CN103864810A - Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs - Google Patents

Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs Download PDF

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Publication number
CN103864810A
CN103864810A CN201210531581.2A CN201210531581A CN103864810A CN 103864810 A CN103864810 A CN 103864810A CN 201210531581 A CN201210531581 A CN 201210531581A CN 103864810 A CN103864810 A CN 103864810A
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hydroxycamptothecine
methyl
ethyl
camptothecine
cancer
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郁彭
温少鹏
王义乾
贾海永
吕建
吕蕾
郭娜
杨尧
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Tianjin University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

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Abstract

The invention relates to a preparation method of novel substituted 10-hydroxycamptothecine 10-position derivatives and an application in antitumor drugs. With 10-hydroxycamptothecine as a raw material and through a condensation reaction and a substitution reaction, the derivatives having anti-cancer activity and capable of increasing water solubility of 10-hydroxycamptothecine are obtained for the first time.

Description

A kind of 10-hydroxycamptothecine 10 bit derivant preparation methods and the application in antitumor drug thereof of novelty
Technical field
The invention belongs to new compound preparation method field, especially a kind of 10-hydroxycamptothecine 10 bit derivant preparation methods and the application in antitumor drug thereof of novelty.
Background technology
Estimate according to the World Health Organization, the whole world approximately has 5,000,000 people dead because suffering from various malignant tumours every year, and only the U.S. diagnoses out 1,300,000 routine cancers every year.Cancer has become serious harm human life health and has been difficult to one of disease of curing.Camptothecine (CPT) is a kind of cancer therapy drug that derives from plant, the camplotheca acuminata Central-South from China, southwest distributes, extracts and obtains.Early stage biological test shows, natural camptothecine has obvious anti-tumor activity, especially digestive tube, leukemia, bladder cancer etc. is had to significant result for the treatment of.
Camptothecin analogues is the inhibitor of efficient topoisomerase I.Its antitumor mechanism is by the mixture of stable topology isomerase I-DNA, affect DNA copy to realize.The camptothecine of lactonic ring form acts on the binding site of topoisomerase I-DNA mixture, forms stable CPT-DNA-Topol ternary complex, makes DNA break.In the S phase of cell cycle, DNA replication dna fork runs into the roadblock that ternary complex forms, and has suppressed the synthetic of DNA, finally causes the apoptosis of cell in the s cycle.
Wherein anticarcinogen 10-hydroxycamptothecine has gone through to go on the market in China.But clinical application 10-hydroxycamptothecine is not modified natural product, and toxicity is larger, and anti-tumor activity is lower, thereby is restricted in clinical application.Anticarcinogen 10-hydroxycamptothecine is carried out to structural modification research, further develop derivative that curative effect is more good by significant.For improving the result for the treatment of of medicine, reduce toxic side effect, adapt to preparation requirement, convenient application, keeps the basic structure of anticarcinogen 10-hydroxycamptothecine herein, neither destroys vinegar ring in it, improve again that it is water-soluble, only on some function base, make certain chemical structure and change.Select appropriate structural modification, make, under physiological condition, can discharge parent drug, and have the difference of the conditions such as enzyme, acceptor, pH according to body tissue, and reach following object: improve transhipment and the metabolic process of medicine, improve bioavailability; Improve physical and chemical properties of drugs; Be conducive to the interaction of medicine and acceptor or enzyme, cause the transformation of corresponding biological chemistry and biophysics.Finally develop the new drug with wide market outlook, bring benefit to the mankind.
Summary of the invention
