CN102399249A - 13-glycosyl oxime ether-3'-azido daunorubicin new compound with anti-cancer activity and preparation method thereof - Google Patents
13-glycosyl oxime ether-3'-azido daunorubicin new compound with anti-cancer activity and preparation method thereof Download PDFInfo
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- CN102399249A CN102399249A CN2011104036973A CN201110403697A CN102399249A CN 102399249 A CN102399249 A CN 102399249A CN 2011104036973 A CN2011104036973 A CN 2011104036973A CN 201110403697 A CN201110403697 A CN 201110403697A CN 102399249 A CN102399249 A CN 102399249A
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- cancer
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- 0 CC(C(C(*)C1)O)O[C@]1NC Chemical compound CC(C(C(*)C1)O)O[C@]1NC 0.000 description 2
- RHMWVNFRRRZAAQ-UHFFFAOYSA-N NOC(C(C1O)O)OC(CO)C1O Chemical compound NOC(C(C1O)O)OC(CO)C1O RHMWVNFRRRZAAQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a 13-glycosyl oxime ether-3'-azido daunorubicin compound with anti-cancer activity and a synthesis method thereof. The method particularly comprises the step of reacting 3'-azido daunorubicin with various glycosyl donors to synthesize the 13-glycosyl oxime ether-3'-azido daunorubicin compound, wherein the 13-glycosyl oxime ether-3'-azido daunorubicin compound shows high activity in an activity test of cancer cells.
Description
Technical field
The present invention relates to a kind of 13-glycosyl oxime ether-3 with antitumour activity '-azido-daunorubicin compounds and compound method, belong to chemistry and medical technical field.
Background technology
Since the sixties in 20th century, daunorubicin (Daunorubicin) and Zorubicin (Doxorubicin) are used for clinical as the first line anthracycline drug and obtain very big development.Be referred to as anthracycline antibiotics with one type of microbiotic of their similar, have powerful antitumour activity, and be widely used in the clinical treatment of multiple malignant tumour.
Anthracycline antibiotics all contains the quaternary condensed ring system desoxy sugar structure of unifying; Has powerful antitumour activity; Be positioned at the most effectively row of cancer therapy drug, but it produces irreversible cardiac toxic in therapeutic process, also limit their clinical application like myocardosis etc.Lanyan Fang, Guisheng Zhang etc. (J.Med.Chem.2006,49,932-941) reported with daunorubicin 3 '-NH
2Be converted into N
3The compd A DNR that base is produced can change the recognition reaction to P-gp, thereby has overcome the resistance that the P-gp media causes, has reduced cardiac toxic, and domestic patent (200680016329.0) protecting this compounds.
Compd A DNR is reference literature (Alper, P.B. easily; Hung, S.-C.; Wong, C.-H., Tetrahedron Lett.1996,37, method preparation 6029-6032).
Summary of the invention
Technical scheme of the present invention be 13-glycosyl oxime ether-3 with antitumour activity '-azido-daunorubicin-type new compound, it is characterized in that this compound has following structure:
Wherein X is H or OMe; Y is OH, OAc, CH
3, CH
2OH; M is a monose.
Described compound and salt thereof, wherein M is:
R ' is N
3Or NH
2
Described compound and salt thereof, wherein X is OMe, Y is OH.
Described compound and salt thereof, wherein said compound partly is selected from:
In the present invention, the compound method of this compounds is simple, and compound has biological activity preferably.
The practical implementation method
1. glycosyl donor is synthetic
I. in the 250mL three-necked bottle, add 2.5g sodium acetate and 30mL diacetyl oxide, be heated to backflow, add dextrose anhydrous 5g then in batches, continue reflux and continue 40min.Then solution is poured in the 100mL trash ice, stirs 2h, obtain ethanoyl glucose.
Ii. in the 50mL flask, add ethanoyl glucose 1mmol, the NHS of 5eq and 20mL methylene dichloride dropwise add BF again
3Et
2O solution (20eq), reaction is 24 hours under cryosel is bathed.
Iii. the compound 200mg with the ii preparation is dissolved in the 8mL methyl alcohol, adds 3mL NH
3H
2O, refluxing and stirring 16h, stopped reaction revolves dry reaction liquid with Rotary Evaporators, can obtain compound a, and using the same method to prepare compound b, c and d.
