CN105859742B - The preparation and its application of novel hydroxyl dihydroartemisinine sulfur-bearing ester derivative - Google Patents
The preparation and its application of novel hydroxyl dihydroartemisinine sulfur-bearing ester derivative Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to chemical medicines, are related to the preparation and its application of a kind of novel hydroxyl dihydroartemisinine sulfur-bearing ester derivative.Specifically, the invention discloses hydroxyl dihydro arteannuin derivant or its pharmaceutically acceptable salt of the class formation as shown in Formulas I and Formula II, or its enantiomter, diastereoisomer or racemic modification, wherein Alkyl or Aromatic group are as defined herein.The invention also discloses purposes of the compound in prevention and/or treating cancer disease medicament.
Description
Technical Field
The invention belongs to the field of chemical medicine. In particular to a novel hydroxy dihydroartemisinin sulfur-containing ester derivative and application thereof.
Background
Artemisinin is an antimalarial active component extracted from Artemisia annua L of Compositae, and has a structure of sesquiterpene lactone containing peroxide bridge. In recent years, it has been found that it has activities such as antitumor, antiviral, antifungal, anti-inflammatory and immunosuppressive activities in addition to antimalarial activities. The antitumor activity of the compound has the characteristics of strong selectivity, reversion of multidrug resistance, sensitization of radiotherapy and chemotherapy and the like, and the pharmacophore is a peroxy bridge in the structure. The pharmacokinetic data of the artemisinin show that the artemisinin has poor lipid solubility and water solubility, short half-life and low bioavailability. In order to overcome the defects, chemists have improved the structure of the artemisinin by different modification means, but the modification product of the artemisinin is mostly established on the basis of the reduction product dihydroartemisinin and is derived by taking the dihydroartemisinin as a raw material. The artemisinin derivative is modified at the positions of C-11, C-12 and C-13 mostly at present, and the artemisinin derivative is modified at other positions less frequently, which is also caused by the instability of a peroxybridge which plays an active pharmacophore.
the biological transformation is a chemical reaction generated by carrying out structural modification on an exogenous substrate by utilizing an enzyme preparation of a biological system comprising bacteria, fungi, plants, animals, plants or animals, and the biological system has the advantages of mild transformation conditions, high selectivity and strong stereospecificity, can complete the reaction which can not be usually carried out by a chemical method, and is simple and convenient.
The prior art mainly aims at discovering antitumor drugs with more potential (namely high efficiency and low toxicity) on the structural modification of C-12 position of artemisinin, and technicians in the field need to develop a novel artemisinin derivative which has novel structure, is modified only at C-12 position or simultaneously modified at C-9 position and C-12 position and has excellent antitumor effect, wherein C-9 position is hydroxyl.
Disclosure of Invention
The invention relates to a novel hydroxy dihydroartemisinin sulfur-containing ester derivative shown in a general formula I and a general formula II or pharmaceutically acceptable salt thereof, or enantiomer, diastereomer or racemate thereof,
wherein,
an Alkyl group is an aliphatic chain optionally containing a different number of carbon atoms. The Aromatic group is an aryl group optionally containing carbon chains of different lengths or containing carbon chains of different lengths and different substitutions.
The invention preferably relates to novel hydroxy dihydroartemisinin sulfur-containing ester derivatives or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers or racemates thereof, which are shown in the following general formula I and general formula II,
wherein, Alkyl group is CH2CH3，CH2CH2CH2CH3. Aromatic group is CH2C6H5，C6H5OCH3，C6H11。
The invention also particularly preferably selects the novel hydroxy dihydroartemisinin sulfur-containing ester derivatives shown in the following general formula I and general formula II or pharmaceutically acceptable salts thereof, or enantiomers, diastereoisomers or racemes thereof,
9 α, 12 α -bis- (3-p-methoxyphenylthiophenylbenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-p-methoxyphenylthiophenylbenzoic acid) dihydroartemisinin ester;
9 α, 12 α -bis- (3-ethylsulfanylbenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-ethylsulfanilic benzoic acid) dihydroartemisinin ester;
9 α, 12 α -bis- (3-n-butylthiobenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-n-butylthiobenzoic acid) dihydroartemisinin ester;
9 α, 12 α -bis- (3-benzylthiobenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-benzylthiobenzoic acid) dihydroartemisinin ester;
9 α, 12 α -bis- (3-cyclohexanebenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-cyclohexanebenzoic acid) dihydroartemisinin ester
The invention comprises a pharmaceutical composition, which contains hydroxy dihydroartemisinin sulfur-containing ester compounds with general formulas I and II, pharmaceutically acceptable salts thereof, enantiomers, diastereomers and racemes thereof as active ingredients, and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field; for example, oral formulations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are immediately ready for use by addition of water for injection prior to injection); topical formulations (e.g. ointments or solutions).
