CN102532151B - There is 7-ethyl-20 (the S)-O-substituted benzoyl camptothecine compounds of anti-tumor activity - Google Patents
There is 7-ethyl-20 (the S)-O-substituted benzoyl camptothecine compounds of anti-tumor activity Download PDFInfo
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Abstract
The invention discloses 7-ethyl-20 (the S)-O-substituted benzoyl camptothecine compounds that a class has anti-tumor activity, it has formula (3) structure, wherein, and R
1hydrogen, nitro or trifluoromethyl; R
2hydrogen, halogen, nitro, cyano group or trifluoromethyl; R
3hydrogen or nitro; Compound of the present invention can be applicable to prepare anticancer medicine aspect.
Description
Technical field
The invention belongs to medical compounds field, relate to antitumour drug compounds, more specifically, relate to new 7-ethyl-20 (S)-O-substituted benzoyl camptothecine compounds with efficient antitumour activity of a class and preparation method thereof.
Background technology
Camptothecine from Nyssaceae plant camptotheca acuminata, was first separated by people such as Wall a kind of alkaloid with very powerful antitumor activity obtained in 1966.The water-soluble extreme difference of Native camptothecins, early clinic uses the water-soluble sodium salt of camptothecine, but has serious, unpredictalbe toxicity (as hemorrhagic cystitis etc.) because of it, causes clinical study once to be stagnated.Until 1985, the people such as Hsiang find that camptothecins anti-tumor activity suppresses copying and transcribing of DNA by acting on topoisomerase I (Topo I), just make the research of camptothecine enter brand-new stage.In order to obtain low toxicity, efficiently camptothecin antineoplastic agents, people have carried out a large amount of complete synthesis, semi-synthetic and structural modification work to it, achieve gratifying progress.Topotecan (Topotecan), irinotecan (Irinotecan) and Belotecan (Belotecan) have been applied to clinical, and tens of kinds of camptothecin derivatives are in each clinical stage.
From structure activity relationship: in camptothecin molecule the integrity of lactonic ring structure and its anti-tumor activity closely related, its lactone structure is the important group suppressing Topo I.Camptothecine also exists the balance between the lactone form of closed loop and the carboxylate form of open loop in vivo, and under physiological ph conditions, camptothecine is very easily carboxylate form by lactone ring form open loop.Plasbumin-25 (HAS) is preferentially combined with the carboxylate form of camptothecine, forms stable mixture, and balance is moved to the carboxylate form of open loop, make proper in have anti-tumor activity lactone form content reduce, toxic side effect increase.There are 20 intramolecular hydrogen bonds between hydroxyl and lactone carbonyl in camptothecin molecule, it has not only activated the interaction that lactone also weakens 20 hydroxyls and enzyme simultaneously.If by 20 of camptothecine hydroxy esterifications, hydrogen bond in camptothecin molecule can be eliminated, increase the steric hindrance of contiguous carbonyl, reduce the activity of carbonyl, make nucleophilic reagent not easily attack carbonyl, thus lactonic ring open loop in vivo can be slowed down, be conducive to camptothecine and play antitumor action.
Meanwhile, it is found that and can improve fat-soluble at 7 introducing lipophilic groups of camptothecine, increase the stability of compound, prolong drug is the metabolism time in vivo, may increase anti-tumor activity, thus reduce dosage, reduces medicine to the injury of human body.The people such as Tanizawa find that 7-ethyl has important effect in the reacting to each other of camptothecin derivative and DNA-Topo I mixture.
Summary of the invention
The object of the invention is to provide class 7-ethyl-20 (S)-O-substituted benzoyl camptothecine compounds on the basis of existing technology.The present invention is at 7 introducing ethyls of camptothecine; on 20 hydroxyls, introduce the benzoyl of specified substituent simultaneously; strengthened the anti-tumor activity of camptothecine compounds by the synergy of ethyl and specific substituted benzoyl further, and reduce the toxic side effect of camptothecine.
Another object of the present invention is to provide the application of above-claimed cpd at anti-tumor aspect.
3rd object of the present invention is to provide a kind of preparation method of above-claimed cpd.
Object of the present invention can be reached by following measures:
The antineoplastic compound of formula (3) structure that what one class was new have,
Wherein,
R
1hydrogen, nitro or trifluoromethyl;
R
2hydrogen, halogen, nitro, cyano group or trifluoromethyl;
R
3hydrogen or nitro.
In each group of formula (3), more preferably R
1or R
3hydrogen respectively, R
2hydrogen, halogen, nitro, cyano group or trifluoromethyl.
Another kind of preferred version is R
1hydrogen or nitro, R
2hydrogen, R
3it is nitro.
Halogen in the present invention specifically refers to fluorine, chlorine, bromine or iodine.
The present invention is particularly preferably from following compound:
Compound 3a:7-ethyl-20 (S)-O-benzoyl camptothecine;
Compound 3b:7-ethyl-20 (S)-O-is to fluoro benzoyl camptothecine;
Compound 3c:7-ethyl-20 (S)-O-is to chlorobenzene formacyl camptothecine;
Compound 3d:7-ethyl-20 (S)-O-is to benzoyl bromide camptothecine;
Compound 3e:7-ethyl-20 (S)-O-is to iodobenzoyl camptothecine;
Compound 3f:7-ethyl-20 (S)-O-p-nitrophenyl formyl radical camptothecine;
Compound 3g:7-ethyl-20 (S)-O-m-nitro benzoyl camptothecine;
Compound 3h:7-ethyl-20 (S)-O-(3,5-dinitrobenzene) benzoyl camptothecine;
Compound 3i:7-ethyl-20 (S)-O-is to cyanobenzoyl camptothecine;
Compound 3j:7-ethyl-20 (S)-O-is to TRIFLUOROMETHYLBENZOYL camptothecine;
Compound 3k:7-ethyl-20 (S)-O-m-trifluoromethyl benzoyl camptothecine.
