CN101182321A - Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof - Google Patents
Indolizine heterocyclic nitrogen naphthoquinone derivatives as well as preparation method and anticancer use thereof Download PDFInfo
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- CN101182321A CN101182321A CNA2007100323563A CN200710032356A CN101182321A CN 101182321 A CN101182321 A CN 101182321A CN A2007100323563 A CNA2007100323563 A CN A2007100323563A CN 200710032356 A CN200710032356 A CN 200710032356A CN 101182321 A CN101182321 A CN 101182321A
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Abstract
The present invention discloses an indolizine and nitrogen heterocyclic naphthoquinone derivative, a preparation method and an anticancer application thereof. The structure of the indolizine and nitrogen heterocyclic naphthoquinone derivative is shown as a formula (I). The preparation method is that 6, 7-dichloro nitrogen heterocyclic naphthoquinone and active methylene reagent are put in to anhydrous alcohol, and pyridine derivative is added under stirring for the reflux reaction for 5 to 20 hours; the reaction finished for cooling, solid is separated out to be filtered and processed for the chromatographic separation by silicon gel column to obtain the target compound. The indolizine and nitrogen heterocyclic naphthoquinone derivative has obvious inhibitory effect towards various kinds of tumour cells, has comparatively small virulence towards the normal cell and has the prospect of preparing for the anticancer medicine.
Description
Technical field
The present invention relates to a class indolizino azanaphthalenes quinone derivative and the purposes in preparation treatment cancer drug thereof.
Background technology
Tumour is the principal disease that threatens human health and life security.The research and development of new type antineoplastic medicine are the important research field that chemist and medicine scholar pay close attention to always.
Camptothecine is a class natural alkaloid, has good antineoplastic activity.Discover that camptothecine is mainly by suppressing topoisomerase 1 (TOP1) the performance antitumous effect in the tumour cell.But the anti-tumor activity of camptothecine is still undesirable, if can carry out structural modification to it, strengthens its anti-tumor activity, and application prospect is with boundless.
Summary of the invention
The purpose of this invention is to provide the new indolizino azanaphthalenes quinone derivative of a class.
Another object of the present invention provides the application of above-mentioned indolizino azanaphthalenes quinone derivative in preparation treatment cancer drug.
The indolizino azanaphthalenes quinone derivative that the present invention relates to is suc as formula shown in (I):
Wherein, M, X, Y and Z are CH or N respectively;
R
1Be selected from following radicals: H, C respectively
1-C
4Alkyl, COOCH
3, COOC
2H
5, COOC
3H
7, COOC
4H
9, COCH
3, COC
2H
5, COC
3H
7, COC
4H
9, CN or aromatic base;
R
2Be selected from following radicals: H, F, Cl, Br, OH, NH respectively
2, COOH or C
1-C
4Alkyl;
R
3Be selected from following radicals: H, F, Cl, Br, OH, COOH or C respectively
1-C
4Alkyl.
Indolizino azanaphthalenes quinone derivative of the present invention can obtain by the method for chemosynthesis, can obtain (II) by following reaction.
With 6,7-dichloro azepine naphthoquinones and active methylene group reagent join in the dehydrated alcohol, stir to add pyridine derivate, back flow reaction 5～20 hours down; Stop, cooling has solid to separate out; Filter, the solid that obtains obtains target compound with the silica gel column chromatography separation.In this reaction, can obtain a pair of isomer A and B simultaneously, or single product (being that product A is identical with B).
Described active methylene group reagent is Acetacetic acid alkyl ester, itrile group ethyl acetate, methyl ethyl diketone or nitroparaffins.
Show by the tumor cell in vitro inhibition test, indolizino azanaphthalenes quinone derivative of the present invention has obvious inhibiting activity to various tumor cell strains as GLC-82 (human lung adenocarcinoma cell), NCI-H460 (National People's Congress's cell lung cancer cell), HL-60 (people's promyelocytic leukemia cancer cells) and human breast cancer cell (MCF-7) etc.Animal acute toxicity experiment shows that the acute toxicity of this compounds is very low, LD
50Greater than 2.2g/kg mouse body weight.Therefore indolizino azanaphthalenes quinone derivative of the present invention can be used to prepare antitumor drug.Indolizino azanaphthalenes quinone derivative can with pharmaceutically acceptable auxiliary, make injection, tablet, pill, capsule, suspension agent or emulsion or the like.Its form of medication can through oral, through skin, vein or intramuscular injection.