2.13-glycosyl oxime ether-3 '-azido-daunorubicin synthetic
In the round-bottomed flask of 50mL, add ADNR (1mmol) and compound a (8eq), add the 30mL THF, 0.1M HCl (1eq), backflow is spent the night.Use column chromatography and obtain compound 1, yield is respectively 81%.Using the same method to obtain compound 2,3,4, and productive rate is respectively 75%, 35%, and 78%.
Compound 1
1H NMR (400MHz, DMSO-d
6) 14.02 (1H, s, H-6), 13.27 (1H, s, H-11), 7.91 (2H, m, H-1, H-2), 7.65 (1H, m, H-3), 5.34 (1H, m, H-7), 5.16 (2H, d, H-6 ", J
5 " 6 "=5.2Hz), 5.10 (1H, d, H-1 ", J
1 " 2 "=4.8Hz), 4.76 (1H, t, J=12.8Hz, J=8.0Hz, H-4 "), 4.41 (1H, m, H-1 '), 4.02 (1H; m, H-5 '), 3.97 (3H, s, 4-OMe), and 3.59 (2H, d, J=6.4Hz, H-2 '), 3.43-3.47 (2H; m, H-3 ', H-4 '), 3.05-3.14 (3H, m, H-2 ", H-3 ", H-5 "), 2.91 (2H, s; H-10), 1.98 (2H, s, H-8), 1.90 (3H, s, H-14), 1.81 (1H, s, H-6 ') ppm.
13C NMR (100MHz, DMSO-d
6) 186.8,186.7,170.8,161.4,161.2,156.8,154.9,136.4,135.3,135.1,120.4; 120.2,119.4,111.0,111.0,105.2,100.3,77.3,77.2,72.5,71.5; 71.2,69.9,69.4,67.3,61.0,60.2,57.0,56.0,40.6,40.4; 40.1,40.0,39.7,39.5,39.3,28.6,21.2,17.3,14.5,10.6ppm.
Compound 2
1H NMR (400MHz, DMSO-d
6) 14.02 (1H, s, H-6), 13.25 (1H, s, H-11), 7.88 (2H, s, H-1, H-2), 7.63 (1H, m; H-3), 5.32 (1H, d, H-1 ", J=6Hz), 5.23 (1H, d, H-7, J=2.8Hz), 5.17 (3H, m, H-3 "; H-4 ", H-5 "), 4.33 (1H, m, H-1 '), 4.08 (1H, m, H-5 '), 3.86 (3H, s, 4-OMe), 3.78 (1H; M, H-6 "), 3.69 (1H, m, H-2 "), 3.48 (1H, d, H-4 '), 3.36 (2H, m, H-2 ', H-3 '); 2.84-3.12 (2H, m, H-10), 1.91-2.07 (2H, m, H-8), 1.90 (3H, s, H-14), 1.52 (1H, dd, H-6 ') ppm.
13C NMR (100MHz, DMSO-d
6) 186.9,186.8,161.9,161.2,156.8,154.9,136.6,136.2,135.5; 135.1,120.4,120.1,119.4,111.1,111.0,102.5,100.3; 75.1,71.6,71.5,69.6,69.4,67.4,67.0,61.3; 57.0,56.0,38.5,33.5,30.5,28.6,17.3,10.2ppm.
Compound 3
1H NMR (400MHz, DMSO-d
6) 14.06 (1H, s, H-6), 13.32 (1H, s, H-11), 7.93 (2H, d, J=4.4Hz, H-1, H-2), 7.67 (1H, m; H-3), 5.38 (1H, d, H-1 ", J=6Hz), 5.32 (1H, d, J=2.8Hz, H-7), 5.18 (3H, m, H-3 "; H-4 ", H-5 "), 4.68 (1H, m, H-1 '), 4.02 (1H, m, H-5 '), 3.98 (3H, s, 4-OMe), 3.91 (1H; M, H-6 "), 3.74 (1H, m, H-2 "), 3.59 (1H, d, H-4 '), 3.45 (2H, m, H-2 ', H-3 '); 2.93-3.09 (2H, m, H-10), 1.91-2.07 (2H, m, H-8), 1.90 (3H, s, H-14), 1.68 (1H, m, H-6 ') ppm.
