CN115181112A - Synthesis of 6-bromocyclo-icaritin chromane 3, 4-diketone derivative and anti-tumor application thereof - Google Patents
Synthesis of 6-bromocyclo-icaritin chromane 3, 4-diketone derivative and anti-tumor application thereof Download PDFInfo
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Abstract
Synthesis of 6-bromocyclo-icaritin chromane 3, 4-diketone derivatives and anti-tumor application thereof. The application discloses a 6-bromocyclo-icaritin chromane 3, 4-diketone derivative with a structural formula shown in a formula I,
the invention designs and synthesizes a 6-bromo-ring icaritin chromane 3, 4-diketone derivative shown as I, which is obtained by taking ring icaritin as a starting material, reacting the starting material with various suitable alcohols under the action of a suitable brominating reagent at a suitable reaction temperature for a certain time, and synthesizing the derivative with a moderate yield, wherein R is selected from alkenyl, alkynyl, alicyclic group and substituted or unsubstituted benzyl, and the derivative is obtained by reacting the ring icaritin with various suitable alcohols at a suitable reaction temperature for a certain time and has a structure which is synthesized by 1 H NMR、 13 C NMR, HRMS. The synthesis method has mild conditions and is easy to implement and operate. Synthesized by the inventionThe 6-bromocyclo-icaritin chromane 3, 4-diketone derivative shows good anticancer activity on HepG2 and MCF-7 cell lines in vitro.
Description
Technical Field
The invention belongs to the field of new drug design and synthesis, and particularly relates to synthesis of 6-bromocyclo-icaritin chromane 3, 4-diketone derivatives and antitumor application thereof.
Background
Icariin is one of flavonoid compounds, and has various pharmacological and biological activities, such as neuroprotective effect, osteogenic differentiation promotion, osteoclast differentiation inhibition, and antitumor activity.
Halogenation is a classical organic chemical reaction, and a halogen group is used as a good pharmacodynamic group, so that lipophilicity of a drug molecule can be effectively changed, and drug activity can be increased. For the reasons described above, the applicant designed: a halogen group is introduced into the C-6 position of the icaritin by utilizing bromination reaction so as to improve the lipophilicity of the icaritin. Accordingly, a series of novel 6-bromoicaritin chromane 3, 4-diketone derivatives are synthesized and prepared.
Disclosure of Invention
Aiming at the defects of the prior art, the invention researches and designs a series of novel 6-bromoicaritin chroman 3, 4-diketone derivatives, and the activity research shows that the novel derivatives have better inhibiting effect on liver cancer and breast cancer.
One of the purposes of the invention is to provide a 6-bromocyclo-icaritin chromane 3, 4-diketone derivative, the structural formula of which is shown in a formula I,
wherein R is selected from saturated alkyl or substituted alkyl.
Preferably, the 6-bromo cyclo-icaritin chromane 3, 4-diketone derivative I and R are selected from C1-C5 saturated alkyl or benzyl.
On the other hand, the invention provides a synthetic method of the 6-bromocyclo-icaritin chromane 3, 4-diketone derivative I, and the synthetic route is as follows:
the method specifically comprises the following steps: cycloicaritin is taken as a raw material and reacts with a bromination reagent under proper alcohol reagent and proper conditions to obtain the 6-bromo-cycloicaritin chromane 3, 4-diketone derivative I.
The synthesis method of the 6-bromocyclo-icaritin chromane 3, 4-diketone derivative I is as above, wherein the bromination reagent is selected from N-bromosuccinimide (NBS for short) and liquid bromine (Br for short) 2 ) Hydrobromic acid (HBr), naBr/H 2 O 2 NBS/AIBN or alpha, beta-dibromocinnamic acid; preferably NBS.
A method of synthesis of I as described above, wherein the suitable alcohol is selected from the group consisting of saturated alkyl alcohols or substituted alkyl alcohols; preferably, the alkyl or benzyl alcohol is a C1-C5 saturated alkyl alcohol.
The synthesis method of I, wherein the appropriate conditions comprise a reaction time of 1-48 hours, a reaction temperature of 0 ℃ to the reflux temperature of the used alcohol reagent; preferably, the reaction time is 2 to 6 hours and the reaction temperature is 0 ℃ to room temperature.