Above-mentioned each compound has following structure respectively:
The present invention also comprises the pharmaceutical composition of above-mentioned each compound, its with above-mentioned each compound for activeconstituents or main active ingredient.Said composition also can comprise pharmaceutically acceptable auxiliary material further and make can for Clinical practice oral, injection or local administration preparation.
The preparation of concrete Gong Clinical practice can be tablet, capsule, oral liquid, granule, injection, solution, powder injection, lyophilized injectable powder, liposome or externally-applied ointment.
The present invention also comprises above-mentioned each compound and is preparing the application in anticancer medicine.
The application of the compounds of this invention, described cancer is: lung cancer, liver cancer, cancer of the stomach, esophagus cancer, mammary cancer, ovarian cancer, the cancer of the brain, prostate cancer, the rectum cancer or leukemia.Compound of the present invention particularly can be applicable to the medicine aspect preparing anti-human lung adenocarcinoma cell (95D), gastric carcinoma cells (BGC-803), gastric carcinoma cells (HGC-27), human liver cancer cell (7721), human liver cancer cell (HCLLM3), human lung carcinoma cell (LLC-E9FP), gastric carcinoma cells (MNK-45), gastric carcinoma cells (BGC-823).
Experiment finds, (particularly R under the combination, cooperation of specified substituent
2for hydrogen, halogen or trifluoromethyl and another two groups be hydrogen time, or when only having a substituting group to be nitro), this compounds has excellent restraining effect to some tumour.The compounds of this invention has highly selective, has good tumor-inhibiting action to tumour cell, simultaneously to the growth of normal cell tissue and metabolic effect less.Compared to other camptothecine compounds (as SN38, SN-38), the compounds of this invention in anti-tumor experiment to the body weight gain unrestraint effect of test mice or restraining effect less, show good low toxic side effect performance.
The present invention also comprises the preparation method of invention compound: with camptothecine (1) for 7-ethyl-camptothecin (2) prepared by raw material, then prepare compound 3 with the benzoic acid of specific replacement, it comprises following steps:
In a kind of preferred version, compound of the present invention, particularly 7-ethyl-20 (S)-O-substituted benzoyl camptothecine compounds 3a ~ 3k, can be prepared by following building-up reactions equation:
With camptothecine (1) for raw material, obtain 7-ethyl-camptothecin (2) through free radical reaction.Under EDCI and DMAP catalysis (imines catalytic condensation), obtain 7-ethyl-20 (S)-O-substituted benzoyl camptothecin target compound (3a ~ 3k) by 2 with substituted benzoyl acid-respons.
The invention has the beneficial effects as follows:
Use imines catalytic condensation, high productivity has synthesized 7-ethyl-20 (S)-O-substituted benzoyl camptothecin new compound (particularly 3a ~ 3k).
The compounds of this invention shows anti tumor activity in vitro test results such as human lung adenocarcinoma cell (95D), gastric carcinoma cells (BGC-803), gastric carcinoma cells (HGC-27), human liver cancer cell (7721), human liver cancer cell (HCLLM3), human lung carcinoma cell (LLC-E9FP), gastric carcinoma cells (MNK-45), gastric carcinoma cells (BGC-823): compound of the present invention is inhibited to above-mentioned cancer cells, and wherein 3b, 3e have to human lung carcinoma cell (LLC-E9FP) inhibit activities being obviously better than camptothecine; 3h, 3i, 3j, 3k also have obvious inhibit activities to tumour cell HGC-27,95D, 7721.
The anti-tumor in vivo experimental result of the compounds of this invention to S180 sarcoma in body shows: it is active that the compounds of this invention has good anti-tumor in vivo to S180 sarcoma, wherein 3a, 3c, 3g, 3j have excellent anti-tumor in vivo activity, its inhibition rate of tumor growth (%) is respectively 68.54,55.85,54.96 and 57.25, all higher than positive control drug SN38 (SN-38); Above-claimed cpd has no significant effect (and SN-38 has obvious restraining effect to tumor-bearing mice body weight gain) tumor-bearing mice body weight gain, shows that the toxic side effect of the compounds of this invention is less than contrast medicine (SN-38) and other similar compounds.
In body, human breast carcinoma Nude Mice (MDA-MB-435) anti-tumor experiment result shows: compound 3a, 3c, 3g, 3j all have excellent anti-tumor activity, intraperitoneal administration 8mg/kg dosage its Relative tumor proliferation rate T/C (%) is respectively 55.86 (SN-38 is 34.88), 50.78 (SN-38 is 31.74), 57.84 (SN-38 is 30.78) and 68.04 (SN-38 is 58.82), and less on the growth metabolism impact of nude mouse normal cell tissue.