The object of the present invention is to provide 10-hydroxycamptothecine 10 bit derivants and preparation method thereof and application thereof, that the present invention has is simple to operate, reaction conditions is gentle, synthetic route is short, yield is higher, low cost and other advantages.
Object of the present invention is achieved through the following technical solutions:
10-hydroxycamptothecine 10 bit derivants, is characterized in that: the general structure of derivative is as follows:
Figure BSA00000821564500021
Wherein R 1for H, low alkyl group or containing substituent low alkyl group.
Wherein R 2for H, methyl or ethyl.
Specilization compound of the present invention comprises
1.10-[(glycine) carbamate]-camptothecine
2.10-[(glycine methyl ester) carbamate]-camptothecine
3.10-[(glycine ethyl ester) carbamate]-camptothecine
4.10-[(L-Ala) carbamate]-camptothecine
5.10-[(alanine methyl ester) carbamate]-camptothecine
6.10-[(alanine ethyl ester) carbamate]-camptothecine
7.10-[(leucine) carbamate]-camptothecine
8.10-[(leucine methyl esters) carbamate]-camptothecine
9.10-[(leucinethylester) carbamate]-camptothecine
10.10-[(Isoleucine) carbamate]-camptothecine
11.10-[(Isoleucine methyl esters) carbamate]-camptothecine
12.10-[(Isoleucine ethyl ester) carbamate]-camptothecine
13.10-[(α-amino-isovaleric acid) carbamate]-camptothecine
14.10-[(valine methyl ester) carbamate]-camptothecine
15.10-[(α-amino-isovaleric acid ethyl ester) carbamate]-camptothecine
16.10-[(methionine(Met)) carbamate]-camptothecine
17.10-[(methionine(Met) methyl esters) carbamate]-camptothecine
18.10-[(methionine(Met) ethyl ester) carbamate]-camptothecine
19.10-[(Serine) carbamate]-camptothecine
20.10-[(serine methylester) carbamate]-camptothecine
21.10-[(serine ethyl ester) carbamate]-camptothecine
22.10-[(Threonine) carbamate]-camptothecine
23.10-[(Threonine methyl esters) carbamate]-camptothecine
24.10-[(Threonine ethyl ester) carbamate]-camptothecine
25.10-[(halfcystine) carbamate]-camptothecine
26.10-[(acthiol-J) carbamate]-camptothecine
27.10-[(ethycysteine) carbamate]-camptothecine
Detailed Description Of The Invention
Synthetic route
Figure BSA00000821564500031
Illustrate 1
10-(4-nitro carbonic acid phenyl ester)-camptothecine
10-hydroxycamptothecine (5.0g, 13.7mmol) is dissolved in to methylene dichloride (500mL), at 0 DEG C, adds triethylamine (10mL, 68.6mmol).After stir about ten minutes, slowly drip nitroxyl chloride phenyl formate (8.3g, 41.2mmol), at 0 DEG C, react 9h.After reaction 9h, TLC detects raw material disappearance, add 400mL water, then dichloromethane extraction (100mL × 3), merge organic phase, anhydrous sodium sulfate drying, desolventizing is revolved in decompression, with methylene dichloride: methyl alcohol=150: 1,200-300 order silicagel column purifying, obtains intermediate 10-(4-nitro carbonic acid phenyl ester)-camptothecine 6.5g, productive rate 90%.
1H?NMR(d 6-DMSO?400MHz)：δ/ppm?0.897(t，J＝7.6Hz，3H)，1.851-1.921(m，2H)，5.317(s，2H)，5.442(s，2H)，6.539(s，1H)，7.371(s，1H)，7.776(d，J＝9.2Hz，2H)，7.970-7.993(m，1H)，8.2(d，J＝2.4Hz，1H)，8.29(d，J＝9.2Hz，1H)，8.40(d，J＝9.2Hz，2H)，8.739(s，1H)。
Illustrate 2
10-[(glycine methyl ester) carbamate]-camptothecine
Get intermediate 10-(4-nitro carbonic acid phenyl ester)-camptothecine (1.0g, 1.89mmol) be dissolved in DMF (20mL), at 0 DEG C, add salt of wormwood (0.5g, 3.78mmol), glycine methyl ester hydrochloride (0.48g, 3.78mmol), at 0 DEG C, react 5 hours, after reaction 5h, TLC detects raw material disappearance, adds 50mL water, then dichloromethane extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, desolventizing is revolved in decompression, methylene dichloride: methyl alcohol=120: 1,200-300 order silicagel column purifying.Obtain 10-[(glycine methyl ester) carbamate]-camptothecine 0.7g, productive rate 77%.
1H?NMR(d 6-DMSO?400MHz)：δ/ppm?0.871-0.906(m，3H)，1.841-1.911(m，2H)，3.698(s，3H)，3.935(d，2H)，5.298(s，2H)，5.298(s，2H)，5.431(s，2H)，6.520(s，1H)，7.345(s，1H)，7.639-7.662(m，1H)，7.916(s，1H)，8.187(d，1H)，8.410-8.439(m，1H)，8.681(s，1H)。
Illustrate 3
10-[(alanine methyl ester) carbamate]-Comptothecin compounds (2)