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art and include: binders, lubricants, disintegrants, solubilizing agents, diluents, stabilizers, suspending agents, non-coloring agents, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
We have found that the compounds of the present invention have anti-tumor activity against tumor cell proliferation and tumor growth in tumor bearing mice. Therefore, it can be used as a medicament for preventing and/or treating cancer. Especially has special curative effect on lung cancer, gastric cancer, prostatic cancer and breast cancer.
The derivatives according to the present invention are useful as active ingredients for the prevention and/or treatment of cancer, and the present invention also provides a method for the prevention and/or treatment of the above-mentioned diseases, which comprises administering a therapeutically effective amount of the derivatives of the present invention to a patient susceptible to or suffering from the diseases. The clinical dosage of the thioesters derivatives of hydroxydihydroartemisinin of formula I and formula II for a patient will necessarily vary depending on the subject to be treated, the particular route of administration, the severity of the disease to be treated, and the optimal dosage will be determined by the physician treating the particular patient.
The active compounds of the present invention may be used as the sole anticancer agent or may be used in combination with one or more other antitumor agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
Scheme a describes the preparation of the compounds of general formulae I and II of the present invention, all starting materials being prepared by the methods described in scheme a, by methods well known to those of ordinary skill in the art of organic chemistry or being commercially available. All of the final compounds of the present invention are prepared by the methods described in scheme a below, or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in scheme a are as defined below or in the claims.
Route A
Preparation route B of A-2
Route B
In the above routes A and B, the starting material A-1 was obtained by biotransformation in this laboratory, and the starting materials B-1, B-2 were obtained commercially. The preparation method is simple, and the prepared compound has obvious in vivo and in vitro anti-tumor activity.
Drawings
FIG. 1 shows the inhibition effect of 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester on nude mouse lung cancer A549 subcutaneous tumor model, wherein A is the change of weight of nude mouse in experimental process, and B is the tumor weight of nude mouse after sacrifice
FIG. 2 shows the inhibition effect of 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester on gastric cancer SGC-7901 subcutaneous tumor model of nude mice, wherein A is the change of weight of nude mice in the experimental process, and B is the tumor weight of nude mice after sacrifice
Detailed Description
The examples are intended to illustrate, but not to limit, the scope of the invention. The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the derivative are measured by Bruker AVANCE-400 or Bruker 300, and the high-resolution mass spectrum is measured by Aglient LC-Q-TOF-MS 6520B; the solvents used are either analytically pure or chemically pure.
EXAMPLE 1 preparation of 9 α, 12 α -bis- (3-p-methoxyphenylphenylbenzoic acid) dihydroartemisinin ester
adding (1equiv)9 α -hydroxy dihydroartemisinin, (2equiv) 3-p-methoxyphenylaminobenzoic acid, (2.6equiv) DMAP and (3equiv) EDCI into a dry three-neck round-bottom flask, adding 10mL of anhydrous dichloromethane for dissolving, reacting at a natural temperature for 12 hours while stirring, performing TLC detection reaction, performing spin-drying, dissolving with ethyl acetate, washing with water, washing with saturated sodium chloride, drying with anhydrous magnesium sulfate, performing spin-drying, performing column chromatography on the residue to obtain the target compound, and performing eluent of petroleum ether and ethyl acetate at a ratio of 4: 1 (V: V).