Compound 4
1H NMR (400MHz, DMSO-d
6) 14.06 (1H, s, H-6), 13.30 (1H, s, H-11), 7.91 (2H, m, H-1, H-2), 7.66 (1H, m, H-3); 5.42 (1H, d, H-1 ", J=6Hz), 5.33 (1H, d, H-7, J=2.8Hz), 5.17 (3H, m, H-3 ", H-4 "; H-5 "), 4.50 (1H, m, H-1 '), 4.02 (1H, m, H-5 '), 3.98 (3H, s, 4-OMe), 3.91 (1H, m; H-6 "), 3.74 (1H, m, H-2 "), 3.59 (1H, d, J=7.2Hz, H-4 '), 3.45 (2H, m, H-2 ', H-3 '); 2.93-3.09 (2H, m, H-10), 1.91-2.07 (2H, m, H-8), 1.90 (3H, s, H-14), 1.68 (1H, dd, H-6 ') ppm.
13C NMR (100MHz, DMSO-d
6) 186.9,186.8,161.5,161.2,156.8,154.9,136.6,136.2,135.6; 135.1,120.4,120.1,119.4,111.0,111.0,110.2,100.3,82.7; 80.6,76.2,71.3,71.0,70.7,69.4,67.3,63.0; 60.2,57.0,56.0,38.2,33.3,28.6,17.3,10.5ppm.
3. activity research
Preliminary biological activity test shows, 13-glycosyl oxime ether-3 '-azido-daunorubicin compounds in breast cancer cell (MCF-7 cell) and leukemia cell's (K562 cell), cancer cells is had good inhibitory effect.
Claims (10)
1. the compound and the pharmacologically acceptable salts thereof that have formula:
Wherein: X is H or OMe;
Y is OH, OAc, CH
3, CH
2OH;
M is a monose.
2. compound according to claim 1 and salt thereof, wherein M is:
R ' is N
3Or NH
2
3. compound according to claim 2 and salt thereof, wherein X is OMe.
4. compound according to claim 3 and salt thereof, wherein Y is OH.
5. compound according to claim 4 and salt thereof, wherein said compound partly is selected from:
6. treat curee's method for cancer, it comprises the described compound of claim 1 or its pharmacologically acceptable salts of the curee being treated significant quantity.
7. method according to claim 6, wherein said cancer is selected from mammary cancer, uterus carcinoma, ovarian cancer, cervical cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, thyroid carcinoma, lung cancer, carcinoma of testis, kidney, bladder cancer, tracheocarcinoma, carcinoma of small intestine, carcinoma vulvae, liver cancer, carcinoma of the pancreas, prostate cancer and white blood disease etc.
8. method according to claim 7, wherein said curee is a human subject.
9. treatment cancer patients's preparation comprises the described compound or its salt of claim 1 or its combination.
10. preparation according to claim 9, it further comprises carrier.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4112217A (en) * | 1977-09-02 | 1978-09-05 | Sri International | Bis-hydrazones of daunomycin and adriamycin |
| US4125704A (en) * | 1977-09-14 | 1978-11-14 | Sri International | Phenyl-substituted rubidazone analogs |
| CN102086219A (en) * | 2010-11-24 | 2011-06-08 | 河南师范大学 | Anthracycline antibiotic simple analogues with anticancer activities and preparation method of analogues |
| CN102146108A (en) * | 2011-01-14 | 2011-08-10 | 河南师范大学 | Synthesis of 3'-triazoepirubicin with anticancer activity |
-
2011
- 2011-11-28 CN CN2011104036973A patent/CN102399249A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4112217A (en) * | 1977-09-02 | 1978-09-05 | Sri International | Bis-hydrazones of daunomycin and adriamycin |
| US4125704A (en) * | 1977-09-14 | 1978-11-14 | Sri International | Phenyl-substituted rubidazone analogs |
| CN102086219A (en) * | 2010-11-24 | 2011-06-08 | 河南师范大学 | Anthracycline antibiotic simple analogues with anticancer activities and preparation method of analogues |
| CN102146108A (en) * | 2011-01-14 | 2011-08-10 | 河南师范大学 | Synthesis of 3'-triazoepirubicin with anticancer activity |
Non-Patent Citations (2)
| Title |
|---|
| 孙凤容，等: "新型蒽环类抗肿瘤先导物的糖基衍生物合成及其药物活性研究", 《中国化学会第六届有机化学学术会议论文集（下册）》 * |
| 薛冰林，等: "新型蒽环类抗生素简单结构类似物的合成", 《河南省化学会2010年学术年会论文摘要集》 * |
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Application publication date: 20120404 |