Accompanying drawing explanation
Fig. 1. compound 3b, 3e, 3h, 3g, 3j are to the growth-inhibiting effect of S180 sarcoma
Fig. 2. compound 3b, 3e, 3h, 3g, 3j treated animal body weight change figure
Fig. 3. compound 3a, 3i, 3f are to the growth-inhibiting effect of S180 sarcoma
Fig. 4. compound 3a, 3i, 3f treated animal body weight change figure
Fig. 5. compound 3c, 3d, 3k are to the growth-inhibiting effect of S180 sarcoma
Fig. 6. compound 3c, 3d, 3k treated animal body weight change figure
Fig. 7. compound 3a is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Fig. 8. compound 3a is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Fig. 9. compound 3a is on the impact of human breast carcinoma MDA-MB-435 nude mouse body weight
Figure 10. compound 3c is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Figure 11. compound 3c is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Figure 12. compound 3c is on the impact of human breast carcinoma MDA-MB-435 nude mouse body weight
Figure 13. compound 3g is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Figure 14. compound 3g is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Figure 15. compound 3g is on the impact of human breast carcinoma MDA-MB-435 nude mouse body weight
Figure 16. compound 3j is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Figure 17. compound 3j is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Figure 18. compound 3j is on the impact of human breast carcinoma MDA-MB-435 nude mouse body weight
Embodiment
The instrument used in following examples and reagent: X-4 type numerical monitor micro-meldometer (thermometer does not correct); EssentiaLC-15C type high performance liquid chromatograph (Luna 18 alkyl silica gel post, moving phase is methanol-water 80: 20,267nm); BRUKERAVANCE AV-500 type nuclear magnetic resonance spectrometer (CDCl
3for solvent, TMS is interior mark); Thermo Nicolet iS10 type infrared spectrometer (KBr compressing tablet); Waters Q-TOF MicroTM type mass spectrograph.
Camptothecine is provided by Chengdu Lan Qi pharmaceutical Co. Ltd, and EDCI, DMAP are provided by Suzhou Highfine Biotech Co., Ltd., and other raw materials used and reagent are analytical pure, CH
2cl
2through CaH
2backflow drying treatment, the front heavy steaming of positive propionic aldehyde.
The synthesis of 7-ethyl-camptothecin (2):
Camptothecine (1) 3.00g (8.60mmol) is dissolved in Glacial acetic acid 80mL, slowly drips 98% sulfuric acid 20mL in 5 ~ 10 DEG C, drip and finish, be stirred to glassy yellow, obtain camptothecine solution.
FeSO is added in reaction flask
47H
2o 2.50g (9.00mmol) and deionized water 100mL, stirs and makes it dissolve; Add above-mentioned alkaline solution in about 2 DEG C, after stirring, drip the positive propionic aldehyde 3.0mL (40.0mmol) of new steaming, stir and slowly drip 30%H a moment
2o
2(15min), stirring reaction 45min.In impouring 250mL frozen water, filter, filtrate extracts with chloroform (3 × 100mL), and extraction liquid is evaporated to dry, obtains yellow solid.Through silica gel (100 ~ 200 order) column chromatography (chloroform wash-out) purifying, obtain pale yellow powder 22.40g, purity >=99.0% (HPLC normalization method, lower same), yield 74.0%, mp 259 ~ 260 DEG C.
The synthesis of 7-ethyl-20 (S)-O-benzoyl camptothecine (3a):
Phenylformic acid 0.73g (6.00mmol) is dissolved in CH
2cl
2in 100mL, add 20.75g (2.00mmol) successively under ice bath (about 2 DEG C) cooling and stirring, EDCI 1.53g (8.00mmol) and DMAP 1.47g (12mmol), lucifuge stirs 15min.Room temperature lucifuge stirring reaction 2.0h.By in reaction solution impouring 100mL frozen water, separate organic layer, successively with diluted acid (pH=3.3), saturated common salt water washing, anhydrous Na
2sO
4dry.Be evaporated to 1/10 volume, with purification by silica gel column chromatography (CH
2cl
2-THF gradient elution), obtain white powder, then with CH
2cl
2-MeOH recrystallization, obtains 3a 0.62g, purity>=99.0%, yield 64.4%, mp 282 ~ 285 DEG C.
Replace phenylformic acid with substituted benzoic acid, by similar approach synthesis 3b ~ 3k, the results are shown in Table 1.
The preparation situation of table 1. compound 3a ~ 3k
7-ethyl-20 (S)-O-benzoyl camptothecine (3a): white powdery solids, productive rate 64.4%, mp 282 ~ 285 DEG C;
1hNMR (CDCl
3, 500MHz) and δ: 1.09 (t, J=7.5Hz, 3H, 19-H), 1.37 (t, J=7.8Hz, 3H, 30-H), 2.33 ~ 2.46 (m, 2H, 18-H), 3.18 (q, 2H, 29-H), 5.23 (d, J=19.0Hz, H, 5-H), 5.25 (d, J=18.5Hz, H, 5-H), 5.48 (d, J=17.0Hz, H, 17-H), 5.78 (d, J=17.0Hz, H, 17-H), 7.26 (s, H, 14-H), 7.46 ~ 8.12 (m, 9H, 9 ~ 12-H, 24 ~ 28-H); IR:v 3492,2980,2943,2880,1768,1725,1657,1610,1451,1274,1100,761,712cm
-1; ESI-MS m/z:481.2 (M+1)
+; Anal.Called for C
29h
24n
2o
5: C, 72.49; H, 5.03; N, 5.83; Found:C, 72.20; H, 5.11; N, 5.74.
7-ethyl-20 (S)-O-is to fluoro benzoyl camptothecine (3b): off-white powder shape solid, productive rate 67.2%, mp 274 ~ 276 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.09 (t, J=7.5Hz, 3H, 19-H), 1.37 (t, J=7.7Hz, 3H, 30-H), 2.32 ~ 2.46 (m, 2H, 18-H), 3.19 (q, 2H, 29-H), 5.22 (d, J=18.5Hz, H, 5-H), 5.27 (d, J=18.5Hz, H, 5-H), 5.48 (d, J=17.0Hz, H, 17-H), 5.76 (d, J=17.0Hz, H, 17-H), 7.15 (t, J=8.5Hz, 2H, 25, 27-H), 7.25 (s, H, 14-H), 7.66 (t, J=7.5Hz, H, 10-H), 7.77 (t, J=7.5Hz, H, 11-H), 8.10 ~ 8.16 (m, 4H, 9, 12, 24, 28-H), IR:v 3432,2976,2939,2881,1759,1729,1665,1617,1277,1230,1103,852,766,725cm
-1, ESI-MS m/z:499.2 (M+1)
+, Anal.Called for C
29h
23fN
2o
5: C, 69.87, H, 4.65, N, 5.62, Found:C, 69.70, H, 4.70, N, 5.56.
