CN106800563B - A kind of lavo-ofloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application - Google Patents
A kind of lavo-ofloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application Download PDFInfo
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- IZDSFCWBXIEPJR-UHFFFAOYSA-N CN(CC1)CCN1c(c(F)c1)c2OCC3(CC3)N(C=C3C(O)=O)c2c1C3=O Chemical compound CN(CC1)CCN1c(c(F)c1)c2OCC3(CC3)N(C=C3C(O)=O)c2c1C3=O IZDSFCWBXIEPJR-UHFFFAOYSA-N 0.000 description 2
- KVVQEZFPDIFEMN-CCVNUDIWSA-N CCCCCNC(N/N=C/C1=CN(C2(CC2)COc2c(c(F)c3)N4CCN(C)CC4)c2c3C1=O)=S Chemical compound CCCCCNC(N/N=C/C1=CN(C2(CC2)COc2c(c(F)c3)N4CCN(C)CC4)c2c3C1=O)=S KVVQEZFPDIFEMN-CCVNUDIWSA-N 0.000 description 1
- VHKXNUCYQYJYOG-UHFFFAOYSA-O CN(CC1)CCN1C(C(C1C(C2O)=C3)OCC4(CC4)N1C=C2C=[NH2+])=C3F Chemical compound CN(CC1)CCN1C(C(C1C(C2O)=C3)OCC4(CC4)N1C=C2C=[NH2+])=C3F VHKXNUCYQYJYOG-UHFFFAOYSA-O 0.000 description 1
- ITBAWEOWXVVAJS-UHFFFAOYSA-N CN(CC1)CCN1C(C(OCC12CC1)=C(C1C3)N2C=C(C(NN)=O)C1=N)=C3F Chemical compound CN(CC1)CCN1C(C(OCC12CC1)=C(C1C3)N2C=C(C(NN)=O)C1=N)=C3F ITBAWEOWXVVAJS-UHFFFAOYSA-N 0.000 description 1
- GNEFFEXYIXFERV-UHFFFAOYSA-N CN(CC1)CCN1c(c(F)c1)c2OCC3(CC3)N(C=C3C(NN)=O)c2c1C3=O Chemical compound CN(CC1)CCN1c(c(F)c1)c2OCC3(CC3)N(C=C3C(NN)=O)c2c1C3=O GNEFFEXYIXFERV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of lavo-ofloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application, using the general formula of the chemical structure being shown below：
Description
Technical field
The invention belongs to novel drugs discoveries and original new drug synthesis technical field, and in particular to a kind of lavo-ofloxacin aldehyde contracting
Thiosemicarbazides analog derivative also relates to the preparation method of above-mentioned lavo-ofloxacin aldehyde thiosemicarbazone derivatives, and
Its application in anti-tumor drug.
Background technique
New drug innovation originates from the discovery of primer, and is based on the split of advantage pharmacophore skeleton building primer molecule
Most economical and effective strategy.By aldehydes or ketones and the thiosemicarbazone derivatives of thiosemicarbazide building because of it with macromolecular or
Metal ion is also easy to produce complex or chelation and shows extensive pharmacological activity and be concerned.However, building contracting amino
The aldehydes or ketones of thiocarbamide molecule are mostly the aldehyde and ketone of common benzene class or heteroaromatic class, and to quinoline aldehyde, especially fluoro quinolinone
The (thiosemicarbazone) that aldehydes is formed has not been reported yet.On the other hand, quinoline advantage pharmacophore skeleton is not only important day
Right product alkaloid, such as the pharmacophore bone of the important structural unit and antibacterial fluoroquinolone class drug of quinine and camptothecin
Frame.Meanwhile fluoroquinolones increases its water solubility due to the presence of hydrophilic piperazinyl, improves bioavilability.Especially
It is the important function target spot that action target spot-topoisomerase of fluoroquinolones is also anti-tumor drug, can be resisted
Active Transforming bacterium is anti-tumor activity.For this purpose, being that formoxyl forms corresponding fluoquinolone C- by fluoquinolone C-3 converting carboxylate groups
Then 3 aldehyde are condensed with thiosemicarbazides or substituted thiosemicarbazides, and then realize the split of quinoline and thiosemicarbazones pharmacophore,
To reach the activity superposition between different pharmacophores, it is therefrom found to have the fluoquinolone candidate compound of anti-tumor activity.
