CN106831704B - A kind of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application - Google Patents
A kind of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives and its preparation method and application, using such as following formula I general formula of the chemical structure:
Description
Technical field
The invention belongs to new drug discoveries and original new drug synthesis technical field, and in particular to a kind of N- methyl gatifloxacin aldehyde
Thiosemicarbazone derivatives also relate to a kind of preparation side of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives
Method 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 thiosemicarbazide, and then realize the split between chinoline backbone and thiosemicarbazones pharmacophore, to reach
Activity superposition between different structure pharmacophore, is therefrom found to have the fluoquinolone candidate compound of anti-tumor activity.
Summary of the invention
For this purpose, having anti-the object of the present invention is to provide a kind of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives
The effect and effect of tumour, while providing the preparation method of above-mentioned N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives.
In order to achieve the goal above, the technical scheme adopted by the invention is that: a kind of N- methyl gatifloxacin aldehyde contracting amino
Thiourea derivatives, chemical structural formula is as shown in logical formula (I):
Wherein, substituent R is the alkyl or cyclopropyl of H atom or 1~5 carbon atom.Such compound is tool below
The typical compound of body structure:
Invention also provides a kind of preparation methods of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives, with formula
(II) gatifloxacin shown in is prepared as a raw material,
Specific preparation process is as follows for the preparation method of the N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives:
1) formula (III) institute is made in the methylation reaction that piperazine occurs for gatifloxacin shown in formula (II) and formic acid and formaldehyde
Show N- methyl gatifloxacin；
2) with hydrazine hydrate hydrazinolysis is occurred into for N- methyl gatifloxacin shown in formula (III) and reacts N- first shown in obtained formula (IV)
Base gatifloxacin hydrazides；
3) by N- methyl gatifloxacin hydrazide compound shown in formula (IV) and the potassium ferricyanide chloroform ammonium hydroxide alkaline medium
Middle normal-temperature reaction 8~12 hours, separates organic layer, and with saturated common salt water washing, anhydrous sodium sulfate is dry, evaporating solvent under reduced pressure,
N- methyl gatifloxacin C-3 aldehyde crude intermediate shown in formula (V) is made, is directly used in the next step；
4) Methyl hydrazinecarbodithioate shown in N- methyl gatifloxacin aldehyde shown in formula (V) and formula (VI) is condensed,
N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in (VII) can be made through processing after complete reaction；Specifically
Operating procedure can refer to document (Hu Weixiao, etc., the synthesis of thiosemicarbazones compound and its research of anticancer activity, high
School chemistry journal, 2001,22 (12): 2014-2017) preparation method；
5) N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate and aminated compounds shown in formula (VII) are being had
N- methyl gatifloxacin C-3 aldehyde crude product shown in nucleophilic substitution or formula (V) and thiosemicarbazides occur in solvent organic
Condensation reaction is carried out in solvent, handled after complete reaction shown in target compound such as formula (I), wherein substituent R H
The alkyl or cyclopropyl of atom or 1~5 carbon atom.
As a further improvement, organic solvent used in preparation formula I may be selected methanol, ethyl alcohol, normal propyl alcohol, isopropanol,
At least one of isobutanol, n-butanol, wherein preferred alcohol or n-butanol.
Preferably, the molar ratio of N- methyl gatifloxacin hydrazides shown in formula (IV) and the potassium ferricyanide is in the step 3)
1:3.0~5.0.N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate and amine shown in formula (VII) in the step 5)
The molar ratio of class compound is 1:3.0~10.0；The aminated compounds is fatty amine or cyclopropylamine.
The N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives application in preparation of anti-tumor drugs.It is described
Anti-tumor drug is treatment liver cancer, cancer of pancreas or leukemia medicament.
The N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives of the invention split rational drug based on pharmacophore point
Sub- design principle by the efficient combination between three kinds of fluoquinolone, imines schiff bases and thiocarbamide etc. different pharmacophores, and then devises
N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives realize the complementation and active superposition of different structure pharmacophore, from
And achieve synergistic and detoxifying effects, it can be used as the anti-tumor drug exploitation of brand new.