Compared with prior art, the present invention has following beneficial effect:
The present invention is based on the camptothecine mother nucleus structure, and a series of indolizino azanaphthalenes quinoness have been synthesized in design, find that this compounds has very strong inhibition activity to TOP1.Experiment showed, that further the indolizino azanaphthalenes quinones that the present invention relates to has the obvious suppression effect to kinds of tumor cells.Less relatively to normal cytotoxicity, have preparation cancer therapy drug prospect.
Embodiment
Embodiment 1, indolizino azanaphthalenes quinone derivative NP1-A and NP1-B's is synthetic
With 6 of 0.01mol, 7-two chloro-5,8-quinolyl dione and 0.04mol methyl aceto acetate join in 20～80ml dehydrated alcohol, stir the 3-fluorine pyridine that adds 0.01～0.08mol down, back flow reaction 5～20 hours.Stop, cooling has solid to separate out.Filter, the solid that obtains separates with silica gel column chromatography, obtains a pair of indolizino azanaphthalenes quinone derivative isomer NP1-A and NP1-B simultaneously.
NP1-A: productive rate is 12%; M.p.=197-200 ℃; ESI:339.0 (100%), 340.1 (20%) [M+1]
+ 1H NMR (300MHz, CDCl
3, TMS): δ 9.64 (d, 1H, J=6.8Hz), 9.06 (dd, 1H, J=4.8,1.6Hz), 8.54 (dd, 1H, J=8.0,1.6Hz), 7.67 (dd, 1H, J=8.0,4.8Hz), 7.16-7.06 (m, 2H), 4.54 (q, 2H, J=7.2Hz), 1.47 (t, 3H, J=7.2Hz).
NP1-B: productive rate is 18%.m.p.=200-202 ℃; ESI:339.0 (100%), 340.1 (20%) [M+1]
+ 1H NMR (300MHz, CDCl
3, TMS): δ 9.49 (dd, 1H, J=6.3,1.2Hz), 9.00 (dd, 1H, J=4.7,1.7Hz), 8.57 (dd, 1H, J=7.8,1.8Hz), 7.68 (dd, 1H, J=7.8,4.5Hz), 7.14-7.03 (m, 2H), 4.54 (q, 2H, J=7.2Hz), 1.48 (t, 3H, J=7.2Hz).
The structural formula of NP1-A and NP1-B is as follows respectively:
Embodiment 2, indolizino azanaphthalenes quinone derivative NP2-A and NP2-B's is synthetic
Method is with embodiment 1, and different is to replace methyl aceto acetate with nitroethane, replaces 3-fluorine pyridine with pyridine, obtains a pair of indolizino azanaphthalenes quinone derivative isomer NP2-A and NP2-B simultaneously.
NP2-A: productive rate is 19%; M.p.=233 ℃; ESI:263.3 (100%) [M+1]
+ 1HNMR (300MHz, CDCl
3, TMS): δ 9.77 (d, 1H, J=6.6Hz), 8.99 (d, 1H, J=3.0Hz), 8.49 (d, 1H, J=7.5Hz), 7.67 (d, 1H, J=9.0Hz), 7.57 (dd, 1H, J=7.4,4.8Hz), 7.27 (t, 1H, J=7.4Hz), 7.11 (t, 1H, J=6.6Hz), 2.70 (s, 3H).
NP2-B: productive rate is 15%; M.p.=238 ℃; ESI:263.3 (100%) [M+1]
+ 1HNMR (300MHz, CDCl
3, TMS): δ 9.64 (d, 1H, J=6.6Hz), 8.94 (d, 1H, J=2.6Hz), 8.58 (d, 1H, J=7.5Hz), 7.69 (d, 1H, J=9.0Hz), 7.63 (dd, 1H, J=7.4,4.8Hz), 7.26 (t, 1H, J=7.4Hz), 7.10 (t, 1H, J=6.6Hz), 2.74 (s, 3H).
The structural formula of NP2-A and NP2-B is as follows respectively:
Embodiment 3, indolizino azanaphthalenes quinone derivative NP3-A and NP3-B's is synthetic
Method is with embodiment 1, and different is to replace 3-fluorine pyridine with pyridine, obtains a pair of indolizino azanaphthalenes quinone derivative isomer NP3-A and NP3-B simultaneously.
NP3-A: productive rate is 31%; M.p.=226-227 ℃; ESI:321.2 (100%) [M+1]
+ 1H NMR (300MHz, CDCl
3, TMS): δ 9.92 (d, 1H, J=7.2Hz), 9.01 (d, 1H, J=3.9Hz), 8.54 (d, 1H, J=7.5Hz), 8.34 (d, 1H, J=9.0Hz), 7.64 (dd, 1H, J=7.5,4.5Hz), 7.49 (t, 1H, J=8.0Hz), 7.24 (t, 1H, J=6.9Hz), 4.52 (q, 2H, J=7.1Hz), 1.51 (t, 3H, J=7.1Hz).