7-ethyl-20 (S)-O-is to chlorobenzene formacyl camptothecine (3c): white powdery solids, productive rate 62.1%, mp 279 ~ 283 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.09 (t, J=7.5Hz, 3H, 19-H), 1.39 (t, J=7.8Hz, 3H, 30-H) 2.31 ~ 2.45 (m, 2H, 18-H), 3.19 (q, 2H, 29-H), 5.20 (d, J=18.5Hz, H, 5-H), 5.27 (d, J=18.5Hz, H, 5-H), 5.48 (d, J=17.0Hz, H, 17-H), 5.75 (d, J=17.0Hz, H, 17-H), 7.23 (s, H, 14-H), 7.45 (t, J=8.5Hz, 2H, 25, 27-H), 7.64 (t, J=7.5Hz, H, 10-H), 7.77 (t, J=7.5Hz, H, 11-H), 8.03 (d, J=8.5Hz, 2H, 24, 28-H), 8.13 (m, 2H, 9, 12-H), IR:v 3438,2977,2939,2879,1762,1729,1666,1617,1452,1274,1155,1101,848,761,724cm
-1, ESI-MS m/z:515.1 (M+1)
+, Anal.Called forC
29h
23clN
2o
5: C, 67.64, H, 4.50, N, 5.44, Found:C, 67.51, H, 4.57, N, 5.35.
7-ethyl-20 (S)-O-is to benzoyl bromide camptothecine (3d): white powdery solids, productive rate 84.9%, mp 269 ~ 273 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.08 (t, J=7.5Hz, 3H, 19-H3), 1.39 (t, J=7.8Hz, 3H, 30-H) 2.31 ~ 2.44 (m, 2H, 18-H), 3.19 (q, 2H, 29-H), 5.22 (d, J=18.5Hz, H, 5-H), 5.26 (d, J=18.5Hz, H, 5-H), 5.47 (d, J=17.0Hz, H, 17-H), 5.76 (d, J=17.0Hz, H, 17-H), 7.23 (s, H, 14-H), 7.64 (t, J=8.5Hz, 2H, 25, 27-H), 7.66 (t, J=7.5Hz, H, 10-H), 7.77 (t, J=7.5Hz, H, 11-H), 7.95 (d, J=8.5Hz, 2H, 24, 28-H), 8.10 (d, J=8.5Hz, H, 9-H), 8.15 (d, J=8.5Hz, H, 12-H), IR:v 3438,2978,2938,2879,1762,1728,1665,1617,1273,1156,1100,844,763,725cm
-1, ESI-MS m/z:561.1 (M+1)
+, Anal.Called for C
29h
23brN
2o
5: C, 62.26, H, 4.14, N, 5.01, Found:C, 62.14, H, 4.19, N, 4.95.
7-ethyl-20 (S)-O-is to iodobenzoyl camptothecine (3e): white powdery solids, productive rate 74.2%, mp 268 ~ 270 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.08 (t, J=7.5Hz, 3H, 19-H), 1.37 (t, J=7.8Hz, 3H, 30-H), 2.28 ~ 2.33 (m, 2H, 18-H), 3.17 (q, 2H, 29-H), 5.20 (d, J=18.5Hz, H, 5-H), 5.25 (d, J=18.5Hz, H, 5-H), 5.46 (d, J=17.0Hz, H, 17-H), 5.77 (d, J=17.0Hz, H, 17-H), 7.22 (s, H, 14-H), 7.65 (t, J=7.5Hz, H, 10-H), 7.75 (s, H, 11-H), 7.77 (t, J=8.5Hz, 2H, 25, 27-H), 7.82 (d, J=8.5Hz, 2H, 24, 28-H), 8.09 (d, J=8.5Hz, H, 9-H), 8.14 (d, J=8.5Hz, H, 12-H), IR:v 3619,3418,2974,2935,2877,1757,1726,1662,1615,1268,1230,1177,849,750,725cm
-1, ESI-MS m/z:607.1 (M+1)
+, Anal.Called for C
29h
23iN
2o
5: C, 57.44, H, 3.82, N, 4.62, Found:C, 57.40, H, 3.89, N, 4.58.
7-ethyl-20 (S)-O-p-nitrophenyl formyl radical camptothecine (3f): off-white powder shape solid, productive rate 83.7%, mp258 ~ 261 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.11 (t, J=7.5Hz, 3H, 19-H), 1.37 (t, J=7.8Hz, 3H, 30-H), 2.33 ~ 2.47 (m, 2H, 18-H), 3.19 (q, 2H, 29-H), 5.24 (d, J=18.5Hz, H, 5-H), 5.28 (d, J=18.5Hz, H, 5-H), 5.48 (d, J=17.0Hz, H, 17-H), 5.79 (d, J=17.0Hz, H, 17-H), 7.22 (s, H, 14-H), 7.66 (t, J=7.5Hz, H, 10-H), 7.76 (s, H, 11-H), 8.12 (t, J=8.0Hz, 2H, 9, 12-H), 8.24 (d, J=9.0Hz, 2H, 24, 28-H), 8.30 (d, J=9.0Hz, 2H, 25, 27-H), IR:v 3648,3532,2979,2940,2881,1758,1731,1664,1616,1526,1276,1109,869,764,721cm
-1, ESI-MS m/z:526.2 (M+1)
+, Anal.Called for C
29h
27n
3o
7: C, 66.28, H, 4.41, N, 8.00, Found:C, 66.21, H, 4.50, N, 7.95.