Summary of the invention
For this purpose, having anti-swollen the object of the present invention is to provide a kind of lavo-ofloxacin aldehyde thiosemicarbazone derivatives
The effect and effect of tumor, while providing the preparation method of above-mentioned lavo-ofloxacin aldehyde thiosemicarbazone derivatives.
In order to achieve the goal above, the technical scheme adopted by the invention is that：A kind of lavo-ofloxacin aldehyde thiosemicarbazones
Analog derivative, chemical structural formula is as shown in logical formula (I)：
Wherein, substituent R is the alkyl or cyclopropyl of hydrogen atom, 1~5 carbon atom.
Above-mentioned lavo-ofloxacin aldehyde thiosemicarbazone derivatives, specifically the compound of the following structure：
Or
Or
Or
Or
Or
Or
Or
The preparation method of lavo-ofloxacin aldehyde thiosemicarbazone derivatives of the present invention, with levofloxacin shown in formula (II)
Star (Levofloxacin) is prepared as a raw material,
Specific preparation process is as follows：
1) lavo-ofloxacin shown in formula (II) is subjected to hydrazinolysis with hydrazine hydrate and reacts left oxygen fluorine shown in obtained formula (III)
Husky star hydrazides；Concrete operation step can refer to document, and (Hu Guoqiang waits synthesis and the antibacterial activity of quinolone C-3 acylhydrazone, China
Pharmaceutical journal, 2010,45 (11):867-870.) method preparation；
2) by lavo-ofloxacin hydrazides shown in formula (III) and the potassium ferricyanide, room temperature is anti-in the ammonium hydroxide alkaline medium of chloroform
It answers 8~12 hours, separates organic layer, with saturated common salt water washing, anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, and formula is made
(IV) intermediate lavo-ofloxacin aldehyde crude product, is directly used in the next step shown in.
3) it is reacted after hydrazine hydrate is condensed in alkaline medium with carbon disulfide with dimethyl suflfate and hydrazine shown in formula (V) is made
Base dithiocarbonic acid methyl ester intermediate；
4) with Methyl hydrazinecarbodithioate shown in (V) condensation reaction occurs for lavo-ofloxacin aldehyde shown in formula (IV),
Fully reacting is post-treated to be made lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in (VI)；
5) by lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate and aminated compounds shown in formula (VI) in n-butanol
It carries out lavo-ofloxacin aldehyde crude product shown in nucleophilic substitution or formula (IV) and thiosemicarbazides carries out condensation reaction, wait react
It is handled after completely and the target compound as shown in formula (I) is made, the Detailed operating procedures of preparation are shown in embodiment part.
Substituent R is the chain alkylene or cyclopropyl of H atom, 1~5 carbon atom.
Specifically, the molar ratio of lavo-ofloxacin hydrazides shown in formula (III) and the potassium ferricyanide is 1 in step 2):3.0
~5.0.
Specifically, in step 4), lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI) and amine
The molar ratio for closing object is 1:3.0~10.0.The aminated compounds is preferably fat primary amine or cyclopropylamine.As further changing
Into lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI) and aminated compounds are during the reaction, used
At least one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, isobutanol, n-butanol may be selected in solvent, wherein it is preferred that n-butanol.
Above-mentioned lavo-ofloxacin aldehyde thiosemicarbazone derivatives application in preparation of anti-tumor drugs.
The anti-tumor drug is treatment liver cancer, cancer of pancreas or leukemia medicament.
Compared to the prior art, beneficial effects of the present invention：Lavo-ofloxacin aldehyde thiosemicarbazone derivatives of the present invention
Split rational drug molecular design theory based on pharmacophore, not by three kinds of chiral fluoroquinolone, imines schiff bases and thiocarbamide etc.
With the efficient combination between pharmacophore, and then lavo-ofloxacin aldehyde thiosemicarbazone derivatives are devised, realizes different structure
The complementation of pharmacophore can be used as the anti-tumor drug of brand new to achieve synergistic and detoxifying effects with active superposition
Exploitation.