Yield：41.3％.White powder.mp.75℃.1H NMR(400MHz，CDCl3)δ＝7.89-7.82(m，3H)，7.80-7.74(m，1H)，7.47-7.41(m，4H)，7.30(td，J＝5.3，1.9Hz，4H)，6.95-6.89(m，4H)，5.92(d，J＝9.8Hz，1H)，5.61(s，1H)，4.68(td，J＝10.8，4.4Hz，1H)，3.83(s，3H)，3.82(s，3H)，2.79-2.66(m，1H)，2.41(dd，J＝18.5，8.8Hz，1H)，2.18(ddd，J＝15.0，9.7，5.3Hz，1H)，2.14-2.06(m，1H)，2.00-1.88(m，2H)，1.78-1.51(m，4H)，1.44(s，3H)，0.99(d，J＝6.2Hz，3H)，0.86(d，J＝7.1Hz，3H).13C NMR(100MHz，CDCl3)δ＝165.64，164.71，160.26，160.23，140.08，139.89，135.92(×2)，135.90(×2)，132.46，132.24，130.72，130.19，129.00，128.87，128.74，128.71，127.25，126.68，123.18，123.10，115.40(×4)，104.58，92.34，91.22，79.08，76.26，55.40(×2)，49.09，42.77，41.33，36.08，31.63，27.48，25.88，24.54，15.44，12.05.HR-ESI-MS m/z 807.2262[M+Na]+，(calcd for C43H44NaO10S2，807.2268).
EXAMPLE 2 preparation of 9 α -hydroxy-12 α - (3-p-methoxyphenylthiophenylbenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 1.
Yield：59.7％.White powder.mp.64℃.1H NMR(400MHz，CDCl3)δ＝7.90(d，J＝0.9Hz，1H)，7.89-7.85(m，1H)，7.47-7.40(m，2H)，7.33-7.27(m，2H)，6.97-6.88(m，2H)，5.95(d，J＝9.8Hz，1H)，5.57(s，1H)，3.84(s，3H)，3.25(td，J＝10.6，4.3Hz，1H)，2.77-2.58(m，1H)，2.40(td，J＝14.4，3.9Hz，1H)，2.09(ddd，J＝8.9，4.5，1.7Hz，1H)，1.90(ddd，J＝16.4，8.6，5.1Hz，1H)，1.83(dd，J＝9.3，4.9Hz，1H)，1.64-1.47(m，3H)，1.44(s，3H)，1.40-1.29(m，2H)，1.08(d，J＝6.1Hz，3H)，0.88(d，J＝7.1Hz，3H).13C NMR(100MHz，CDCl3)δ＝164.75，160.21，139.85，135.91，135.88，132.44，130.24，129.18，128.87，127.29，123.18，115.22(×2)，104.54，92.50，91.31，79.45，73.81，55.40，49.10，44.15，42.99，36.12，31.60，31.07，25.90，24.49，15.43，12.15.HR-ESI-MS m/z 565.1858[M+Na]+，(calcd forC29H34NaO8S，565.1867).
EXAMPLE 3 preparation of 9 α, 12 α -bis- (3-ethylthiobenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 1 substituting 3-ethinylbenzoic acid for the starting material 3-p-methoxyphenylbenzoic acid in example 1. The eluent of column chromatography is petroleum ether and ethyl acetate which are 8: 1 (V: V).
Yield：34.2％.White powder.mp.69-72℃.1H NMR(400MHz，CDCl3)δ＝8.21(dt，J＝26.8，1.7Hz，2H)，8.06-7.96(m，2H)，7.76-7.68(m，2H)，7.40-7.30(m，2H)，6.01(d，J＝9.7Hz，1H)，5.65(s，1H)，4.76(td，J＝10.8，4.3Hz，1H)，3.01(q，J＝7.4Hz，2H)，2.99(q，J＝7.5Hz，2H)，2.85-2.74(m，1H)，2.43(dt，J＝14.4，3.8Hz，1H)，2.26-2.17(m，1H)，2.12(t，J＝12.4Hz，1H)，2.00-1.91(m，2H)，1.83-1.51(m，4H)，1.46(s，3H)，1.34(t，J＝11.4Hz，3H)，1.32(t，J＝11.4Hz，3H)，1.03(d，J＝6.3Hz，3H)，0.93(d，J＝7.1Hz，3H).13C NMR(100MHz，CDCl3)δ＝165.73，164.81，136.68，136.38，136.16，133.18，132.60，130.07(×2)，128.73，128.18，127.41，122.60，122.46，104.65，92.37，91.27，79.02，76.53，49.07，42.79，41.33，36.08，31.68，29.69，27.55(×2)，25.86，24.55，15.50，14.20(×2)，12.11.HR-ESI-MS m/z651.2061[M+Na]+，(calcd for C33H40NaO8S2，651.2057).