7-ethyl-20 (S)-O-m-nitro benzoyl camptothecine (3g): off-white powder shape solid, productive rate 77.1%, mp272 ~ 274 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.11 (t, J=7.5Hz, 3H, 19-H), 1.40 (t, J=7.8Hz, 3H, 30-H), 2.37 ~ 2.49 (m, 2H, 18-H), 3.20 (q, 2H, 29-H), 5.25 (d, J=18.5Hz, H, 5-H), 5.29 (d, J=19.0Hz, H, 5-H), 5.49 (d, J=17.0Hz, H, 17-H), 5.79 (d, J=17.0Hz, H, 17-H), 7.25 (s, H, 14-H), 7.68 (m, 2H, 10, 25-H), 7.77 (t, J=7.5Hz, H, 11-H), 8.13 (t, J=9.8Hz, 2H, 9, 12-H), 8.40 (d, J=7.5Hz, H, 24-H), 8.46 (m, H, 26-CH), 8.93 (s, H, 28-H), IR:v 3483,3086,2970,2939,2879,1761,1730,1659,1612,1534,1453,1344,1288,1264,1126,977,764,719cm
-1, ESI-MS m/z:526.2 (M+1)
+, Anal.Called for C
29h
27n
3o
7: C, 66.28, H, 4.41, N, 8.00, Found:C, 66.20, H, 4.49, N, 7.92.
7-ethyl-20 (S)-O-(3,5-dinitrobenzene) benzoyl camptothecine (3h): off-white powder shape solid, productive rate 70.1%, mp 276 ~ 278 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.13 (t, J=7.5Hz, 3H, 19-H), 1.40 (t, J=7.8Hz, 3H, 30-H), 2.39 ~ 2.53 (m, 2H, 18-H), 3.21 (q, 2H, 29-H), 5.25 (s, 2H, 5-H), 5.49 (d, J=17.0Hz, H, 17-H), 5.79 (d, J=17.0Hz, H, 17-H), 7.22 (s, H, 14-H), 7.65 (t, J=9.8Hz, H, 10-H), 7.75 (q, H, 11-H), 8.10 (t, J=9.8Hz, 2H, 9, 12-H), 8.40 (d, J=7.5Hz, H, 24-H), 8.46 (m, H, 26-H), 8.93 (s, H, 28-H), IR:v 3166,2972,2942,2881,1772,1742,1661,1605,1544,1345,1277,1165,1077,762,720cm
-1, ESI-MS m/z:571.2 (M+1)
+, Anal.Called for C
29h
22n
4o
9: C, 61.05, H, 3.89, N, 9.82, Found:C, 60.95, H, 3.94, N, 9.75.
7-ethyl-20 (S)-O-is to cyanobenzoyl camptothecine (3i): white powdery solids, productive rate 66.3%, mp 284 ~ 287 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.10 (t, J=7.5Hz, 3H, 19-H), 1.40 (t, J=7.8Hz, 3H, 30-H), 2.33 ~ 2.45 (m, 2H, 18-H), 3.20 (q, 2H, 29-H), 5.24 (d, J=17.0Hz, H, 5-H), 5.28 (d, J=17.0Hz, H, 5-H), 5.47 (d, J=17.0Hz, H, 17-H), 5.78 (d, J=17.0Hz, H, 17-H), 7.22 (s, H, 14-H), 7.67 (t, J=7.8Hz, H, 10-H), 7.78 (t, J=8.0Hz, 3H, 11, 25, 27-H), 8.11 ~ 8.20 (m, 4H, 9, 12, 24, 28-H), IR:v 3604,2978,2940,2880,2231,1757,1734,1667,1618,1453,1277,1155,1102,858,765,708cm
-1, ESI-MS m/z:506.2 (M+1)
+, Anal.Called for C
29h
27n
3o
7: C, 71.28, H, 4.59, N, 8.31, Found:C, 71.20, H, 5.64, N, 8.26.
7-ethyl-20 (S)-O-is to TRIFLUOROMETHYLBENZOYL camptothecine (3j): white powdery solids, productive rate 82.0%, mp 252 ~ 254 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.10 (t, J=7.5Hz, 3H, 19-H), 1.40 (t, J=7.8Hz, 3H, 30-H), 2.34 ~ 2.47 (m, 2H, 18-H), 3.21 (q, 2H, 29-H), 5.24 (d, J=19.0Hz, H, 5-H), 5.28 (d, J=19.0Hz, H, 5-H), 5.47 (d, J=17.0Hz, H, 17-H), 5.78 (d, J=17.0Hz, H, 17-H), 7.26 (s, H, 14-H), 7.64 (t, J=7.5Hz, H, 10-H), 7.78 (q, 3H, 11, 25, 27-H), 8.14 (q, 2H, 9, 12-H), 8.22 (d, J=8.0Hz, 2H, 24, 28-H), IR:v 2975,2938,2882,1760,1732,1665,1613,1326,1276,1160,1130,1100,1065,860,766,703cm
-1, ESI-MS m/z:549.2 (M+1)
+, Anal.Called forC
30h
23f
2n
2o
5: C, 65.69, H, 4.23, N, 5.11, Found:C, 65.60, H, 4.29, N, 5.01.
