝10.10Hz,1H,20-CH2),4.28(m,1H,-CHNH2),3.92(d,J＝10.10Hz,1H,20-CH2),3.24(m,2H,Ar-CH2),2.95(m,1H,13-CH),2.62(m,1H,-CH2),2.37(s,1H,10-CH),2.24(m,1H,8-CH),1.49-2.08(m,7H,-CH2),1.19(s,3H,18-CH3),1.05(s,3H,19-CH3).13C NMR(CD3OD,100MHz)δ199.14,177.27,169.83,168.68,148.57,135.74,130.34(×2),130.11(×2),128.73,122.47,77.48,76.30,72.33,61.28,55.11,51.91,48.20,41.73,36.93,36.87,33.93,32.30,30.73,27.70,24.05,23.95,19.62。
Pharmacological test
Experimental equipment and reagent
Instrument clean bench (Sujing group Antai company)
Constant temperature incubator (Thermo electronic Corporation)
Enzyme-linked immunosorbent assay (BIO-RAD company)
Inverted biological microscope (Chongqing optical instrument factory)
Reagent cell culture Medium RPMI-1640, DMEM (high sugar) (GIBCO Co., Ltd.)
Fetal bovine serum (Hangzhou Sijiqing Co., Ltd.)
CCK-8(Biosharp company product)
Trypan blue (Solarbio company product)
DMSO (Sigma Co.)
Cell line human breast cancer cell line MCF-7, human liver cancer cell line Bel-7402, human stomach
Cancer cell line SGC-7901, human acute promyelocytic leukemia cell HL-60,
Human prostate cancer cell PC-3, human lung adenocarcinoma cell A-549, and human chronic marrow
Leukemia cell line K562 and human normal liver cell L-02
Experimental methods
Cell inhibitory activity test method
Cells were incubated at 37 ℃ with 5% CO2Culturing in an incubator with saturated humidity. The culture medium is RPMI1640 cell culture medium containing 10% heat-inactivated fetal calf serum, penicillin 100U/mL and streptomycin 100U/mL. The culture medium was changed for 48h, and after the cells were attached to the wall, they were digested with 0.25% trypsin for passage. The experimental cells are all in logarithmic growth phase, and trypan blue dye exclusion method shows cell viability>95％。
Taking a bottle of cells in a logarithmic phase, adding a digestive juice (0.125% trypsin and 0.01% EDTA) for digestion, and counting by 2-4 × 104cell/mL, preparing cell suspension, inoculating on 96-well plate, 100 μ L/well, and placing in constant temperature CO2The culture was carried out in an incubator for 24 hours. The solution was changed, the test drug was added at 100. mu.L/well, and cultured for 72 hours. CCK-8 was added to 96-well plates at 50. mu.L/well and incubated in an incubator for 4 hours. The supernatant was aspirated, DMSO was added at 200. mu.L/well and shaken on a shaker for 10 min. The test substances were examined at 6 concentrations of 0.001 to 100. mu.M in ten-fold increments, and the cell inhibition rate at each concentration was calculated by measuring the absorbance of each well at a wavelength of 450nm using an enzyme-linked immunosorbent assay.
The inhibition rate calculation method comprises the following steps:
relative OD value of drug sensitive well (absolute OD value of drug sensitive well) — absolute OD value of blank control well
Results of the experiment
Table 1 examples of 7 human cancer cell lines and 1 human normal cellIC with antiproliferative activity50Value (μ M)
NT: not tested.
Pharmacological tests prove that the plectranthin diterpene amino acid ester derivative has better anti-tumor cell proliferation activity, the activity is stronger than that of the plectranthin mother nucleus, and the plectranthin diterpene amino acid ester derivative has unexpected growth inhibition effect on certain tumor cell lines. And has certain selectivity on tumor cells and normal cells, and can be used for further preparing antitumor drugs.
Claims (8)
1. Plectranthin diterpene amino acid ester derivatives and isomers shown in a general formula I and pharmaceutically acceptable salts thereof:
wherein R is substituted C1-C4An alkyl group, the substituent is phenyl or indolyl,
。
2. the plectranthin-type diterpene amino acid ester derivative, isomer and pharmaceutically acceptable salt thereof of claim 1, of the general formula I:
wherein R is
、
、
、
、
、
。
3. The plectranthin diterpene amino acid ester derivatives and pharmaceutically acceptable salts thereof are selected from the following:
4. a pharmaceutical composition comprising a therapeutically effective amount of the plectranthin-type diterpene amino acid ester derivative, isomer and pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
5. The process for preparing plectranthin-type diterpene amino acid ester derivatives and pharmaceutically acceptable salts thereof according to claim 1, which is characterized in that:
dissolving rubescensine A1 in water, reacting with sodium periodate at room temperature to obtain an plectranthin type derivative 2, dissolving 2 in acetone, and reacting with Jones reagent to obtain a 6-site oxidized plectranthin type derivative 3;
dissolving the 6-position oxidation plectranthin type derivative 3 in dichloromethane, and reacting with tert-butyloxycarbonyl (Boc) -L-amino acid or Boc-D-amino acid 4 at room temperature under EDCI/DMAP condition to obtain a 6-oxidation plectranthin type-Boc-amino acid ester derivative 5;
and (3) reacting the 6-oxo-plectranthin type-Boc-amino acid ester derivative 5 under the condition of DCM/TFA (trifluoroacetic acid) at low temperature, and removing the Boc protecting group to obtain a target compound 6:
the amino acid is glycine;
wherein R is as defined in claim 1.
6. Use of the plectranthin-type diterpene amino acid ester derivative, isomer and pharmaceutically acceptable salt thereof according to any one of claims 1-3 for the manufacture of a medicament for the treatment of neoplastic diseases.
7. Use of the pharmaceutical composition of claim 4 for the preparation of a medicament for the treatment of a neoplastic disease.
8. The use of claim 6 or 7, wherein the tumor is breast cancer, liver cancer, stomach cancer, prostate cancer, lung cancer or leukemia.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295649A (en) * | 2011-08-31 | 2011-12-28 | 中国药科大学 | Oridonin with antitumor resistance activity, 6,7-open ring oridonin fluorine-containing derivative, preparation method and application |
| CN104017000A (en) * | 2013-03-01 | 2014-09-03 | 江苏恒瑞医药股份有限公司 | L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof |
| CN106749305A (en) * | 2016-11-16 | 2017-05-31 | 中国药科大学 | Oridonin derivative, the Preparation Method And The Use of A- rings transformation |
-
2019
- 2019-03-01 CN CN201910154628.XA patent/CN109761995B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295649A (en) * | 2011-08-31 | 2011-12-28 | 中国药科大学 | Oridonin with antitumor resistance activity, 6,7-open ring oridonin fluorine-containing derivative, preparation method and application |
| CN104017000A (en) * | 2013-03-01 | 2014-09-03 | 江苏恒瑞医药股份有限公司 | L-alanine-(14-oridonin) ester trifluoroacetate as well as preparation method and application thereof |
| CN106749305A (en) * | 2016-11-16 | 2017-05-31 | 中国药科大学 | Oridonin derivative, the Preparation Method And The Use of A- rings transformation |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis and biological evaluation of novel 1-O- and 14-O-derivatives of oridonin as potential anticancer drug candidates;Jinyi Xu;《Bioorganic & Medicinal Chemistry Letters》;20080703;第18卷;摘要，第4743页化合物IIa，IId * |
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