Specific embodiment
The technical scheme of the invention is described in detail through specific implementation examples.
In following embodiments, compound shown in formula (IV) is obtained through following step：
1) lavo-ofloxacin shown in formula (II) is subjected to hydrazinolysis with hydrazine hydrate and reacts left oxygen fluorine shown in obtained formula (III)
Husky star hydrazides；Concrete operation step can refer to document, and (Hu Guoqiang waits synthesis and the antibacterial activity of quinolone C-3 acylhydrazone, China
Pharmaceutical journal, 2010,45 (11):867-870.) method preparation；
2) by lavo-ofloxacin hydrazides shown in formula (III) and the potassium ferricyanide, room temperature is anti-in the ammonium hydroxide alkaline medium of chloroform
It answers 8~12 hours, separates organic layer, with saturated common salt water washing, anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure, and formula is made
(IV) intermediate lavo-ofloxacin aldehyde crude product, is directly used in the next step shown in.Concrete operation step is：Lavo-ofloxacin acyl
Hydrazine (10.0g, 27.0mmol) is suspended in the mixed liquor of chloroform (200 milliliters) and concentrated ammonia liquor (22-25%, 20 milliliters), room temperature
Water (120 milliliters) solution of the potassium ferricyanide (38.0g, 115.0mmol) is slowly added dropwise, stirring at normal temperature reacts 8~12 hours to original
Material disappears, and (TLC is detected, VChloroform：VMethanol=5:1).Separate organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dry, subtracts
Solvent is evaporated off in pressure, obtains lavo-ofloxacin aldehyde crude product shown in formula (IV), spare.
In following embodiments, formula (VI) compound represented is obtained through following step：
1) it is reacted after hydrazine hydrate is condensed in alkaline medium with carbon disulfide with dimethyl suflfate and hydrazine shown in formula (V) is made
Base dithiocarbonic acid methyl ester intermediate；Concrete operation step can refer to document (Hu Weixiao, etc. the conjunction of thiosemicarbazones compound
At and its anticancer activity research, Chemical Journal of Chinese Universities, 2001,22 (12)：Preparation method 2014-2017)；
2) lavo-ofloxacin aldehyde crude product shown in formula (IV) is condensed with Methyl hydrazinecarbodithioate shown in formula (V)
Reaction, fully reacting is post-treated to be made lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in (VI)；Specially：
Lavo-ofloxacin aldehyde crude product (10.0g) shown in formula (IV) is dissolved in dehydrated alcohol (150 milliliters), hydrazine shown in formula (V) is added
Base dithiocarbonic acid methyl esters (3.9g, 32.0mmol), back flow reaction 10 hours, placement was cooled to room temperature.It filters and collects generation
Solid, it is dry.Crude product methanol-chloroform (V/V=3：1) it recrystallizes, obtains lavo-ofloxacin shown in pale yellow crystals formula (VI)
Aldehyde contracting Methyl hydrazinecarbodithioate I10.6g, m.p.202~204 DEG C.1H NMR (400MHz, DMSO-d6)：11.37(s,1H,
CH=N), 8.87 (1H, s, 2-H), 8.42 (s, 1H, NH), 7.46 (1H, d, 5-H), 4.78~4.34 (m, 3H, OCH2CHN),
3.24 (t, 4H, piperazine-H), 2.53 (t, 4H, piperazine-H), 2.23 (s, 3H, s, N-CH3), 1.86 (s, 3H,
SCH3), 1.44 (d, 3H, CH3)；MS(m/z)：Calcd.for C20H24FN5O2S2：449.57[M]+；Found：450[M+H]+。
Embodiment 1
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting ammonia
Base thiocarbamide (I-1), chemical structural formula are：
R i.e. in Formulas I is H atom.