EXAMPLE 4 preparation of 9 α -hydroxy-12 α - (3-ethylthiobenzoic acid) dihydroartemisinin ester
The title compound was prepared according to the procedure for example 3.
Yield：36.1％.White powder.75-77℃.1H NMR(400MHz，CDCl3)δ＝8.26-7.88(m，1H)，8.08-8.01(m，1H)，7.72-7.48(m，1H)，7.42-7.30(m，1H)，6.01(d，J＝9.7Hz，1H)，5.65(s，1H)，4.76(td，J＝10.8，4.3Hz，1H)，3.00(q，J＝7.4Hz，2H)，2.84-2.72(m，1H)，2.39(dt，J＝14.4，3.7Hz，1H)，2.26-2.16(m，1H)，2.10(d，J＝14.4Hz，1H)，1.97(dd，J＝21.4，11.6Hz，2H)，1.85-1.53(m，4H)，1.45(s，3H)，1.32(t，J＝7.8Hz，3H)，1.03(d，J＝6.3Hz，3H)，0.91(t，J＝8.3Hz，3H).13C NMR(100MHz，CDCl3)δ＝164.83，136.35，133.59，133.02，129.93，127.40，122.45，104.58，92.71，91.37，79.46，73.80，49.11，44.16，42.98，36.12，31.65，31.09，27.55，25.89，24.50，15.43，14.21，12.21.HR-ESI-MS m/z 487.1712[M+Na]+，(calcd for C24H32NaO7S，487.1761).
example 5 preparation of 9 α, 12 α -bis- (3-n-butylthiobenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 1 substituting the starting material 3-p-methoxyphenylaminobenzoic acid in example 1 with the starting material 3-n-butylthiobenzoic acid. The eluent of column chromatography is petroleum ether and ethyl acetate which are 7: 1 (V: V).
Yield：30.3％.White powder.mp.115-118℃.1H NMR(400MHz，CDCl3)δ＝8.00(dt，J＝24.0，1.6Hz，2H)，7.92-7.86(m，1H)，7.84-7.80(m，1H)，7.54-7.48(m，2H)，7.36(dd，J＝17.1，7.8Hz，2H)，6.00(d，J＝9.8Hz，1H)，5.65(s，1H)，4.74(td，J＝10.9，4.4Hz，1H)，2.97(q，J＝5.6Hz，4H)，2.83-2.73(m，1H)，2.49-2.38(m，1H)，2.22(dt，J＝12.8，4.4Hz，1H)，2.10(dd，J＝15.0，3.8Hz，1H)，2.03-1.91(m，2H)，1.77(td，J＝10.8，6.1Hz，1H)，1.72-1.55(m，9H)，1.51-1.46(m，2H)，1.45(s，3H)，1.04(d，J＝6.3Hz，3H)，0.92(d，J＝7.2Hz，3H)，0.93(t，J＝7.3Hz，3H)，0.94(t，J＝7.3Hz，3H).13C NMR(100MHz，CDCl3)δ＝165.74，164.82，138.25，138.05，133.45，133.12，130.67，130.12，129.86，129.32，128.86，128.73，127.27，126.67，104.60，92.36，91.27，79.10，76.22，49.12，42.82，41.38，36.09，33.13，33.09，31.68，31.08，31.05，27.55，25.88，24.56，21.93(×2)，15.49，13.63，13.61，12.12.HR-ESI-MS m/z 707.2700[M+Na]+，(calcd for C37H48NaO8S2，707.2683).
example 6 preparation of 9 α -hydroxy-12 α - (3-n-butylthiobenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 5. The eluent of column chromatography is petroleum ether and ethyl acetate which are 2: 1 (V: V).