Specific embodiment
The technical scheme of the invention is described in detail through specific implementation examples.N- methyl shown in formula (III) adds
Preparation step for husky star is as follows: gatifloxacin (50.0g, 133.0mmol) is dissolved in the formaldehyde of 85% formic acid (100mL) and 37%
(20.0g, 200.0mmol) in the mixed solvent is stirred at reflux reaction 12 hours.Evaporating solvent under reduced pressure adds water (1000mL), uses
30% sodium hydroxide solution tune pH 7.0 is placed and solid is precipitated.Filter collection solid, it is dry, with dehydrated alcohol-DMF (V:V=3:
2) mixed solvent recrystallizes, and obtains pale yellow crystals formula (III), yield 87%, 172~174 DEG C of mp.1H NMR(400MHz,
CDCl3)δ:15.64(brs,1H,COOH),8.76(s,1H,1H,2-H),7.78(d,1H,5-H),4.15(m,1H,CH),
3.85(s,3H,OCH3), 3.38~2.56 (m, 7H, piperazine-H), 2.34 (s, 3H, N-CH3),1.36(d,3H,CH3),
1.22~1.06 (m, 4H, CH2CH2)；MS(m/z):Calcd.for C20H24FN3O4:389.43[M]+；Found:390[M+H
]+。
The preparation step of N- methyl gatifloxacin hydrazides shown in formula (IV) is as follows: N- methyl gatifloxacin (50.0g,
It 129.0mmol) is dissolved in the in the mixed solvent of 85% hydrazine hydrate (100mL) and dehydrated alcohol (300mL), it is small to be stirred at reflux reaction 24
When.Evaporating solvent under reduced pressure, adds dehydrated alcohol (500mL) and active carbon (2.0g), reflux decoloration 1 hour, and heat filtering is placed and is precipitated
Solid.Filter collection solid, is washed with dehydrated alcohol, drains solvent, dry, obtains pale yellow crystals formula (IV), yield 74.6%, mp
175~177 DEG C.1H NMR(400MHz,CDCl3)δ:11.42(s,1H,CONH),8.78(s,1H,1H,2-H),7.82(d,1H,
5-H),4.57(s,2H,NH2),4.17(m,1H,CH),3.86(s,3H,OCH3), 3.37~2.55 (m, 7H, piperazine-
H),2.34(s,3H,N-CH3),1.37(d,3H,CH3), 1.23~1.07 (m, 4H, CH2CH2)；MS(m/z):Calcd.for
C20H26FN5O3:
403.46[M]+；Found:404[M+H]+。
The preparation step of N- methyl gatifloxacin C-3 aldehyde intermediate shown in formula (V) is as follows: N- methyl gatifloxacin hydrazides
(10.0g, 25.0mmol) is suspended in the mixed solvent of chloroform (200 milliliters) and concentrated ammonia liquor (concentration is 22~25%, 20 milliliters)
In, water (120 milliliters) solution of the potassium ferricyanide (38.0g, 115.0mmol) is slowly added dropwise in room temperature, and stirring at normal temperature reaction 8~10 is small
Disappearing up to raw material, (TLC is detected, VChloroform: VMethanol=5:1).Organic layer is separated, with saturated common salt water washing, anhydrous sodium sulfate is dry
Dry, it is spare to obtain N- methyl gatifloxacin C-3 aldehyde intermediate shown in crude product formula (V) for evaporating solvent under reduced pressure.
Methyl hydrazinecarbodithioate shown in formula (VI) the preparation method is as follows: hydrazine hydrate and carbon disulfide are situated between in alkalinity
It is reacted after being condensed in matter with dimethyl suflfate and Methyl hydrazinecarbodithioate intermediate shown in formula (VI) is made；Concrete operations step
Suddenly can refer to document (Hu Weixiao, etc., the synthesis of thiosemicarbazones compound and its research of anticancer activity, institution of higher education chemistry
Journal, 2001,22 (12): 2014-2017) preparation method.