The method for synthesizing I, wherein the appropriate conditions further comprise the reaction of cyclic icaritin: the molar ratio of the bromination reagent is 1-1: the molar ratio of the alcohol reagent is 1:100.
furthermore, the invention also provides the application of the 6-bromocyclo-icaritin chromane 3, 4-diketone derivative in the preparation of antitumor drugs. Preferably, in particular to the application in preparing two antitumor drugs of human liver cancer and human breast cancer.
The invention has the beneficial effects that: the raw materials, reagents and solvents adopted in the synthesis method are cheap and easy to obtain; the synthesis method has mild conditions and is easy to implement and operate. The 6-bromoicaritin chromane 3, 4-diketone derivative synthesized by the invention has better inhibiting effect on HepG2 and MCF-7 tumor cells.
Detailed Description
The following is further detailed by way of specific embodiments:
in the examples described below, unless otherwise indicated, the test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown in the above were all obtained by commercially available methods.
EXAMPLE 1 preparation of Compounds Ia-j
(1) 6-bromoepimediumPreparation of crochroman 3, 4-diketones (Ia)
Cycloicaritin (50mg, 0.135mmol) and methanol (2 mL) were added to a round bottom flask under nitrogen. The mixture was then cooled to 0 ℃ and NBS (48mg, 2eq.) was added portionwise. The reaction mixture was then warmed to room temperature and stirred for 4 hours. Upon disappearance of the starting material, the reaction solvent was concentrated under reduced pressure by TLC. Adding CH into the residue 2 Cl 2 (10 mL) and water (2 mL) to dilute the mixture. The organic phase is extracted and separated, and dried by magnesium sulfate. The use of petroleum ether: ethyl acetate =6: the residue was purified by column chromatography on a elution machine 1 to give the title compound Ia in 65% yield as a pale yellow solid. M.p.149.5-150.2 deg.C, R f =0.34 (petroleum ether: ethyl acetate = 2. 1 H NMR(400MHz,CDCl 3 )δ＝11.30(s,1H),7.67(dd,J＝18.7,8.7Hz,2H),6.98(dd,J＝14.6,8.8Hz,2H),4.71(d,J＝49.1Hz,1H),3.84(dd,J＝4.3,1.4Hz,3H),3.06(s,1H),3.01(s,3H),2.89–2.77(m,1H),2.71–2.63(m,1H),1.87(q,J＝6.9Hz,2H),1.42(s,6H)。 13 C NMR(100MHz,CDCl 3 ) δ:192.33,160.39,160.10,157.44,154.08,129.97,129.76,125.16,113.80,113.31,106.12,102.97,99.77,92.87,55.26,50.51,50.11,31.59,27.27,26.36,16.41.HRMS-ESI (m/z) with molecular formula C 22 H 21 BrO 7 Na，[M+Na] + Calculated 499.0363 and measured 499.0362.
(2) Preparation of Compound Ib
Referring to the above synthesis procedure, using ethanol as the reagent and solvent, compound Ib was obtained in 67% yield as a pale yellow solid. M.p.153.5-154 deg.C, R f =0.45 (petroleum ether: ethyl acetate =2, 1 H NMR(400MHz,CDCl 3 )δ＝11.31(s,1H),7.68(dd,J＝18.4,8.8Hz,2H),7.02–6.90(m,2H),3.84(d,J＝5.2Hz,3H),3.43–3.32(m,1H),3.24–3.10(m,1H),3.01(s,1H),2.81(ddt,J＝16.8,8.2,6.4Hz,1H),2.63(dq,J＝17.4,6.1Hz,1H),1.87(dt,J＝13.3,6.5Hz,1H),1.46–1.34(m,6H),0.97(dt,J＝11.6,7.1Hz,3H)。 13 C NMR(100MHz,CDCl 3 ) δ =191.47,160.77,160.14,157.58,154.25,129.82,124.71,113.70,106.37,102.93,99.64,91.93,89.76,59.72,55.34,31.56,27.24,26.31,16.46,14.98.HRMS-ESI (m/z) with molecular formula C 23 H 23 BrO 7 Na，[M+Na] + The calculated value is 513.0519, and the measured value is 513.0519.