Yield：33.7％.White powder.mp.72-75℃.1H NMR(300MHz，CDCl3)δ＝8.04(t，J＝1.6Hz，1H)，7.94-7.87(m，1H)，7.51(ddd，J＝7.8，1.7，1.1Hz，1H)，7.35(t，J＝7.8Hz，1H)，6.01(d，J＝9.8Hz，1H)，5.57(s，1H)，3.25(td，J＝10.7，4.3Hz，1H)，3.02-2.92(m，2H)，2.83-2.67(m，1H)，2.48-2.31(m，1H)，2.07(dt，J＝13.7，4.2Hz，2H)，1.86(m，2H)，1.71-1.45(m，6H)，1.43(s，3H)，1.40-1.24(m，2H)，1.10(d，J＝5.9Hz，3H)，0.94(d，J＝7.1Hz，3H)，0.95(t，J＝7.2Hz，3H).13C NMR(100MHz，CDCl3)δ＝164.84，138.03，133.42，130.19，129.85，128.73，127.26，104.54，92.50，91.36，79.46，73.81，49.11，44.17，43.01，36.14，33.13，31.65，31.12，31.07，25.89，24.50，21.93，15.43，13.61，12.21.HR-ESI-MS m/z515.2078[M+Na]+，(calcd for C26H36NaO7S，515.2074).
example 7 preparation of 9 α, 12 α -bis- (3-benzylthiobenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 1 substituting the starting material 3-p-methoxyphenylaminobenzoic acid in example 1 with the starting material 3-benzylthiobenzoic acid. The eluent of column chromatography is petroleum ether and ethyl acetate which are 6: 1 (V: V).
Yield：17.2％.White powder.mp.72℃.1H NMR(400MHz，CDCl3)δ＝8.00(dt，J＝33.1，1.7Hz，2H)，7.93-7.89(m，1H)，7.86-7.82(m，1H)，7.47(tdd，J＝8.8，1.9，1.1Hz，2H)，7.36-7.21(m，12H)，6.00(d，J＝9.8Hz，1H)，5.65(s，1H)，4.73(td，J＝10.9，4.4Hz，1H)，4.18(s，2H)，4.15(s，2H)，2.82-2.72(m，1H)，2.50-2.40(m，1H)，2.20(dt，J＝12.9，4.4Hz，1H)，2.11(dt，J＝7.2，6.2Hz，1H)，2.02-1.92(m，2H)，1.79-1.54(m，4H)，1.46(s，3H)，1.01(d，J＝6.3Hz，3H)，0.90(d，J＝7.1Hz，3H).13C NMR(100MHz，CDCl3)δ＝165.58，164.67，137.35，137.16，136.91，134.49，134.16，130.90，130.66，130.36，130.11，128.84(×6)，128.73，128.57(×4)，127.97，127.40，127.35(×2)，104.61，92.34，91.26，79.07，76.18，49.09，42.78，41.36，38.81(×2)，36.09，31.66，27.52，25.88，24.57，15.51，12.12.HR-ESI-MS m/z 775.2388[M+Na]+，(calcd for C43H44NaO8S2，775.237).
example 8 preparation of 9 α -hydroxy-12 α - (3-benzylthiobenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 7. The eluent of column chromatography is petroleum ether and ethyl acetate which are 4: 1 (V: V).
Yield：47.4％.White powder.mp.83℃.1H NMR(300MHz，CDCl3)δ＝8.05(s，1H)，7.91(d，J＝7.8Hz，1H)，7.46(d，J＝7.8Hz，1H)，7.31(dd，J＝8.8，5.6Hz，6H)，5.99(d，J＝9.8Hz，1H)，5.57(s，1H)，4.16(s，2H)，3.25(td，J＝10.6，4.2Hz，1H)，2.80-2.66(m，1H)，2.40(dt，J＝14.8，3.7Hz，1H)，2.12-1.99(m，2H)，1.96-1.77(m，2H)，1.61-1.45(m，2H)，1.44(s，3H)，1.41-1.24(m，2H)，1.08(t，J＝7.4Hz，3H)，0.91(d，J＝7.1Hz，3H).13C NMR(75MHz，CDCl3)δ＝164.66，137.13，136.93，134.45，130.89，130.77，130.19，128.82，128.69，128.55，127.95，127.84，127.31，104.51，92.48，91.33，79.41，73.82，49.11，44.16，43.00，38.82，36.13，31.61，31.10，25.85，24.48，15.39，12.16.HR-ESI-MS m/z549.1925[M+Na]+，(calcd for C29H34NaO7S，549.1917).