Get intermediate 10-(4-nitro carbonic acid phenyl ester)-camptothecine (1.0g, 1.89mmol) l is dissolved in DMF (20mL), at 0 DEG C, add salt of wormwood (0.5g, 3.78mmol), alanine methyl ester hydrochloride (0.51g, 3.78mmol), at 0 DEG C, react 5 hours, after reaction 5h, TLC detects raw material disappearance, adds 50mL water, then dichloromethane extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, desolventizing is revolved in decompression, methylene dichloride: methyl alcohol=120: 1,200-300 order silicagel column purifying.Obtain 10-[(alanine methyl ester) carbamate]-camptothecine 0.73g, productive rate 78%.
1HNMR(d 6-DMSO?400MHz)：δ/ppm?0.889(t，3H)，1.395(d，3H)，1.841-1.929(m，2H)，3.695(s，3H)，4.068-4.107(m，1H)，4.216-4.253(m，1H)，5.296(s，1H)，5.43l(s，2H)，6.521(s，1H)，7.343(s，1H)，7.625-7.654(m，1H)，7.904(d，1H)，8.183(d，1H)，8.498(d，1H)，8.679(s，1H)。
Illustrate 4
10-[(valine methyl ester) carbamate]-camptothecine
Get intermediate 10-(4-nitro carbonic acid phenyl ester)-camptothecine (1.0g, 1.89mmol) l is dissolved in DMF (20mL), at 0 DEG C, add salt of wormwood (0.5g, 3.78mmol), Valine methyl ester hydrochloride (0.63g, 3.78mmol), at 0 DEG C, react 5 hours, after reaction 5h, TLC detects raw material disappearance, adds 50mL water, then dichloromethane extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, desolventizing is revolved in decompression, methylene dichloride: methyl alcohol=120: 1,200-300 order silicagel column purifying.Obtain 10-[(valine methyl ester) carbamate]-camptothecine 0.8g, productive rate 81%.
1H?NMR(d 6-DMSO?400MHz)：δ/ppm?0.804-0.906(m，3H)，0.946-0.994(m，6H)，1.822-1.911(m，2H)，2.124-2.191(m，1H)，3.702(s，3H)，4.023-4.059(m，1H)，5.301(s，2H)，5.432(s，2H)，7.345(s，1H)，7.628-7.658(m，1H)，7.918(d，1H)，8.816(d，1H)，8.444(d，1H)，8.683(s，1H)。
Illustrate 5
10-[(leucine methyl esters) carbamate]-camptothecine
Get intermediate 10-(4-nitro carbonic acid phenyl ester)-camptothecine (1.0g, 1.89mmol) l is dissolved in DMF (20mL), at 0 DEG C, add salt of wormwood (0.5g, 3.78mmol), L-Leu methyl ester hydrochloride (0.69g, 3.78mmol), at 0 DEG C, react 5 hours, after reaction 5h, TLC detects raw material disappearance, adds 50mL water, then dichloromethane extraction (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, desolventizing is revolved in decompression, methylene dichloride: methyl alcohol=120: 1,200-300 order silicagel column purifying.Obtain 10-[(leucine methyl esters) carbamate]-camptothecine 0.8g, productive rate 79%.
1H?NMR(d 6-DMSO?400MHz)：δ/ppm?0.870-0.961(m，10H)，1.559-1.777(m，2H)，1.823-1.912(m，2H)，3.696(s，3H)，4.145-4.202(m，1H)，5.296(s，2H)，5.431(s，2H)，6.519(s，1H)，7.343(s，1H)，7.619-7.642(m，1H)，7.912(d，1H)，8.329(d，1H)，8.568(d，1H)，8.682(s，1H)。
Illustrate 6
The experiment that 10-hydroxycamptothecine 10 bit derivants suppress K562, TH-29, HepG2 selectivity
Cell K562, HT-29, HepG2 are purchased from Shanghai cell bank, get in K562, TH-29, the HepG2 cell of growth logarithmic phase and are inoculated in 96 orifice plates, every hole 5 × 10 3individual cell/100 μ L at 37 DEG C, passes into 5% CO simultaneously 2under condition, cultivate 24 hours.Medicine is dissolved in to 5 different pharmaceutical concentration of preparation in dimethyl sulfoxide (DMSO) (being dissolved in hydrochloric acid Virahol for measuring the medicine of K562) and prepares against mensuration (drug level scope is 0-10 μ M), the drug solution of getting 0.5 each concentration gradient of μ L adds in 96 orifice plates and at 37 DEG C, continues to cultivate 48 hours, (K562 is suspension cell to discard nutrient solution, without discarding nutrient solution), every hole adds the tetramethyl-azo azoles indigo plant (MTT) of 0.5g/mL, under 490 wavelength, measure the optical density(OD) OD value (measuring the optical density(OD) of K562 under 570 wavelength) in 96 each hole of orifice plate.3-4 parallel hole established in each test, repeats 3-4 time.
Medicine growth inhibition ratio (%)=(the average OD value of the average OD value-medication of solution control group group) average OD value of/control group to cell, the then IC of the growth inhibition ratio to cell (%) calculating medicine according to different pharmaceutical concentration 50value is all less than 30 μ mol.
Fig. 1 is the proton nmr spectra analysis chart of compound 10-(4-nitro carbonic acid phenyl ester)-camptothecine;
Fig. 2 is compound 10-[(valine methyl ester) carbamate] the proton nmr spectra analysis chart of-camptothecine;
Fig. 3 is compound 10-[(glycine methyl ester) carbamate] the proton nmr spectra analysis chart of-camptothecine;