NP3-B: productive rate is 12%; M.p.=200-201 ℃; ESI:321.2 (100%) [M+1]
+ 1H NMR (300MHz, CDCl
3, TMS): δ 9.78 (d, 1H, J=6.9Hz), 8.99 (d, 1H, J=3.6Hz), 8.55 (d, 1H, J=7.8Hz), 8.38 (d, 1H, J=9.0Hz), 7.65 (dd, 1H, J=7.8,4.5Hz), 7.47 (ddd, 1H, J=8.7,6.9,0.9Hz), 7.20 (td, 1H, J=6.9,1.2Hz), 4.50 (q, 2H, J=7.2Hz), 1.52 (t, 3H, J=7.2Hz).
The structural formula of NP3-A and NP3-B is as follows:
Embodiment 4, indolizino azanaphthalenes quinone derivative NP4-A and NP4-B's is synthetic
Method is with embodiment 1, and different is to replace methyl aceto acetate with methyl ethyl diketone, obtains a pair of indolizino azanaphthalenes quinone derivative isomer NP4-A and NP4-B simultaneously.
NP4-A: productive rate is 13%; M.p.=252 ℃; ESI:291.2 (100%) [M+1]
+ 1HNMR (300MHz, CDCl
3, TMS): δ 9.93 (d, 1H, J=6.9Hz), 9.03 (d, 1H, J=3.6Hz), 8.53 (d, 1H, J=7.8Hz), 8.46 (d, 1H, J=9.3Hz), 7.66 (dd, 1H, J=7.7,4.7Hz), 7.51 (t, 1H, J=7.8Hz), 7.25 (t, 1H, J=7.5Hz), 2.88 (s, 3H).
NP4-B: productive rate is 2.5%; M.p.=234 ℃; ESI:291.2 (100%) [M+1]
+ 1HNMR (300MHz, CDCl
3, TMS): δ 9.80 (d, 1H, J=6.8Hz), 8.99 (d, 1H, J=3.6Hz), 8.56 (dd, 1H, J=7.8,1.5Hz), 8.46 (d, 1H, J=9.0Hz), 7.67 (dd, 1H, J=7.7,4.7Hz), 7.49 (ddd, 1H, J=8.6,6.9,1.2Hz), 7.23 (td, 1H, J=6.9,1.2Hz), 2.91 (s, 3H).
The structural formula of NP4-A and NP4-B is as follows respectively:
Embodiment 5, indolizino azanaphthalenes quinone derivative NP5-A and NP5-B's is synthetic
Method is with embodiment 1, and different is to replace 3-fluorine pyridine with the 3-chloropyridine, obtains a pair of indolizino azanaphthalenes quinone derivative isomer NP5-A and NP5-B simultaneously.
NP5-A: productive rate is 16%; M.p.=185-190 ℃; ESI:355.2 (100%), 357.3 (33%) [M+1]
+ 1H NMR (300MHz, CDCl
3, TMS): δ 9.58 (d, 1H, J=6.9Hz), 8.98 (d, 1H, J=4.5Hz), 8.57 (d, 1H, J=7.5Hz), 7.67 (dd, 1H, J=7.8,4.5Hz), 7.36 (d, 1H, J=7.5Hz), 7.07 (t, 1H, J=7.2Hz), 4.56 (q, 2H, J=7.2Hz), 1.49 (t, 3H, J=7.2Hz).
NP5-B: productive rate is 12%; M.p.=195 ℃; ESI:355.2 (100%), 357.3 (33%) [M+1]
+ 1H NMR (300MHz, CDCl
3, TMS): δ 9.72 (d, 1H, J=6.3Hz), 9.03 (d, br, 1H, J=3.3Hz), 8.52 (d, 1H, J=7.2Hz), 7.65 (dd, 1H, J=7.8,4.6Hz), 7.38 (d, 1H, J=7.2Hz), 7.09 (t, 1H, J=7.2Hz), 4.55 (q, 2H, J=7.2Hz), 1.47 (t, 3H, J=7.2Hz).
The structural formula of NP5-A and NP5-B is as follows respectively:
Embodiment 6, indolizino azanaphthalenes quinone derivative NP6-A and NP6-B's is synthetic
Method is with embodiment 1, and different is to replace 3-fluorine pyridine with the 3-aminopyridine, obtains a pair of indolizino azanaphthalenes quinone derivative isomer NP6-A and NP6-B simultaneously.