7-ethyl-20 (S)-O-m-trifluoromethyl benzoyl camptothecine (3k): off-white powder shape solid, productive rate 45.9%, mp 277 ~ 281 DEG C,
1hNMR (CDCl
3, 500MHz) δ: 1.09 (t, J=7.5Hz, 3H, 19-H), 1.40 (t, J=7.8Hz, 3H, 30-H), 2.35 ~ 2.49 (m, 2H, 18-H), 3.20 (q, 2H, 29-H), 5.24 (d, J=18.5Hz, H, 5-H), 5.29 (d, J=18.5Hz, H, 5-H), 5.47 (d, J=17.0Hz, H, 17-H), 5.78 (d, J=17.0Hz, H, 17-H), 7.26 (s, H, 14-H), 7.62 ~ 7.79 (m, 2H, 10, 25-H), 7.77 (t, J=8.0Hz, H, 11-H), 7.88 (d, J=7.5Hz, H, 26-H), 8.12 (d, J=8.0Hz, H, 9-H), 8.16 (d, J=8.5Hz, H, 24-H), 8.29 (d, J=8.0Hz, H, 12-H), 8.36 (s, H, 28-H), IR:v 3499,2980,2941,2882,1763,1729,1664,1613,1454,1337,1254,1122,1070,975,825,759,696cm
-1, ESI-MS m/z:549.2 (M+1)
+, Anal.Called for C
30h
23f
2n
2o
5: C, 65.69, H, 4.23, N, 5.11, Found:C, 65.54, H, 4.31, N, 5.03.
Anti tumor activity in vitro is tested:
Compound 3a ~ 3k is measured to the inhibiting rate of human lung adenocarcinoma cell (95D), gastric carcinoma cells (BGC-803), gastric carcinoma cells (HGC-27), human liver cancer cell (7721), human liver cancer cell (HCLLM3), human lung carcinoma cell (LLC-E9FP), gastric carcinoma cells (MNK-45) and gastric carcinoma cells (BGC-823) with mtt assay.
Get and be in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion makes attached cell come off, counting 2 ~ 4 × 10
4individual/mL, makes cell suspension.Obtained cell suspension is inoculated on 96 orifice plates, and 180 μ L/ holes, put constant temperature CO
224h is cultivated in incubator.Change liquid, add test medicine, 20 μ L/ holes, cultivate 72h.Added by MTT reagent in 96 orifice plates, 20 μ L/ holes, react 4h in incubator.Suck supernatant liquor, add DMSO, 150 μ L/ holes, jolting 5min on plate shaker.Be the light absorption value (OD:Optical Density, optical density(OD)) in the every hole of mensuration, 570nm place at wavelength with enzyme-linked immunosorbent assay instrument, revision test is averaged for 3 times and is calculated inhibition rate of tumor cell (%):
Result and conclusion:
Experimental result and anti-tumor activity judging criterion are in table 2, table 3.Preliminary activation the selection result shows: 7 ethylizations of camptothecine and 20 liftings of hydroxyl-substituted formic acid esterification to camptothecins anti-tumor activity play a positive role.The difference of this type of Compound ira vitro anti-tumor activity may be caused by different substituents in substituted benzoic acid: when substituting group is strong electron-withdrawing group group, show good anti tumor activity in vitro; When substituting group is halogen, the inhibit activities of human lung carcinoma cell (LLC-E9FP) is obviously strengthened.
The inhibition rate of tumor cell of table 2. compound 3a ~ 3k
The inhibition rate of tumor cell (Continued) of table 2. compound 3a ~ 3k
Table 3. Antitumor Activity of Drugs judging criterion
S180 sarcoma anti-tumor activity test:
Test the growth-inhibiting effect of compound 3a ~ 3k to S180 sarcoma.
Experiment material:
(1) animal: ICR mouse, 18 ~ 22g, SPF level, female, provided by Jiangsu Yangzhou University comparative medicine center, conformity certification SCXK (Soviet Union) 2007-0001.
(2) knurl kind: S180 sarcoma;
(3) medicine: compound 3a ~ 3k makes by oneself; Contrast medicine SN38 (SN-38), Chengdu Lan Qi pharmaceutical Co. Ltd provides.
(4) compound method: take medicine 8mg, adds 1mL Viscotrol C, then adds 1mL dehydrated alcohol, shakes up dissolving.Add 8mL physiological saline again, shake up, be mixed with the solution that concentration is 0.8mg/mL.
Medication and the course for the treatment of: the S180 sarcoma knurl kind selecting 18 ~ 22g Female ICR mice and well-grown 7 ~ 11 days, is inoculated in ICR right side of mice armpit subcutaneous, about 4.5 ~ 5 × 10
6cell/only, random point cage after inoculation 24h, compound 3a ~ 3k group every other day intraperitoneal administration once, negative control group gives the solvent of administration group equivalent.Within 9th day, put to death animal, to weigh, knurl weight.Calculate each group of average knurl weight, press formula and obtain tumor control rate and carry out T inspection.
Result and conclusion:
(1) compound 3b, 3e, 3h, 3g, 3j is to the growth-inhibiting effect of S180 sarcoma
Experimental result is in table 4, Fig. 1 and Fig. 2.
SN-38 intraperitoneal administration 8mg/kg is 47.33% to the growth inhibition ratio of S180 sarcoma; 3b intraperitoneal administration 2.5mg/kg is to the growth of S180 sarcoma without obvious restraining effect, and inhibiting rate is 38.93%; The growth of 3e intraperitoneal administration 8mg/kg to S180 sarcoma has restraining effect, and inhibiting rate is 48.09%; The growth of 3g intraperitoneal administration 8mg/kg to S180 sarcoma has restraining effect, and inhibiting rate is 54.96%; The growth of 3h intraperitoneal administration 8mg/kg to S180 sarcoma has restraining effect, and inhibiting rate is 49.62%; The growth of 3j intraperitoneal administration 8mg/kg to S180 sarcoma has restraining effect, and inhibiting rate is 57.25%.The tumor-inhibiting action of compound 3g, 3j is significantly better than SN-38.
SN-38 increases Mouse Weight obvious restraining effect (toxic side effect), and SN-38 group Mouse Weight rate of increase is only 0.44%, far below blank group; Compound 3b, 3e, 3h, 3g, 3j group Mouse Weight increases normal (see table 4, Fig. 2).