(3) Preparation of Compound Ic
Referring to the above synthetic procedure, using propanol as the reagent and solvent, compound Ic was obtained in 61% yield as a pale yellow solid, M.p.163-164 ℃ R f =0.5 (petroleum ether: ethyl acetate = 2. 1 H NMR(400MHz,CDCl 3 )δ11.31(s,1H),7.69(d,J＝8.7Hz,2H),6.98(d,J＝8.6Hz,2H),3.84(s,3H),3.31(dt,J＝9.3,6.6Hz,1H),3.06(dt,J＝9.3,6.8Hz,1H),2.78(q,J＝3.6,2.9Hz,1H),2.70–2.61(m,1H),1.89–1.79(m,2H),1.41(d,J＝2.5Hz,6H),1.36(qd,J＝6.8,2.0Hz,2H),0.63(t,J＝7.4Hz,3H)。 13 C NMR(100MHz,CDCl 3 ) Delta 191.48,160.77,160.12,157.57,154.25,129.89,124.57,113.69,106.14,103.00,99.65,91.90,89.80,65.56,55.34,31.57,27.18,26.33,22.55,16.50,10.45.HRMS-ESI (m/z) with molecular formula C 24 H 25 BrO 7 K[M+K] + 543.0415 is calculated and 543.0821 is measured.
(4) Preparation of Compound Id
Referring to the above synthetic method, using isopropanol as the reactant and solvent, compound Id was obtained in yield54 percent of light yellow solid, M.p.186.5-188 ℃, R f =0.34 (petroleum ether: ethyl acetate = 2. 1 H NMR(400MHz,CDCl 3 )δ＝11.28(s,1H),7.79(d,J＝8.8Hz,2H),6.98(d,J＝8.9Hz,2H),3.85(s,3H),3.82(d,J＝4.6Hz,1H),2.87–2.80(m,1H),2.72–2.65(m,1H),1.90–1.85(m,1H),1.81(d,J＝7.3Hz,1H),1.41(d,J＝11.8Hz,6H),1.02(d,J＝6.2Hz,3H),0.75(d,J＝6.2Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta =160.91,160.29,157.67,154.86,130.40,125.46,106.83,102.84,99.54,91.84,90.01,26.97,26.76,23.86,22.94,16.99 HRMS-ESI (m/z): formula C 24 H 25 BrO 7 Na，[M+Na] + Calculated 527.0676 and measured 527.0675.
(5) Preparation of Compound Ie
With reference to the above synthesis, using n-butyl alcohol as the reaction reagent and solvent, compound Ie was obtained in 60% yield as a pale yellow solid, M.p.158.5-160 ℃, R f =0.36 (petroleum ether: ethyl acetate = 2. 1 H NMR(400MHz,CDCl 3 )δ11.31(s,1H),7.70(d,J＝8.5Hz,2H),6.99(d,J＝8.5Hz,2H),3.84(d,J＝8.6Hz,3H),3.34(dd,J＝9.5,6.6Hz,1H),3.16–3.10(m,1H),2.84–2.77(m,1H),2.68–2.63(m,1H),1.86(q,J＝6.8,6.4Hz,1H),1.83–1.77(m,1H),1.41(s,6H),1.35–1.29(m,2H),1.12–1.03(m,2H),0.70(t,J＝7.4Hz,3H)。 13 C NMR(100MHz,CDCl 3 ) Delta 191.45,160.79,160.12,157.57,154.23,129.87,128.91,124.54,113.98,113.71,106.16,102.96,99.63,91.90,89.79,63.61,55.34,31.59,31.27,27.13,26.37,19.02,16.51,13.60.HRMS-ESI (m/z) with molecular formula C 25 H 27 BrO 7 Na，[M+Na] + The calculated value is 541.0832, and the measured value is 541.0832.