The preparation step of N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VII) is as follows: by formula (V)
Shown in N- methyl gatifloxacin C-3 aldehyde crude product (10.0g) be dissolved in dehydrated alcohol (150 milliliters), be added the thio first of diazanyl two
Sour methyl esters (8.0g), back flow reaction 10 hours, placement was cooled to room temperature.The solid that filter collection generates, it is dry.Crude product methanol-chlorine
Imitative (V/V=3:1) recrystallization, obtains N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in pale yellow crystals formula (VI)
214~216 DEG C of 12.6g, mp.1H NMR (400MHz, DMSO-d6): 11.72 (s, 1H, CH=N), 8.88 (s, 1H, 2-H),
8.52(s,1H,NH),7.87(d,1H,5-H),4.17(m,1H,CH),3.85(s,3H,OCH3), 3.36~2.57 (m, 7H,
piperazine-H),2.33(s,3H,N-CH3),2.12(s,3H,SCH3), 1.36~1.07 (m, 7H, CH3and CH2CH2)；
MS(m/z):Calcd.for C20H25FN5O2S2:477.63[M]+；Found:478[M+H]+。
Embodiment 1
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
Thiosemicarbazides (I-1), chemical structural formula are as follows:
R substituent i.e. in Formulas I is H atom.
The compound the preparation method comprises the following steps: the aldehyde of N- methyl gatifloxacin shown in formula (V) crude product (1.0g) is taken to be dissolved in anhydrous second
Alcohol (20 milliliters) is added thiosemicarbazides (0.5g, 5.5mmol), back flow reaction 10 hours, filters while hot, ethanol washing 2 times, steams
Distilled water is washed 2 times, dry, is recrystallized with DMF- ethyl alcohol (V:V=5:3) mixed solvent, and pale yellow crystals object formula (I-1) is made,
Obtain product 0.53g, m.p.232~234 DEG C.1H NMR (400MHz, DMSO-d6) δ: 11.78 (s, 1H, CH=N), 9.06 (s,
1H, 2-H), 8.53 (s, 1H, NH), 8.45 (s, 1H, NH2),8.34(s,1H,NH2), 7.87 (d, 1H, 5-H), 3.83 (s, 3H,
OCH3), 4.15 (m, 1H, CH), 3.36~2.55 (mt, 7H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.36~1.12
(m,7H,CH3and CH2CH2)；MS (m/z): Calcd.for C21H27FN6O2S:446.55 [M]+；Found:447 [M+H]+。
Embodiment 2
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
4- methylamino thiocarbamide (I-2), chemical structural formula are as follows:
R i.e. in Formulas I is methyl.
The compound the preparation method comprises the following steps: taking N- methyl gatifloxacin aldehyde contracting diazanyl dithiocarbonic acid first shown in formula (VI)
Ester (1.0g, 2.1mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and methylamine (0.53g, 17.0mmol) 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 0.40g, m.p.223~225 DEG C are made.1H NMR
(400MHz, DMSO-d6) δ: 11.76 (s, 1H, CH=N), 8.97 (s, 1H, 2-H), 8.44 (s, 1H, NH), 8.35 (s, 1H,
NH), 7.88 (d, 1H, 5-H), 4.16 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.53~3.36 (m, 7H, piperazine-H
and CH3), 2.57 (m, 3H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.38~1.05 (m, 7H, CH3and
CH2CH2)；MS (m/z): Calcd.for C22H29FN6O2S:460.58 [M]+；Found:461 [M+H]+。
Embodiment 3
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
4- ethylamino thiocarbamide (I-3), chemical structural formula are as follows:
R i.e. in Formulas I is ethyl.
The compound the preparation method comprises the following steps: taking N- methyl gatifloxacin aldehyde contracting diazanyl dithiocarbonic acid first shown in formula (VI)
Ester (1.0g, 2.1mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and ethamine (0.77g, 17.0mmol) 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 0.42g, m.p.225~227 DEG C are made.1H NMR
(400MHz, DMSO-d6) δ: 11.78 (s, 1H, CH=N), 8.93 (s, 1H, 2-H), 8.44 (s, 1H, NH), 8.37 (s, 1H,
NH), 7.88 (d, 1H, 5-H), 4.17 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.36~3.14 (m, 6H, piperazine-H
and CH2), 2.56 (m, 3H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.68~1.06 (m, 10H, 2 × CH3and
CH2CH2)；MS (m/z): Calcd.for C23H31FN6O2S:474.60 [M]+；Found:475 [M+H]+。
Embodiment 4
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
4- isopropylamino thiocarbamide (I-4), chemical structural formula are as follows:
R i.e. in Formulas I is isopropyl.