Table 4. compound 3b, 3e, 3g, 3h, 3j are to the growth-inhibiting effect of S180 sarcoma
(2) compound 3a, 3f, 3i is to the growth-inhibiting effect of S180 sarcoma
Experimental result is in table 5, Fig. 3 and Fig. 4.
SN-38 intraperitoneal administration 8mg/kg is 60.33% to the growth inhibition ratio of S180 sarcoma; The growth of 3a intraperitoneal administration 8mg/kg to S180 sarcoma has obvious restraining effect, and inhibiting rate is 68.54%; The growth of 3f intraperitoneal administration 8mg/kg to S180 sarcoma has restraining effect, and inhibiting rate is 48.09%; The growth of 3i intraperitoneal administration 8mg/kg to S180 sarcoma has restraining effect, and inhibiting rate is 53.48%.The tumor-inhibiting action of compound 3a is significantly better than SN-38.
Table 5. compound 3a, 3f, 3i are to the growth-inhibiting effect of S180 sarcoma
(3) compound 3c, 3d, 3k is to the growth-inhibiting effect of S180 sarcoma
Experimental result is in table 6, Fig. 5 and Fig. 6.
SN-38 intraperitoneal administration 8mg/kg is 40.43% to the growth inhibition ratio of S180 sarcoma; The growth of 3c intraperitoneal administration 8mg/kg to S180 sarcoma has restraining effect, and inhibiting rate is 55.85%; 3d intraperitoneal administration 8mg/kg is to the growth unrestraint effect of S180 sarcoma, and inhibiting rate is 9.57%; 3k intraperitoneal administration 8mg/kg is to the growth unrestraint effect of S180 sarcoma, and inhibiting rate is-37.23%.The tumor-inhibiting action of compound 3c is significantly better than SN-38.
SN-38 increases Mouse Weight obvious restraining effect (toxic side effect), and SN-38 group Mouse Weight rate of increase is 0, is starkly lower than blank group; Compound 3c, 3d, 3k group Mouse Weight increases normal (see table 6, Fig. 6).
Table 6. compound 3c, 3d, 3k are to the growth-inhibiting effect of S180 sarcoma
Human breast carcinoma MDA-MB-435 Nude Mice anti-tumor activity test:
Compound 3a, 3c, 3g, 3j are investigated to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice and action intensity.
Experiment material:
(1) animal: female BAl BIc/cA nude mouse, age in days 35 ~ 40 days, body weight 18 ~ 22g, is provided by hospital general of Nanjing Military Command medical science Correlation Centre, credit number SCXK (army) 2007-012.Every treated animal number is negative control group 12, administration group 6.
(2) transplanted tumor: human breast carcinoma MDA-MB-435 Nude Mice, is inoculated in nude mouse by human breast carcinoma MDA-MB-435 cell strain subcutaneous and set up.Cell inoculum size is 3 × 10
6, inoculation uses after passing for 3 generations again in nude mice after forming transplanted tumor.
(3) medicine: compound 3a, 3c, 3g, 3j make by oneself; Contrast medicine SN-38, Chengdu Lan Qi pharmaceutical Co. Ltd provides.
(4) compound method: take medicine 8mg, adds 2ml Viscotrol C, and concussion shakes up dissolving, then adds 2mL dehydrated alcohol, and concussion shakes up, and then adds 6mL physiological saline, shakes up, and is mixed with the suspension solution that concentration is 0.8mg/kg.
Experimental technique: the tumor tissue getting growth animated period cuts into 1.5mm
3left and right, aseptically, is inoculated in armpit on the right side of nude mouse subcutaneous.Nude Mice vernier caliper measurement transplanted tumor diameter, treats tumor growth to 100 ~ 300mm
3after by animal random packet.Use the method measuring knurl footpath, dynamically observe the effect of tested drugs against tumor.The pendulous frequency of diameter of tumor is 3 times weekly, and each measurement also needs to claim mouse heavy simultaneously.SN-388mg/kg, compound 3a, 3c, 3g, 3j respectively with 2mg/kg, 4mg/kg, 8mg/kg every other day intraperitoneal administration once, each administration 0.2mL.Negative control group gives the solvent of equivalent simultaneously.
Testing index and method of calculation:
(1) gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b
2
Wherein a, b represent length and width respectively.
(2) relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝TV
t/TV
0。
Wherein TV
0for (d during point cage administration
0) gross tumor volume;
TV
tgross tumor volume during for measuring each time.
(3) Relative tumor proliferation rate T/C (%), calculation formula is:
T
rTV: treatment group RTV;
C
rTV: negative control group RTV.
Test-results is using Relative tumor proliferation rate T/C (%) as the evaluation index of anti-tumor activity.
Statistical method: experimental data represents with mean value and standard deviation, statistical method adopts t-inspection.
Result and conclusion:
(1) compound 3a is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Experimental result is in table 7, Fig. 7, Fig. 8 and Fig. 9.
The growth of SN-38 intraperitoneal administration 8mg/kg to human breast carcinoma MDA-MB-435 mice-transplanted tumor has certain restraining effect, and best T/C is 34.88%; 3a intraperitoneal administration 8mg/kg has certain growth-inhibiting effect to human breast carcinoma MDA-MB-435 mice-transplanted tumor, and best T/C is 55.86%; 3a intraperitoneal administration 4mg/kg is to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, and best T/C is 69.48%; 3a intraperitoneal administration 2mg/kg is to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, and best T/C is 75.48%.
SN-38 has obvious restraining effect (toxic side effect) to nude mouse body weight gain, and SN-38 group Mouse Weight rate of increase is-3.03%, is starkly lower than blank group; Compound 3a each dosage group nude mouse body weight gain normal (see table 7, Fig. 9).