The preparation method of the compound is：The crude product of lavo-ofloxacin aldehyde shown in formula (IV) (1.0g) is taken to be dissolved in dehydrated alcohol
(20 milliliters) are added thiosemicarbazides (0.5g, 5.5mmol), back flow reaction 12 hours, filter while hot, solid is successively washed with ethyl alcohol
It washs 2 times, distills water washing 2 times, it is dry, with DMF- ethyl alcohol (V:V=5:3) mixed solvent recrystallizes, and pale yellow crystals object is made
Formula (I-1), obtains product 0.48g, m.p.231~233 DEG C.1H NMR (400MHz, DMSO-d6)δ:11.43 (s, 1H, CH=N),
8.76 (s, 1H, 2-H), 8.44 (s, 1H, NH), 8.36 (s, 1H, NH2),8.33(s,1H,NH2), 7.47 (d, 1H, 5-H), 4.62
~4.34 (m, 3H, OCH2CHN), 3.24 (t, 4H, piperazine-H), 2.55 (t, 4H, piperazine-H), 2.26 (s,
3H, N-CH3), 1.45 (d, 3H, CH3)；MS(m/z)：Calcd.for C19H23FN6O2S：418.50[M]+；Found：419[M+
H]+。
Embodiment 2
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4-
Methylamino thiocarbamide (I-2), chemical structural formula are：
R i.e. in Formulas I is methyl.
The preparation method of the compound is：Take lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI)
(1.0g, 2.23mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and methylamine (0.68g, 22.0mmol) mixed reactant afterwards is added
It back flow reaction 12 hours, filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol
(V:V=1:5) mixed solvent recrystallizes, and yellow crystal object formula (I-2) product 0.33g, m.p.210~212 DEG C are made.1H NMR
(400MHz, DMSO-d6)δ:11.46 (s, 1H, CH=N), 8.77 (s, 1H, 2-H), 8.36 (s, 1H, NH), 8.35 (s, 1H,
NH), 7.46 (d, 1H, 5-H), 4.57~4.32 (m, 3H, OCH2CHN), 3.24 (t, 4H, piperazine-H), 3.12 (d,
3H,NH-CH3), 2.47 (t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.46 (d, 3H, CH3)；MS(m/z)：
Calcd.forC20H25FN6O2S：432.52[M]+；Found：433[M+H]+。
Embodiment 3
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4-
Ethylamino thiocarbamide (I-3), chemical structural formula are：
R i.e. in Formulas I is ethyl.
The preparation method of the compound is：Take lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI)
(1.0g, 2.23mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and ethamine (0.90g, 20.0mmol) mixed reactant afterwards is added
It back flow reaction 12 hours, filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol
(V:V=1:5) mixed solvent recrystallizes, and yellow crystal object formula (I-3) product 0.48g, m.p.204~206 DEG C are made.1H NMR
(400MHz, DMSO-d6)δ:11.42 (s, 1H, CH=N), 8.77 (s, 1H, 2-H), 8.43 (d, 1H, NH), 8.33 (s, 1H,
NH), 7.42 (d, 1H, 5-H), 4.57~4.33 (m, 3H, OCH2CHN), 3.58 (m, 2H, CH2), 3.24 (t, 4H,
Piperazine-H), 2.46 (t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.70 (m, 3H, CH3),1.46(d,
3H,CH3)；MS(m/z)：Calcd.for C21H27FN6O2S：446.55[M]+；Found：447[M+H]+。
Embodiment 4
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4-
Isopropylamino thiocarbamide (I-4), chemical structural formula are：
R i.e. in Formulas I is isopropyl.
The preparation method of the compound is：Take lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI)
(1.0g, 2.23mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and isopropylamine (0.83g, 14.0mmol) hybrid reaction afterwards is added
It object back flow reaction 12 hours, filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol
(V:V=1:5) mixed solvent recrystallizes, and yellow crystal object formula (I-4) product 0.51g, m.p.213~215 DEG C are made.1H NMR
(400MHz, DMSO-d6)δ：11.38 (s, 1H, CH=N), 8.67 (s, 1H, 2-H), 8.32 (s, 1H, NH), 7.81 (d, 1H,
NH), 7.45 (d, 1H, 5-H), 4.64~4.33 (m, 3H, OCH2CHN), 3.32 (m, 2H, CH), 3.25 (t, 4H,
Piperazine-H), 2.43 (t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.46 (d, 3H, CH3),1.24(m,
6H,2×CH3)；MS(m/z)：Calcd.for C22H29FN6O2S：460.58[M]+；Found：461[M+H]+。
Embodiment 5
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4-
Cyclopropylamino thiocarbamide (I-5), chemical structural formula are：
R i.e. in Formulas I is cyclopropyl.