The compound the preparation method comprises the following steps: taking N- methyl gatifloxacin aldehyde contracting diazanyl dithiocarbonic acid first shown in formula (VI)
Ester (1.0g, 2.1mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and isopropylamine (0.89g, 15.0mmol) 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-4) product 0.48g, m.p.216~218 DEG C are made.1H NMR
(400MHz, DMSO-d6) δ: 11.78 (s, 1H, CH=N), 8.90 (s, 1H, 2-H), 8.45 (s, 1H, NH), 8.37 (s, 1H,
NH), 7.88 (d, 1H, 5-H), 4.15 (m, 1H, CH), 3.82 (s, 3H, OCH3), 3.36~3.22 (m, 5H, piperazine-H
And CH), 2.56~2.45 (m, 3H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.36~1.03 (m, 13H, 3 ×
CH3and CH2CH2)；MS (m/z): Calcd.for C24H33FN6O2S:488.63 [M]+；Found:489 [M+H]+。
Embodiment 5
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
4- cyclopropylamino thiocarbamide (I-5), chemical structural formula are as follows:
R i.e. in Formulas I is cyclopropyl.
The compound the preparation method comprises the following steps: taking N- methyl gatifloxacin aldehyde contracting diazanyl dithiocarbonic acid first shown in formula (VI)
Ester (1.0g, 2.1mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and cyclopropylamine (0.91g, 16.0mmol) 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 0.32g, m.p.231~233 DEG C are made.1H NMR
(400MHz, DMSO-d6) δ: 11.78 (s, 1H, CH=N), 8.92 (s, 1H, 2-H), 8.54 (s, 1H, NH), 8.46 (s, 1H,
NH), 7.88 (d, 1H, 5-H), 4.18 (m, 1H, CH), 3.84 (s, 3H, OCH3), 3.52~3.35 (m, 5H, piperazine-H
And CH), 2.57 (m, 3H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.36~0.76 (m, 11H, CH3and 2×
CH2CH2)；MS (m/z): Calcd.for C24H31F2N6O2S:486.62 [M]+；Found:487 [M+H]+。
Embodiment 6
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
The tertiary fourth thiosemicarbazides (I-6) of 4-, chemical structural formula are as follows:
R i.e. in Formulas I is tert-butyl.
The compound the preparation method comprises the following steps: taking N- methyl gatifloxacin aldehyde contracting diazanyl dithiocarbonic acid first shown in formula (VI)
Ester (1.0g, 2.1mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and tert-butylamine (0.88g, 12.0mmol) 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.225~227 DEG C are made.1H NMR
(400MHz, DMSO-d6) δ: 11.77 (s, 1H, CH=N), 8.89 (s, 1H, 2-H), 8.46 (s, 1H, NH), 8.38 (s, 1H,
NH), 7.88 (d, 1H, 5-H), 4.16 (m, 1H, CH), 3.81 (s, 3H, OCH3), 3.37 (m, 4H, piperazine-H), 2.55
(m, 3H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.36~1.03 (m, 16H, 4 × CH3and CH2CH2)；MS(m/
Z): Calcd.for C25H35FN6O2S:502.66 [M]+；Found:503 [M+H]+。
Embodiment 7
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
4- n-butylamino thiocarbamide (I-7), chemical structural formula are as follows:
R i.e. in Formulas I is normal-butyl.