Table 7. compound 3a is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
The RTV that d0 divides RTV and the CONTROL of cage administration time P administration group to organize contrasts *: P < 0.05**:P < 0.01
(2) compound 3c is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Experimental result is in table 8, Figure 10, Figure 11 and Figure 12.
The growth of SN-38 intraperitoneal administration 8mg/kg to human breast carcinoma MDA-MB-435 mice-transplanted tumor has certain restraining effect, and best T/C is 31.74%; 3c intraperitoneal administration 8mg/kg has certain growth-inhibiting effect to human breast carcinoma MDA-MB-435 mice-transplanted tumor, and best T/C is 50.78%; 3c intraperitoneal administration 4mg/kg to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, best T/C is 75.65%.3c intraperitoneal administration 2mg/kg is to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, and best T/C is 77.48%.
SN-38 has obvious restraining effect (toxic side effect) to nude mouse body weight gain, and SN-38 group Mouse Weight rate of increase is-1.67%, significantly lower than blank group; Compound 3c each dosage group nude mouse body weight gain normal (see table 8, Figure 12).
Table 8. compound 3c is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
The RTV that d0 divides RTV and the CONTROL of cage administration time P administration group to organize contrasts *: P < 0.05**:P < 0.01
(3) compound 3g is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Experimental result is in table 9, Figure 13, Figure 14 and Figure 15.
The growth of SN-38 intraperitoneal administration 8mg/kg to human breast carcinoma MDA-MB-435 mice-transplanted tumor has certain restraining effect, and best T/C is 30.78%; 3g intraperitoneal administration 2mg/kg has certain growth-inhibiting effect to human breast carcinoma MDA-MB-435 mice-transplanted tumor, and best T/C is 93.41%; 3g intraperitoneal administration 4mg/kg is to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, and best T/C is 81.97%; 3g intraperitoneal administration 8mg/kg is to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, and best T/C is 57.84%.
SN-38 has obvious restraining effect (toxic side effect) to nude mouse body weight gain, and SN-38 group Mouse Weight rate of increase is-12.81%, significantly lower than blank group; Compound 3g high dose group also has certain restraining effect (see table 9, Figure 15) to nude mouse body weight gain.
Table 9. compound 3g is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
The RTV that d0 divides RTV and the CONTROL of cage administration time P administration group to organize contrasts *: P < 0.05**:P < 0.01
(4) compound 3j is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
Experimental result is in table 10, Figure 16, Figure 17 and Figure 18.
The growth of SN-38 intraperitoneal administration 8mg/kg to human breast carcinoma MDA-MB-435 mice-transplanted tumor has certain restraining effect, and best T/C is 58.82%; 3j intraperitoneal administration 8mg/kg has certain growth-inhibiting effect to human breast carcinoma MDA-MB-435 mice-transplanted tumor, and best T/C is 68.04%; 3j intraperitoneal administration 4mg/kg is to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, and best T/C is 73.93%; 3j intraperitoneal administration 2mg/kg is to human breast carcinoma MDA-MB-435 mice-transplanted tumor without growth-inhibiting effect, and best T/C is 74.35%.
Table 10. compound 3j is to the growth-inhibiting effect of human breast carcinoma MDA-MB-435 Nude Mice
The RTV that d0 divides RTV and the CONTROL of cage administration time P administration group to organize contrasts *: P < 0.05**:P < 0.01
Claims (7)
1. a compounds, is selected from
7-ethyl-20 (
s)-O-benzoyl camptothecine;
7-ethyl-20 (
s)-O-is to chlorobenzene formacyl camptothecine;
7-ethyl-20 (
s)-O-m-nitro benzoyl camptothecine;
7-ethyl-20 (
s)-O-is to TRIFLUOROMETHYLBENZOYL camptothecine.
2. a pharmaceutical composition, is characterized in that said composition with compound according to claim 1 for main active ingredient.
3. composition according to claim 2, it is characterized in that said composition comprise pharmaceutically acceptable auxiliary material and make can for Clinical practice oral, injection or local administration preparation.
4. composition according to claim 3, is characterized in that described preparation is tablet, capsule, granule, solution, powder injection, liposome or externally-applied ointment.
5. composition according to claim 3, is characterized in that described preparation is oral liquid, injection or lyophilized injectable powder.
6. compound described in claim 1 is preparing the purposes in anticancer medicine.
7. purposes according to claim 6, is characterized in that described cancer is lung cancer, liver cancer, cancer of the stomach, esophagus cancer, mammary cancer, ovarian cancer, the cancer of the brain, prostate cancer, the rectum cancer or leukemia.
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| WO2010025337A1 (en) * | 2008-08-29 | 2010-03-04 | Enzon Pharmaceuticals, Inc. | Method of treating ras associated cancer |
| WO2010060098A1 (en) * | 2008-11-24 | 2010-05-27 | Cedars-Sinai Medical Center | Antioxidant camptothecin derivatives and antioxidant antineoplastic nanospheres thereof |
| CN102010418A (en) * | 2010-12-09 | 2011-04-13 | 中国人民解放军第二军医大学 | High-camptothecin compounds and use thereof as medicaments |
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| WO2010025337A1 (en) * | 2008-08-29 | 2010-03-04 | Enzon Pharmaceuticals, Inc. | Method of treating ras associated cancer |
| WO2010060098A1 (en) * | 2008-11-24 | 2010-05-27 | Cedars-Sinai Medical Center | Antioxidant camptothecin derivatives and antioxidant antineoplastic nanospheres thereof |
| CN102010418A (en) * | 2010-12-09 | 2011-04-13 | 中国人民解放军第二军医大学 | High-camptothecin compounds and use thereof as medicaments |
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