NP6-A: productive rate is 24%; M.p.=195-200 ℃; ESI[M+1]
+: 336.2 (100%);
1H NMR (300MHz, DMSO-d6, TMS): δ 9.16 (d, 1H, J=6.6Hz), 8.95 (d, 1H, J=3.6Hz), 8.38 (d, 1H, J=7.8Hz), 7.75 (dd, 1H, J=7.8,3.6Hz), 7.18 (t, 1H, J=6.9Hz), 6.70 (d, 1H, J=7.5Hz), 6.04 (s, br, 2H), 4.41 (q, 2H, J=6.9Hz), 1.38 (t, 3H, J=6.9Hz).
NP6-B: productive rate is 24%; M.p.=323 ℃; ESI[M+1]
+: 336.2 (100%);
1HNMR (300MHz, DMSO-d6, TMS): δ 9.11 (d, 1H, J=6.6Hz), 8.92 (dd, 1H, J=4.5,1.8Hz), 8.46 (dd, 1H, J=7.8,1.5Hz), 7.81 (dd, 1H, J=7.8,4.8Hz), 7.19 (dd, 1H, J=7.5,6.6Hz), 6.71 (d, 1H, J=7.5Hz), 4.42 (q, 2H, J=7.1Hz), 1.38 (t, 3H, J=7.1Hz).
The structural formula of NP6-A and NP6-B is as follows respectively:
Embodiment 7, indolizino azanaphthalenes quinone derivative NP7-A and NP7-B's is synthetic
Method is with embodiment 2, and different is to replace nitroethane with Nitromethane 99Min., obtains a pair of indolizino azanaphthalenes quinone derivative isomer NP7-A and NP7-B simultaneously.
NP7-A: productive rate is 13%; ESI[M+1]
+: 294.3 (100%);
1H NMR (300MHz, CDCl
3, TMS): δ 9.74 (d, 1H, J=5.7Hz), 9.02 (s, br, 1H, J=4.5Hz), 8.51 (d, 1H, J=6.9Hz), 7.71 (d, 1H, J=7.5Hz), 7.50-7.75 (m, 1H), 7.25-7.32 (m, 2H), 7.10 (s, 1H).
NP7-B: productive rate is 8%; ESI[2M+Na]
+: 518.9 (100%);
1H NMR (300MHz, DMSO-d6, TMS): δ 9.49 (d, 1H, J=6.9Hz), 8.91 (d, br, 1H, J=1.8Hz), 8.48 (d, 1H, J=7.5Hz), 7.93 (d, 1H, J=9.3Hz), 7.79 (dd, 1H, J=7.5,4.5Hz), 7.42 (t, 1H, J=7.5Hz), 7.30 (t, 1H, J=6.9Hz), 7.19 (s, 1H).
The structural formula of NP7-A and NP7-B is as follows:
Embodiment 8, indolizino naphthoquinone derivatives NP8's is synthetic
Method is with embodiment 1, and different is with 2,3-two chloro-1, and the 4-naphthoquinones replaces 6,7-two chloro-5, the 8-quinolyl dione replaces 3-fluorine pyridine with pyridine, obtains red crystals indolizino naphthoquinone derivatives NP8.
Productive rate is 43%; ESI[M+1]
+: 320.1 (100%);
1H NMR (300MHz, CDCl
3, TMS): δ 9.82 (d, 1H, J=7.2Hz), 8.29 (d, 1H, J=9.0Hz), 8.22-8.18 (m, 2H), 7.71-7.68 (m, 2H), 7.41 (t, 1H, J=9.0Hz), 7.14 (t, 1H, J=7.2Hz), 4.51 (q, 2H, J=7.2Hz), 1.50 (t, 3H, J=7.2Hz).
The structural formula of NP8 is as follows:
Embodiment 9, indolizino azanaphthalenes quinone derivative NP9's is synthetic
Method is with embodiment 1, and different is with 6, and 7-two chloro-2 quinones replace 6,7-two chloro-5, and the 8-quinolyl dione obtains red crystals indolizino azanaphthalenes quinone derivative NP9.
Productive rate is 26%; ESI[M+1]
+: 340.0 (100%);
1H NMR (300MHz, CDCl
3, TMS): δ 9.97 (s, 1H), 9.86 (s, 1H), 9.50 (d, 1H, J=6.6Hz), 7.22-7.16 (m, 2H), 4.54 (q, 2H, J=7.2Hz), 1.47 (t, 3H, J=7.2Hz).