The compound the preparation method comprises the following steps: taking N- methyl gatifloxacin aldehyde contracting diazanyl dithiocarbonic acid first shown in formula (VI)
Ester (1.0g, 2.1mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and n-butylamine (0.88g, 12.0mmol) 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 0.63g, m.p.214~216 DEG C are made.1H NMR
(400MHz, DMSO-d6) δ: 11.77 (s, 1H, CH=N), 8.88 (s, 1H, 2-H), 8.45 (s, 1H, NH), 8.36 (s, 1H,
NH), 7.88 (d, 1H, 5-H), 4.16 (m, 1H, CH), 3.80 (s, 3H, OCH3), 3.36~3.23 (m, 6H, piperazine-H
and CH2), 2.53 (m, 3H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.37~0.72 (m, 14H, CH3and
CH2CH2and CH2CH2CH3)；MS (m/z): Calcd.for C25H35FN6O2S:502.66 [M]+；Found:503 [M+H]+。
Embodiment 8
The contracting of the fluoro- 7- of 1- cyclopropyl -6- (3,4- dimethyl-piperazinium -1- base) -8- methoxy-auinolin -4 (1H) -one -3- aldehyde
4- n-pentyl thiosemicarbazides (I-8), chemical structural formula are as follows:
R i.e. in Formulas I is n-pentyl.
The compound the preparation method comprises the following steps: taking N- methyl gatifloxacin aldehyde contracting diazanyl dithiocarbonic acid first shown in formula (VI)
Ester (1.0g, 2.1mmol) is dissolved in anhydrous normal butyl alcohol (20 milliliters), and n-amylamine (0.87g, 10.0mmol) 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-8) product 0.73g, m.p.210~212 DEG C are made.1H NMR
(400MHz, DMSO-d6) δ: 11.76 (s, 1H, CH=N), 8.88 (s, 1H, 2-H), 8.45 (s, 1H, NH), 8.35 (s, 1H,
NH), 7.88 (d, 1H, 5-H), 4.16 (m, 1H, CH), 3.80 (s, 3H, OCH3), 3.36~3.07 (m, 6H, piperazine-H
and CH2), 2.55 (m, 3H, piperazine-H), 2.33 (s, 3H, N-CH3), 1.36~0.67 (m, 16H, CH3and
CH2CH2and CH2CH2CH2CH3)；MS (m/z): Calcd.for C26H37FN6O2S:516.69 [M]+；Found:517 [M+H]+。
Test example
One, the anti tumor activity in vitro for the N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided
Measurement
1, test sample
With the N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives that embodiment 1-8 is provided, and classical antitumor TOPO
Inhibitor 10-hydroxycamptothecine (HC) and gatifloxacin (GF) are test sample, and totally 10 kinds, wherein HC and GF is control group, real
Applying a 1-8 sample is 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
The specific steps of measuring method are as follows:
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 cell of logarithmic growth phase
And VERO cell strain is then separately added into the dense with 5 of above-mentioned 10 kinds of samples with 6000, every hole cell inoculation in 96 orifice plates
Spend the working solution of gradient.5gL-is added in every hole after culture 48 hours110 μ L of MTT (thiazolyl blue) solution, after continuing culture 4 hours
Lauryl sodium sulfate (SDS) solution that 100 μ L mass percent concentrations are 10% is added to be further cultured for 24 hours, then with 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 3 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 gatifloxacin (GF), especially compared with small-substituent
Or the compound of cyclopropyl substitution is equivalent to the anti-tumor activity of control hydroxycamptothecin to the activity of human pancreas cancer Panc-1 cell,
Its IC50Value has reached micro-molar concentration.What makes more sense is that the compound that embodiment 1-8 is provided is normally to VERO cells show
Lower cytotoxicity out shows there is stronger selectivity to tumour cell, such compound is prompted to develop with druggability
Potentiality and further new drug development research value.It therefore, is first to carry out conventional resist according to the general way of drug development
Tumor in Vitro screening, is then targetedly studied, so the compound of the present invention has strong anti-tumor activity and lower
Toxicity, can be by being mixed with anti-tumor drug at salt or with pharmaceutical carrier with acid human-acceptable.
Claims (8)
1. a kind of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives, which is characterized in that have the structure such as following formula (I) logical
Formula:
Wherein, substituent R is the alkyl of H atom or 1~5 carbon atom.
2. a kind of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives, which is characterized in that have the structure such as following formula (I) logical
Formula:
Wherein, substituent R is cyclopropyl.