Claims (11)

1.10-hydroxycamptothecine 10 bit derivants, the general structure of derivative is as follows:
Figure FSA00000821564400011
Wherein R 1for H, low alkyl group or containing substituent low alkyl group.
Wherein R 2for H, methyl or ethyl.
2. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for H, R 2for H, methyl, ethyl.
3. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for methyl, R 2for H, methyl, ethyl.
4. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for 2-methyl-propyl group, R 2for H, methyl, ethyl.
5. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for 1-methyl-propyl group, R 2for H, methyl, ethyl.
6. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for 2-propyl group, R 2for H, methyl, ethyl.
7. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for methylthio group propyl group, R 2for H, methyl, ethyl.
8. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for methylol, R 2for H, methyl, ethyl.
9. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for 1-hydroxyl-2-ethyl, R 2for H, methyl, ethyl.
10. 10-hydroxycamptothecine 10 bit derivants according to claim 1, is characterized in that: described R 1for thiopurine methyltransferase, R 2for H, methyl, ethyl.
11. 10-hydroxycamptothecine 10 bit derivants according to claim 1 are in lung cancer, cervical cancer, ovarian cancer, intestinal cancer, cancer of the stomach, kidney, liver cancer, lymphatic cancer, leukemia, multiple marrow cancer, the esophageal carcinoma, bladder cancer, mammary cancer, carcinoma of the pancreas and heart trouble, the application in diabetes.
CN201210531581.2A 2012-12-07 2012-12-07 Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs Pending CN103864810A (en)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN105315294A (en) * 2014-06-26 2016-02-10 王杭祥 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and application thereof
WO2018212206A1 (en) * 2017-05-15 2018-11-22 旭化成株式会社 Isocyanate production method
EP3393490A4 (en) * 2015-12-15 2019-11-20 Icahn School of Medicine at Mount Sinai METHODS OF TREATING EXACERBATED INFLAMMATORY RESPONSE WITH TOPOISOMERASE l INHIBITORS
CN116102567A (en) * 2022-12-09 2023-05-12 天津科技大学 7-substituted camptothecin derivative, synthesis method and application thereof as antitumor drug

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WO2010150255A1 (en) * 2009-06-25 2010-12-29 Aposense Ltd. Conjugates of cytotoxic drugs
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EP0137145A1 (en) * 1983-07-14 1985-04-17 Kabushiki Kaisha Yakult Honsha New camptothecin derivatives and process for preparing same
CN1673225A (en) * 2004-03-23 2005-09-28 中国科学院上海药物研究所 Carbonate medicine precursors of hydroxycamptothecine and its derivative and their prepn and application
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315294A (en) * 2014-06-26 2016-02-10 王杭祥 7-ethyl-10-hydroxycamptothecine drug precursor, preparation method and application thereof
EP3393490A4 (en) * 2015-12-15 2019-11-20 Icahn School of Medicine at Mount Sinai METHODS OF TREATING EXACERBATED INFLAMMATORY RESPONSE WITH TOPOISOMERASE l INHIBITORS
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CN116102567A (en) * 2022-12-09 2023-05-12 天津科技大学 7-substituted camptothecin derivative, synthesis method and application thereof as antitumor drug
CN116102567B (en) * 2022-12-09 2024-03-22 天津科技大学 7-substituted camptothecin derivative, synthesis method and application thereof as antitumor drug

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Application publication date: 20140618