example 9 preparation of 9 α, 12 α -bis- (3-Cyclohexanebenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 1 substituting the starting material 3-p-methoxyphenylbenzoic acid with the starting material 3-cyclohexanebenzoic acid in example 1. The eluent of column chromatography is petroleum ether and ethyl acetate which are 8: 1 (V: V).
Yield：16.7％.White powder.mp.95-97℃.1H NMR(300MHz，CDCl3)δ＝8.08(dt，J＝18.4，1.7Hz，2H)，7.91(dd，J＝20.2，7.7Hz，2H)，7.63-7.53(m，2H)，7.36(q，J＝7.7Hz，2H)，6.01(d，J＝9.8Hz，1H)，5.65(s，1H)，4.74(td，J＝10.7，4.3Hz，1H)，3.23-3.11(m，2H)，2.86-2.72(m，1H)，2.52-2.35(m，1H)，2.24(dt，J＝12.7，4.4Hz，1H)，2.06-1.93(m，8H)，1.78(d，J＝4.6Hz，7H)，1.62(d，J＝10.4Hz，6H)，1.45(s，3H)，1.43-1.22(m，6H)，1.04(d，J＝6.2Hz，3H)，0.93(d，J＝7.1Hz，3H).13C NMR(75MHz，CDCl3)δ＝165.67，164.75，136.43，136.34，136.26，136.16，132.92，132.46，130.63，130.09，128.79，128.65，128.17，127.60，104.56，92.35，91.25，79.07，76.24，49.12，46.61，42.81，41.36，36.08，33.24(×3)，33.20(×3)，31.66，27.52，25.91(×3)，25.85，25.69(×2)，24.54，15.45，12.09.HR-ESI-MS m/z759.3000[M+Na]+，(calcd for C41H52NaO8S2，759.2996).
example 10 preparation of 9 α -hydroxy-12 α - (3-Cyclohexanebenzoic acid) dihydroartemisinin ester
The title compound was prepared by the method of example 9. The eluent of column chromatography is petroleum ether and ethyl acetate which are 2: 1 (V: V).
Yield：26.8％.White powder.mp.90-92℃.1H NMR(300MHz，CDCl3)δ＝8.11(dd，J＝4.5，2.9Hz，1H)，7.98-7.91(m，1H)，7.61-7.55(m，1H)，7.37(q，J＝7.4Hz，1H)，6.00(d，J＝9.8Hz，1H)，5.57(s，1H)，3.32-3.10(m，2H)，2.83-2.68(m，1H)，2.40(dt，J＝14.4，4.0Hz，1H)，2.11-1.95(m，5H)，1.92-1.72(m，4H)，1.67-1.47(m，4H)，1.43(s，3H)，1.41-1.24(m，5H)，1.10(d，J＝5.9Hz，3H)，0.94(d，J＝7.1Hz，3H).13C NMR(75MHz，CDCl3)δ＝164.77，136.40，136.15，132.90，130.16，128.65，128.16，104.50，92.48，91.33，79.42，73.81，49.11，46.60，44.16，43.01，36.13，33.24，33.21，31.62，31.11，25.92(×2)，25.86，25.70，24.48，15.39，12.17.HR-ESI-MS m/z 541.2224[M+Na]+(calcd for C28H38NaO7S，541.223).
Example 11: in vivo and in vitro antitumor activity research of product of the invention
1. Screening of the products of the invention for in vitro antitumor Activity
1.1 cell Resuscitation
The required cell freezing tube is quickly taken out from the liquid nitrogen tank, put into warm water of 37 ℃, and quickly shaken to melt the cell as fast as possible (preferably controlled to be about 1 min). After complete thawing, centrifuge at 1000rpm for 5 min. Carefully discard the supernatant from the frozen tube, add the culture medium, gently blow and beat, transfer the cell suspension to a culture flask, at 37 ℃ and 5% CO2Incubation and culture are carried out, and the solution is changed after 24 hours.