3. N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives according to claim 1 or 2, which is characterized in that tool
Body is with the compound of flowering structure:
4. the preparation method of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives according to claim 1 or 2 or 3,
It is characterized in that, specific preparation step includes:
(1) it with gatifloxacin (Gatifloxacin) shown in formula (II) for raw material, is made shown in formula (III) through methylation reaction
N- methyl gatifloxacin；
(2) N- methyl gatifloxacin shown in formula (III) is reacted through hydrazinolysis and N- methyl gatifloxacin shown in formula (IV) is made
Hydrazides；In the aqueous ammonia medium of chloroform oxidation reaction occurs for the N- methyl gatifloxacin hydrazides potassium ferricyanide shown in formula (IV),
After reaction, post-treated to obtain N- methyl gatifloxacin aldehyde shown in formula (V)；
(3) Methyl hydrazinecarbodithioate shown in N- methyl gatifloxacin aldehyde shown in formula (V) and formula (VI) is condensed, to anti-
N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in (VII) can be made through processing after answering completely；
(4) by N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate and aminated compounds shown in formula (VII) organic
Nucleophilic substitution occurs in solvent, obtains N- methyl gatifloxacin aldehyde contracting ammonia shown in formula (I) to fully reacting is post-treated
Base thiourea derivatives；Methanol, ethyl alcohol, normal propyl alcohol, isopropanol, isobutanol, at least one in n-butanol may be selected in organic solvent
Kind；
Or,
N- methyl gatifloxacin aldehyde shown in formula (V) and thiosemicarbazides carry out condensation reaction, obtain to fully reacting is post-treated
N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives shown in formula (I).
5. the preparation method of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives according to claim 4, feature
Be, in the step (2) molar ratio of N- methyl gatifloxacin hydrazides shown in formula (IV) and the potassium ferricyanide be 1:3.0~
5.0。
6. the preparation method of N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives according to claim 4, feature
It is, N- methyl gatifloxacin aldehyde contracting Methyl hydrazinecarbodithioate shown in formula (VII) and amine chemical combination in the step (4)
The molar ratio of object is 1:3.0~10.0.
7. the N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives as described in claims 1 or 2 or 3 are preparing antineoplastic
Application in object.
8. N- methyl gatifloxacin aldehyde thiosemicarbazone derivatives according to claim 7 are in the preparation of antitumor drugs
Application, it is characterised in that: the anti-tumor drug be treat cancer of pancreas, liver cancer or leukaemia drug.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087211A1 (en) * | 2004-03-05 | 2005-09-22 | The Regents Of The University Of California | Anti-parasitic compounds and methods of their use |
| 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 |
| CN104592252A (en) * | 2015-01-16 | 2015-05-06 | 河南大学 | Oxazinoquinolinone C-3 sym-triazole sulfide ketone thiosemicarbazone derivative as well as preparation method and application thereof |
| CN104628702A (en) * | 2015-01-29 | 2015-05-20 | 河南大学 | Cyclopropylfluoroquinolone C-3 s-triazole thioether ketone thiosemicarbazone compound and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087211A1 (en) * | 2004-03-05 | 2005-09-22 | The Regents Of The University Of California | Anti-parasitic compounds and methods of their use |
| 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 |
| CN104592252A (en) * | 2015-01-16 | 2015-05-06 | 河南大学 | Oxazinoquinolinone C-3 sym-triazole sulfide ketone thiosemicarbazone derivative as well as preparation method and application thereof |
| CN104628702A (en) * | 2015-01-29 | 2015-05-20 | 河南大学 | Cyclopropylfluoroquinolone C-3 s-triazole thioether ketone thiosemicarbazone compound and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| "氟喹诺酮C-3 羧基等排体的合成及抗肿瘤活性Ⅲ.均三唑噁二唑甲硫醚衍生物";许秋菊等;《中国药科大学学报》;20130630;第44卷(第6期);511-514页 * |
| "氟喹诺酮C-3羧基等排体的合成及抗肿瘤活性:均三唑-噁二唑甲硫醚曼尼希碱衍生物";孙玉生等;《中国药科大学学报》;20140131;第45卷(第1期);39-42页 * |
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