The preparation method of the compound is：Take lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI)
(1.0g, 2.23mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and cyclopropylamine (1.03g, 18.0mmol) hybrid reaction afterwards is added
It object back flow reaction 12 hours, filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol
(V:V=1:5) mixed solvent recrystallizes, and yellow crystal object formula (I-5) product 0.36g, m.p.212~214 DEG C are made.1H NMR
(400MHz, DMSO-d6)δ：11.47 (s, 1H, CH=N), 8.76 (s, 1H, 2-H), 8.41~8.33 (m, 2H, 2 × NH),
7.45 (d, 1H, 5-H), 4.64~4.33 (m, 4H, OCH2CHN and CH), 3.24 (t, 4H, piperazine-H), 2.42
(t, 4H, piperazine-H), 2.23 (s, 3H, N-CH3), 1.46 (d, 3H, CH3),0.73(m,4H,CH2CH2)；MS(m/z)：
Calcd.for C22H27FN6O2S：458.56[M]+；Found：459[M+H]+。
Embodiment 6
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4-
Tert-butylamino thiocarbamide (I-6), chemical structural formula are：
R i.e. in Formulas I is tert-butyl.
The preparation method of the compound is：Take lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI)
(1.0g, 2.23mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and tert-butylamine (1.00g, 14.0mmol) hybrid reaction afterwards is added
It object back flow reaction 10 hours, filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol
(V:V=1:5) mixed solvent recrystallizes, and yellow crystal object formula (I-6) product 0.57g, m.p.205~207 DEG C are made.1H NMR
(400MHz, DMSO-d6)δ：11.33 (s, 1H, CH=N), 8.56 (s, 1H, 2-H), 8.34 (s, 1H, NH), 7.62 (s, 1H,
NH), 7.43 (d, 1H, 5-H), 4.66~4.31 (m, 3H, OCH2CHN), 3.24 (t, 4H, piperazine-H), 2.44 (t,
4H, piperazine-H), 2.25 (s, 3H, N-CH3), 1.56~1.43 (m, 12H, 4 × CH3)；MS(m/z)：Calcd.for
C23H31FN6O2S：474.60[M]+；Found：475[M+H]+。
Embodiment 7
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4-
N-butylamino thiocarbamide (I-7), chemical structural formula are：
R i.e. in Formulas I is normal-butyl.
The preparation method of the compound is：Take lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI)
(1.0g, 2.23mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and n-butylamine (1.00g, 14.0mmol) hybrid reaction afterwards is added
It object back flow reaction 10 hours, filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol
(V:V=1:5) mixed solvent recrystallizes, and yellow crystal object formula (I-7) product 0.66g, m.p.211~213 DEG C are made.1H NMR
(400MHz, DMSO-d6)δ：11.35 (s, 1H, CH=N), 8.68 (s, 1H, 2-H), 8.34~8.17 (m, 2H, 2 × NH),
7.45 (d, 1H, 5-H), 3.56~3.25 (m, 5H, CH2And piperazine-H), 2.38 (t, 4H, piperazine-H),
2.23 (3H, s, N-CH3), 1.45 (d, 3H, CH3), 1.25~0.66 (m, 7H, CH2CH2CH3)；MS(m/z)：Calcd.for
C23H31FN6O2S：474.60[M]+；Found：475[M+H]+。
Embodiment 8
(S) the fluoro- 7- of -6- (4- thyl-piperazin -1- base) -1,8- (2,1- oxygen propyl group)-quinoline -4 (1H) -one -3- aldehyde contracting 4-
N-pentyl thiosemicarbazides (I-8), chemical structural formula are：
R i.e. in Formulas I is n-pentyl.