1.2 cell culture and passage
Tumor cell strains A549, SGC-7901 and MDA-MB-435s used in experiments are cultured by a DMEM medium containing 10% fetal bovine serum at 37 ℃ and 5% CO2Culturing under the condition. When the cell density reaches 8X 105At individual/mL, subculture (centrifugation) was performed by centrifuging at 1000rpm for 5min, discarding the supernatant, resuspending the cells in fresh 10% DMEM medium, and resuspending the cells at 2X 105Subculturing at density of one/mL.
The PC-3 cell line was cultured in F-12k medium containing 10% fetal bovine serum in the same manner as above.
1.3 determination of antitumor Activity of the product of the present invention by MTT method
Tumor cells were suspended in medium containing 10% fetal bovine serum at 2X 103Cell density of individual cells/well inoculated into 96-well culture plates (180. mu.L/well) at 37 ℃ with 5% CO2Culturing overnight, adding the product of the invention with different concentrations into each well, adding culture medium containing 1 ‰ DMSO and no drug into negative control group, and culturing at 37 deg.C with 5% CO2After culturing for 72h, the inhibition rate of the product of the invention on cells is detected.
The inhibition rate of the product of the invention to cells is detected by MTT colorimetric method. MTT is a tetramethylazoazolium salt, an aqueous solution of which is pale yellow in appearance and, when taken up by living cells, forms blue-violet crystalline formazan in the cells. Formazan can be dissolved in DMSO, anhydrous ethanol or acidified isopropanolAnd carrying out color comparison on a microplate reader, wherein the detected OD value can reflect the intensity of the metabolic activity of the cells. During detection, the cell culture solution treated by the product is discarded, MTT is added according to the final concentration of 0.5mg/ml, the cell culture solution is incubated in an incubator for 3 hours, the MTT solution is removed, 150 mu L DMSO is added, an oscillator vibrates for 10min to dissolve crystals, and the enzyme-labeling instrument detects the cell culture solution at the double wavelengths of 570nm and 650 nm. IC of drug was calculated using GraphPad Prism 5.0 software50(median inhibitory concentration).
The growth inhibition effect of the product on four tumor cell lines of PC-3, SGC-7901, A549 and MDA-MB-435s is shown in Table 1, and the result shows that the product has stronger inhibition effect on the growth of tumor cells and has the potential of being developed into antitumor drugs.
TABLE 1 screening of the products of the invention for antitumor Activity in vitro
NA：no activity
2. in vivo anti-lung cancer Activity of 9 α -hydroxy-12 α - (3-p-methoxyphenylphenylbenzoic acid) dihydroartemisinin ester in example 2
2.1 nude mouse human Lung cancer model establishment
BALB/c nude mice, 6-8 weeks old, male and female, purchased from the comparative medicine center of Yangzhou university, and bred in SPF-level animal laboratories. A549 cells were cultured at 37 ℃ with 5% CO2Culturing in DMEM medium containing 10% fetal calf serum, digesting the cells in logarithmic growth phase with 0.25% trypsin, and resuspending in sterile PBS to 5 × 107one/mL of single cell suspension, 0.2mL of cell suspension was subcutaneously inoculated in the right inguinal region of each nude mouse, and whether there was red swelling and ulceration at each injection site was observed every day. After 7 days of modeling, obvious skin dune appears on the injection part, subcutaneous nodules with the diameter larger than 5mm appear on all nude mice, and a transplantation tumor model is established.