The structural formula of NP9 is as follows:
Embodiment 10, indolizino azanaphthalenes quinones are to the restraining effect of growth of tumour cell
Select the representative compound of part, with four kinds of tumor cell line: GLC-82 (human lung adenocarcinoma cell), NCI-H460 (National People's Congress's cell lung cancer cell), HL-60 (people's promyelocytic leukemia cancer cells) and MCF-7 (human breast cancer cell) etc. adopt mtt assay to carry out the test of cell in vitro poison.The logarithmic phase cell adds different concns indolizino azanaphthalenes quinones, acts on after 48 hours, measures its absorbancy.Calculate cell growth inhibiting respectively and make a call to 50% o'clock compound concentration, with IC
50Value representation, the result is as shown in table 1.The result shows that the compound of choosing all has the obvious suppression effect in external growth to these four kinds of tumor cell lines.
Table 1 segment bounds I compound is to the restraining effect of tumor cell line growth
| IC50μM | ||||
| GLC-82 | NCI-H460 | HL-60 | MCF-7 | |
| NP1-A | ＜0.25 | ＜0.25 | 1.3 | 6.2 |
| NP1-B | 1.2 | 1.6 | 5.5 | 7.0 |
| NP2-A | 14.2 | 12.2 | 2.4 | ＞25.0 |
| NP2-B | 21.5 | ＞25.0 | ＞25.0 | ＞25.0 |
| NP3-A | ＜0.25 | ＜0.25 | 0.8 | 6.3 |
| NP3-B | 2.4 | 1.9 | 14.4 | ＞25.0 |
| NP4-A | ＜0.025 | ＜0.25 | 0.8 | 7.9 |
| NP4-B | 1.9 | 1.4 | 14.7 | 12.7 |
| NP5-A | ＜0.25 | 2.1 | 6.5 | 7.3 |
| NP5-B | ＜0.25 | 2.2 | 15.4 | 19.9 |
| NP6-A | 1.8 | 0.9 | 16.4 | 16 |
| NP6-B | 23.5 | 19.0 | ＞25 | ＞25 |
Claims (5)
1. indolizino azanaphthalenes naphthoquinone derivatives, its structural formula is suc as formula shown in (I):
Wherein, M, X, Y and Z are CH or N respectively;
R
1Be selected from following radicals: H, C respectively
1-C
4Alkyl, COOCH
3, COOC
2H
5, COOC
3H
7, COOC
4H
9, COCH
3, COC
2H
5, COC
3H
7, COC
4H
9, CN or aromatic base;
R
2Be selected from following radicals: H, F, Cl, Br, OH, NH respectively
2, COOH or C
1-C
4Alkyl;
R
3Be selected from following radicals: H, F, Cl, Br, OH, COOH or C respectively
1-C
4Alkyl.
2. the preparation method of the described indolizino azanaphthalenes of claim 1 naphthoquinone derivatives is characterized in that comprising the steps:
With 6,7-dichloro azepine naphthoquinones and active methylene group reagent join in the dehydrated alcohol, stir to add pyridine derivate, back flow reaction 5～20 hours down; Stop, cooling has solid to separate out; Filter, the solid that obtains obtains target compound with the silica gel column chromatography separation.
3. preparation method as claimed in claim 2 is characterized in that described active methylene group reagent is Acetacetic acid alkyl ester, itrile group ethyl acetate, methyl ethyl diketone or nitroparaffins.
4. the application of the described indolizino azanaphthalenes of claim 1 naphthoquinone derivatives in preparation treatment cancer drug.
5. application as claimed in claim 4 is characterized in that described cancer is meant human lung adenocarcinoma cell, National People's Congress's cell lung cancer cell, people's promyelocytic leukemia cancer cells or human breast cancer cell.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093358A (en) * | 2011-02-21 | 2011-06-15 | 中山大学 | Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament |
| CN113501826A (en) * | 2015-01-08 | 2021-10-15 | 美国政府健康及人类服务部 | Furoquinolinediones as inhibitors of TDP2 |
-
2007
- 2007-12-11 CN CNA2007100323563A patent/CN101182321A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093358A (en) * | 2011-02-21 | 2011-06-15 | 中山大学 | Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament |
| CN102093358B (en) * | 2011-02-21 | 2012-09-05 | 中山大学 | Brominated indolizinoquinoline dione derivative and application of brominated indolizinequinoline dione derivative in preparing antibiotic medicament |
| CN113501826A (en) * | 2015-01-08 | 2021-10-15 | 美国政府健康及人类服务部 | Furoquinolinediones as inhibitors of TDP2 |
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