The preparation method of the compound is：Take lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VI)
(1.0g, 2.23mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and n-amylamine (1.00g, 11.5mmol) hybrid reaction afterwards is added
It object back flow reaction 8 hours, filtering while hot, solid is successively used ethanol washing 2 times, is distilled water washing 2 times, and it is dry, with DMF- ethyl alcohol
(V:V=1:5) mixed solvent recrystallizes, and yellow crystal object formula (I-8) product 0.63g, m.p.202~204 DEG C are made.1H NMR
(400MHz, DMSO-d6)δ：11.36 (s, 1H, CH=N), 8.68 (s, 1H, 2-H), 8.34~8.10 (m, 2H, 2 × NH),
7.44 (d, 1H, 5-H), 3.44~3.33 (m, 5H, CH2And piperazine-H), 2.25 (t, 4H, piperazine-H),
2.23 (3H, s, N-CH3), 1.45 (d, 3H, CH3), 1.23~0.67 (m, 9H, CH2CH2CH2CH3)；MS(m/z)：Calcd.for
C24H33FN6O2S：488.63[M]+；Found：489[M+H]+。
Test example
One, the in vitro antitumor activity assay for the lavo-ofloxacin aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided
1, test sample
Inhibited with the lavo-ofloxacin aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided, and classical antitumor TOPO
Agent 10-hydroxycamptothecine (HC, Hydroxycamptothecin) and lavo-ofloxacin (LOF) are test sample, and totally 10 kinds, wherein HC and LOF are
Control group, embodiment 1-8 sample are experimental group；
Experimental cancer cell line is respectively human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 thin
Born of the same parents' strain is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences.Normal cell uses VERO African green monkey kidney cell, and purchase is logical in Shanghai
Growth Science and Technology Ltd..
2, measuring method
Measuring method the specific steps are：
(1) it uses dimethyl sulfoxide (DMSO) to dissolve respectively above-mentioned 10 kinds of test samples first, is configured to 1.0 × 10- 2mol·L-1The RPMI-1640 culture solution of the stock solution of concentration, the calf serum for being later 10% with mass percent concentration will
Stock solution is diluted to 5 concentration gradients (0.1,1.0,5.0,10.0,50.0 μm of olL-1) working solution；
(2) the human liver cancer Hep-3B cell, human pancreas cancer Panc-1 cell and human leukemia HL60 of logarithmic growth phase are thin
Born of the same parents and VERO cell strain, with 6000, every hole cell inoculation in 96 orifice plates, be then separately added into above-mentioned 10 kinds of samples has 5
The working solution of concentration gradient.5gL is added in every hole after culture 48 hours–110 μ L of MTT (thiazolyl blue) solution continues culture 4 hours
Lauryl sodium sulfate (SDS) solution that 100 μ L mass percent concentrations are 10% is added afterwards to be further cultured for 24 hours, then uses enzyme
Mark instrument measures respective absorbance (OD) value at 570nm wavelength；
(3) inhibiting rate of the test sample to cancer cell of various concentration is calculated by using the formula shown below,
Cancer inhibition rate=[(1- experimental group OD value)/control group OD value] × 100%,
Then linear regression is made to the corresponding cancer inhibition rate of each concentration with the logarithm of each concentration of test sample, obtained
To dose-effect equation, each test sample is calculated to the half-inhibitory concentration of experiment cancer cell from gained dose-effect equation
(IC50)；Each data are measured in parallel three times, are averaged, the results are shown in Table 1.
Anti-tumor activity (the IC of each test sample of table 150)
It can be seen that the compound of embodiment 1-8 offer to three kinds from the initial in vitro antitumor activity screening result of table 1
The growth inhibitory activity of experiment cancer cell is significantly stronger than the activity of parent compound levofloxacin (LOF), especially smaller to take
The compound replaced for base or cyclopropyl is suitable with the activity of control hydroxycamptothecin to the activity of human pancreas cancer Panc-1 cell.More
Significantly, the compound that embodiment 1-8 is provided shows low toxicity normal VERO cell, shows to tumour cell
With stronger selectivity, prompt target compound that there is the potentiality to be exploited of druggability and the valence of further progress new drug research
Value.Therefore, it is first to carry out conventional antitumor in-vitro screening according to the general way of drug development, is then targetedly ground
Study carefully, thus the compound of the present invention have strong anti-tumor activity and lower toxicity, can by with it is human-acceptable acid at
Salt is mixed with anti-tumor drug with pharmaceutical carrier.