2.2 determination of weight, tumor weight and tumor-inhibiting rate of nude mice
nude mice were randomly divided into treatment groups and control groups (6 nude mice per group), 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester was administered at doses of 10mg/kg (low), 30mg/kg (medium), and 90mg/kg (high), administration frequency was administered every other day, administration was performed by gastric lavage for 30 days, the positive control group was administered 5-fluorouracil (5-FU), administration was administered at doses of 30 mg/kg. control groups, physiological saline was injected, tumor volume and growth rate were observed, and nude mice body weight was measured every other day, nude mice were sacrificed on day 2 after drug withdrawal, tumor tissues were isolated, tumor mass was weighed, and tumor inhibition rate was calculated as (1-average tumor mass per control group) × 100%.
the inhibition effect of 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester on the tumor growth of a nude mouse with human lung cancer A549 is shown in Table 2 and figure 1, and the results show that compared with a positive drug 5-FU, the 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester treatment group has no weight reduction trend, which indicates that the compound has no obvious toxic or side effect on the nude mouse.
TABLE 29 in vivo anti-Lung cancer Activity of 29 α -hydroxy-12 29 α - (3-p-methoxyphenylthiophenylbenzoic acid) dihydroartemisinin esters
3. example 2 in vivo anti-gastric cancer Activity of 9 α -hydroxy-12 α - (3-p-methoxyphenylphenylbenzoic acid) dihydroartemisinin ester
3.1 nude mouse human gastric cancer model establishment
BALB/c nude mice, 6-8 weeks old, male and female, purchased from the comparative medicine center of Yangzhou university, and bred in SPF animal laboratories. SGC-7901 cells were incubated at 37 ℃ with 5% CO2Culturing in DMEM medium containing 10% fetal calf serum, digesting the cells in logarithmic growth phase with 0.25% trypsin, and resuspending in sterile PBS to 5 × 106one/mL of single cell suspension, 0.2mL of cell suspension was subcutaneously inoculated in the right inguinal region of each nude mouse, and whether there was red swelling and ulceration at each injection site was observed every day. After 7 days of molding, the injection part shows obvious skin hillock, when the tumor volume reaches 100mm3And establishing a transplantation tumor model.
3.2 determination of weight, tumor weight and tumor-inhibiting rate of nude mice
nude mice were randomly divided into treatment groups and control groups (6 nude mice per group), 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester was administered at doses of 10mg/kg (low), 30mg/kg (medium), and 90mg/kg (high), administration frequency was administered every other day, administration was performed by gastric lavage for 30 days, the positive control group was administered 5-fluorouracil (5-FU), administration was administered at doses of 30 mg/kg. control groups, physiological saline was injected, tumor volume and growth rate were observed, and nude mice body weight was measured every other day, nude mice were sacrificed on day 2 after drug withdrawal, tumor tissues were isolated, tumor mass was weighed, and tumor inhibition rate was calculated as (1-average tumor mass per control group) × 100%.
the inhibition effect of 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester on the growth of tumor of gastric cancer SGC-7901 nude mouse is shown in Table 3 and figure 2, and the results show that compared with the positive drug 5-FU, the 9 α -hydroxy-12 α - (3-p-methoxyphenylaminobenzoic acid) dihydroartemisinin ester treatment group has no descending trend of body weight, which indicates that the compound has no obvious toxic or side effect on nude mouse.
TABLE 39 α in vivo anti-gastric cancer Activity of alpha-hydroxy-12 alpha- (3-p-methoxyphenylthiophenylbenzoic acid) dihydroartemisinin esters
Claims (2)
1. A hydroxy dihydroartemisinin sulfur-containing ester derivative or a pharmaceutically acceptable salt thereof is characterized in that the structure of the derivative is one of the following structures:
9 α, 12 α -bis- (3-p-methoxyphenylthiophenylbenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-p-methoxyphenylthiophenylbenzoic acid) dihydroartemisinin ester;
9 α, 12 α -bis- (3-ethylsulfanylbenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-ethylsulfanilic benzoic acid) dihydroartemisinin ester;
9 α, 12 α -bis- (3-n-butylthiobenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-n-butylthiobenzoic acid) dihydroartemisinin ester;
9 α, 12 α -bis- (3-benzylthiobenzoic acid) dihydroartemisinin ester;
9 α -hydroxy-12 α - (3-benzylthiobenzoic acid) dihydroartemisinin ester.
2. The use of hydroxydihydroartemisinin sulfur-containing ester derivatives as claimed in claim 1 in the preparation of medicaments for the prevention or treatment of cancer diseases.
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