(6) Preparation of Compound If
Referring to the above synthetic method, using n-pentanol as the reaction reagent and solvent, compound If was obtained in 50% yield as a pale yellow solid, M.p.121-123 deg.C, R f =0.48 (petroleum ether: ethyl acetate =2, 1 H NMR(400MHz,CDCl 3 )δ11.31(s,1H),7.68(d,J＝8.8Hz,2H),6.98(d,J＝8.9Hz,2H),3.84(s,3H),3.33(dd,J＝9.5,6.4Hz,1H),3.11(dt,J＝9.4,6.8Hz,1H),2.83–2.76(m,1H),2.69–2.62(m,1H),1.90–1.77(m,2H),1.41(s,6H),1.37–1.31(m,2H),1.07(ddd,J＝13.0,7.9,5.0Hz,2H),1.03–0.96(m,2H),0.71(t,J＝7.1Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta =191.65,160.70,160.09,157.55,154.25,129.89,124.57,113.64,106.17,103.03,99.70,91.88,89.88,78.07,63.78,55.32,31.58,28.89,28.02,27.12,26.42,22.15,16.51,13.94 hrms-ESI (m/z): formula C 26 H 29 BrO 7 Na，[M+Na] + Calculated 555.0989 and measured 555.0988.
(7) Preparation of Compound Ig
Referring to the above synthetic method, using 3-methyl-1-butanol as the reaction reagent and solvent, compound Ig was obtained in 55% yield as a pale yellow solid, M.p.108-110 deg.C, R f =0.56 (petroleum ether: ethyl acetate = 2. 1 H NMR(400MHz,CDCl 3 )δ11.30(s,1H),7.68(d,J＝8.5Hz,2H),6.98(d,J＝8.6Hz,2H),3.84(s,3H),3.37–3.30(m,1H),3.20–3.13(m,1H),2.86–2.77(m,2H),2.69–2.61(m,1H),1.90–1.84(m,1H),1.83–1.76(m,1H),1.40(s,6H),1.22(d,J＝7.4Hz,2H),0.69(d,J＝6.6Hz,3H),0.61(d,J＝6.6Hz,3H). 13 C NMR(100MHz,CDCl 3 ) Delta 191.52,160.76,160.11,157.56,154.22,129.86,124.54,113.70,106.18,102.95,99.63,91.90,89.81,62.19,55.34,38.00,31.59,27.05,26.89,26.44,24.68,22.49,22.04,16.53 HRMS-ESI (m/z): formula C191.52, 160.76,160.11,157.56,154.22,129.86,124.54,113.70,106.18,102.95,99.63,91.90,89.81,62.19,55.34,38.00,31.59,27.05,26.89,26.44,24.68,22.49,22.04,16.53 26 H 29 BrO 7 Na，[M+Na] + Calculated 555.0989 and measured 555.0988.
(3) Preparation of Compound Ih
Referring to the above synthesis method, benzyl alcohol was used as the reaction reagent and solvent to give compound Ih in 35% yield as a pale yellow solid, m.p.98-100 ℃, R f =0.38 (petroleum ether: ethyl acetate = 2. 1 H NMR(400MHz,CDCl 3 )δ＝11.32(s,1H),7.78(d,J＝8.9Hz,2H),7.17(dd,J＝4.9,1.8Hz,3H),7.02(d,J＝8.9Hz,2H),6.97(q,J＝2.9,2.3Hz,2H),4.46(d,J＝12.1Hz,1H),4.24(d,J＝12.2Hz,1H),3.86(d,J＝5.3Hz,3H),2.73(ddd,J＝14.9,8.6,6.3Hz,2H),2.53–2.46(m,1H),1.83–1.77(m,1H),1.36(d,J＝3.5Hz,6H). 13 C NMR(100MHz,CDCl 3 ) δ:160.35,157.75,128.37,127.72,114.03,103.21,31.61,29.84,16.53, HRMS-ESI (m/z) formula C 28 H 25 BrO 7 Na，[M+Na] + Calculated value 575.0676 and measured value 575.0675.
Example 2 antitumor Activity test of 6-bromocyclo-Icaritin chroman 3, 4-dione Compounds
Cell lines and solvents were used: human liver cancer cell HepG2; human breast cancer cell MCF-7; culturing the tumor cells in a DMEM medium containing 10% fetal calf serum; the solvent is dimethyl sulfoxide (DMSO for short).