Claims (7)
1. a kind of lavo-ofloxacin aldehyde thiosemicarbazone derivatives, which is characterized in that have the structure as shown in following formula (I) logical
Formula：
Wherein, R is the alkyl of hydrogen atom, 1~5 carbon atom.
2. lavo-ofloxacin aldehyde thiosemicarbazone derivatives according to claim 1, which is characterized in that be specially following
The compound of typical structure：
3. the preparation method of lavo-ofloxacin aldehyde thiosemicarbazone derivatives described in claim 2, which is characterized in that specific packet
Include following steps：
(1) using lavo-ofloxacin shown in formula (II) as raw material, hydrazinolysis occurs with hydrazine hydrate and reacts a left side shown in obtained formula (III)
Ofloxacin hydrazides；
(2) in the aqueous ammonia medium of chloroform oxidation reaction is occurred into for the lavo-ofloxacin hydrazides potassium ferricyanide shown in formula (III),
After reaction, post-treated to obtain lavo-ofloxacin aldehyde shown in formula (IV)；Then lavo-ofloxacin aldehyde shown in formula (IV)
Condensation reaction occurs with Methyl hydrazinecarbodithioate shown in formula (V), fully reacting is post-treated to be made shown in formula (VI)
Lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate；
(3) nucleophilic substitution or formula (IV) institute are occurred into n-butanol for formula (VI) compound represented and aminated compounds
The lavo-ofloxacin aldehyde and thiosemicarbazides shown carries out condensation reaction, can be made shown in formula (I) after through processing after fully reacting
Lavo-ofloxacin aldehyde thiosemicarbazone derivatives；
The aminated compounds is thiosemicarbazides, methylamine, ethamine, isopropylamine, cyclopropylamine, tert-butylamine, n-butylamine or n-amylamine.
4. the preparation method of lavo-ofloxacin aldehyde thiosemicarbazone derivatives according to claim 3, which is characterized in that step
Suddenly in (2), the molar ratio of lavo-ofloxacin hydrazides shown in formula (III) and the potassium ferricyanide is 1:3.0~5.0.
5. the preparation method of lavo-ofloxacin aldehyde thiosemicarbazone derivatives according to claim 3, which is characterized in that step
Suddenly in (3), the molar ratio of lavo-ofloxacin aldehyde contracting Methyl hydrazinecarbodithioate and aminated compounds shown in formula (VI) is 1:
3.0~10.0.
6. lavo-ofloxacin aldehyde thiosemicarbazone derivatives of any of claims 1 or 2 answering in the preparation of antitumor drugs
With.
7. lavo-ofloxacin aldehyde thiosemicarbazone derivatives according to claim 6 answering in the preparation of antitumor drugs
With, which is characterized in that the anti-tumor drug is the drug for treating cancer of pancreas, liver cancer or leukaemia.
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| US20020103170A1 (en) * | 2000-07-12 | 2002-08-01 | Turner Steven Ronald | Oxazinoquinolones useful for the treatment of viral infections |
| CN102827187A (en) * | 2012-07-18 | 2012-12-19 | 河南大学 | Fluoroquinolone acetal isoniazone, and preparation method and application thereof |
| CN104557974A (en) * | 2015-01-16 | 2015-04-29 | 河南大学 | Chiral fluoroquinolone C-3 s-triazole sulfide ketone thiosemicarbazone compounds as well as preparation method and application thereof |
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| US20020103170A1 (en) * | 2000-07-12 | 2002-08-01 | Turner Steven Ronald | Oxazinoquinolones useful for the treatment of viral infections |
| CN102827187A (en) * | 2012-07-18 | 2012-12-19 | 河南大学 | Fluoroquinolone acetal isoniazone, and preparation method and application thereof |
| CN104557974A (en) * | 2015-01-16 | 2015-04-29 | 河南大学 | Chiral fluoroquinolone C-3 s-triazole sulfide ketone thiosemicarbazone compounds as well as preparation method and application thereof |
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| Title |
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| 缩氨基硫脲类化合物的合成及生物活性研究;李清寒;《西南民族大学学报·自然科学版》;20090331;第35卷(第2期);第1-3页，第309页第1段，第313页2.6节内容 * |
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