The CCK-8 staining method for detecting the anti-tumor activity of the cells comprises the following steps: cells in logarithmic growth phase were taken for experiments. Digesting and counting the cells, preparing a cell suspension, inoculating the cell suspension in a 96-well plate (100. Mu.L/well), incubating at 37 ℃ and 5% CO 2 Culturing in an incubator for 24 hours; adding the test substance with corresponding concentration into each well, and simultaneously establishing a negative control group and a blank group, wherein each 5 wells are repeated; after the plate was placed in an incubator and cultured for 72 hours, the morphology of each group of cells was observed under a microscope, 10. Mu.L of CCK-8 solution was added to each well, incubation was continued for 4 hours in the cell incubator, absorbance was measured at 450nm, and the inhibition of the cells was calculated. Setting the concentration gradient to obtain IC 50 Values (. Mu.M), the experimental results are detailed in Table 1.
TABLE 1 inhibition ratio of 6-bromocyclo-icaritin chroman 3, 4-dione Ia-h against tumor cells and IC 50 Value (μ M)
The experimental results in Table 1 show that the 6-bromocyclo-icaritin chroman 3, 4-dione designed and synthesized by the invention and shown in the formula I has good anti-tumor effect on human liver cancer and human breast cancer. The novel derivatives of the compounds can be used for preparing antitumor drugs, especially for preparing liver cancer and breast cancer drugs.
The foregoing is merely an example of the present invention and common general knowledge of known specific structures and features of the embodiments is not described herein in any greater detail. It should be noted that, for those skilled in the art, without departing from the structure of the present invention, several changes and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
Claims (10)
1, 6-bromo-cyclo-icaritin chromane 3, 4-diketone derivative, which is characterized in that the structural formula is shown as formula I,
wherein R is selected from saturated alkyl or substituted alkyl.
2. The method for synthesizing 6-bromocyclo-icaritin chromane 3, 4-dione derivatives I according to claim 1, wherein the synthetic route is as follows:
the method comprises the following steps: cycloicaritin is taken as a raw material and reacts with a bromination reagent under proper alcohol reagent and proper conditions to obtain the 6-bromo-cycloicaritin chromane 3, 4-diketone derivative I.
3. The method of synthesis according to claim 2, characterized in that: the brominating reagent is selected from NBS and Br 2 、HBr、NaBr/H 2 O 2 NBS/AIBN or alpha, beta-dibromocinnamic acid.
4. The method of synthesis according to claim 2, characterized in that: suitable alcohols are selected from saturated or substituted alkyl alcohols.
5. The method of synthesis according to claim 2, characterized in that: suitable conditions include a reaction time of 1 to 48 hours and a reaction temperature of 0 ℃ to the reflux temperature of the alcohol reagent used.
6. The method of synthesis according to claim 2, characterized in that: suitable conditions include cyclic icaritin: the molar ratio of the bromination reagent is 1: the molar ratio of the alcohol reagent is 1:100.
7. the method of synthesis according to any one of claims 2 to 6, characterized in that: the brominating reagent is selected from NBS.
8. The method of synthesis according to claim 7, characterized in that: suitable alcohols are selected from C1-C5 saturated alkyl or benzyl alcohols.
9. The method of synthesis according to claim 8, characterized in that: suitable conditions include a reaction time of 2 to 6 hours and a reaction temperature of 0 ℃ to room temperature.
10. The use of the 6-bromocyclo-icaritin chromane 3, 4-dione derivatives as claimed in claim 1 in the preparation of antitumor drugs.
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| CN111925378A (en) * | 2020-09-09 | 2020-11-13 | 遵义医科大学 | 5-substituted icaritin derivative and anti-tumor application thereof |
| CN112442004A (en) * | 2021-01-20 | 2021-03-05 | 中国药科大学 | Icaritin analogue and preparation method and application thereof |
| CN113024602A (en) * | 2021-03-30 | 2021-06-25 | 广东工业大学 | Phosphate derivative of epimedium herb and preparation method and application thereof |
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| CN111925378A (en) * | 2020-09-09 | 2020-11-13 | 遵义医科大学 | 5-substituted icaritin derivative and anti-tumor application thereof |
| CN112442004A (en) * | 2021-01-20 | 2021-03-05 | 中国药科大学 | Icaritin analogue and preparation method and application thereof |
| CN113024602A (en) * | 2021-03-30 | 2021-06-25 | 广东工业大学 | Phosphate derivative of epimedium herb and preparation method and application thereof |
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