CN109721603A - A kind of hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor and the preparation method and application thereof - Google Patents
A kind of hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor and the preparation method and application thereof.The compounds of this invention, structural formula are shown in formula I:In Formulas I, R1、R2、R3The alkyl for being 1~4 for H or C.Preparation method, include the following steps: in organic solvent, by compound shown in formula II and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole and triethylamine hybrid reaction, obtained reaction system mixed with compound shown in formula III carry out amidation process to get.The compounds of this invention can be used as hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor, group is activated with hypoxemia, as pro-drug, in the solid tumor region of hypoxemia, energy specific activation discharges active MGMT inhibitor, therefore it specific can overcome the drug resistance that MGMT is mediated in tumour cell, to the toxic side effect of normal cell when reduction and alkylating agent combined chemotherapy, and preparation method is simple.
Description
Technical field
The present invention relates to a kind of hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor and the preparation method and application thereof,
Belong to tumor inhibitor field.
Background technique
In numerous cancer treatment methods, chemotherapy is still occupied an important position, and wherein DNA alkylating agent is mesh
The widest a kind of antineoplastic chemotherapy medicine of preceding clinical application.Alkylating agent can decompose in physiological conditions generates alkyl cation,
And then the base position of attack DNA, a series of DNA damage product is generated, the biochemical metabolisms mistakes such as duplication and the transcription of DNA are inhibited
Journey, and then kill cancer cell.Clinically common alkylating agent mainly has methylating reagent (such as Temozolomide TMZ, Dacarbazine
DTIC, procarbazine PCB and streptozotocin STZ) and chloroethylation reagent, such as chlorethylnitrosourea (Carmustine BCNU, Buddhist nun
Mo Siting ACNU, Semustine MeCCNU and lomustine CCNU etc.).These alkylating agents mainly pass through attack DNA guanine
O6Position generates O6Position alkylguanine DNA adduct inhibits the biochemical metabolisms processes such as duplication and the transcription of DNA, to play anti-
Cancer effect.However, the O expressed in cancer cell6Alkylguanine-DNA alkyl transferase (AGT/MGMT) can be by guanine O6
The damage of position is transferred on the cysteine residues (Cys145) of 145, activity itself center, the DNA of damage is repaired, so that cancer is thin
Born of the same parents generate drug resistance to such alkylating agent, reduce the anticarcinogenic effect of drug.It can be by it according to the active difference of MGMT in cancer cell
It is divided into two types: 1. Mer-Type, to guanine O6Position alkylating agent is very sensitive；②Mer+Type, to guanine O6Position alkylating agent tool
There is drug resistance.Therefore, inhibit Mer+In type cancer cell the activity of MGMT become improve such alkylating agent anticarcinogenic effect it is crucial because
Element, a series of MGMT inhibitor are synthesized as pro-drug adjuvant chemotherapy.
Summary of the invention
The object of the present invention is to provide a kind of hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor and preparation method thereof
With application, the compounds of this invention can be used as hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor, there is hypoxemia to activate base
Group, as pro-drug, in the solid tumor region of hypoxemia, energy specific activation discharges active MGMT inhibitor, therefore can be special
The opposite sex overcomes the drug resistance that MGMT is mediated in tumour cell, reduces and makees with secondary to the poison of normal cell when alkylating agent combined chemotherapy
With, and preparation method is simple.
A kind of compound provided by the invention, structural formula are shown in formula I:
In Formulas I, R1、R2、R3The alkyl for being 1~4 for H or C.
In the present invention, the alkyl that the C is 1~4 is linear chain or branched chain group.
The present invention also provides the preparation method of above-mentioned compound, include the following steps: in organic solvent, by formula II
Shown compound and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole and triethylamine are mixed
Reaction is closed, obtained reaction system mixes progress amidation process with compound shown in formula III to get to compound shown in Formulas I；
In formula II, R1、R2、R3The alkyl for being 1~4 for H or C.
In the present invention, the structural formula of the compound is specific as shown in Formulas I -1:
In above-mentioned preparation method, compound shown in the formula II and the 1- (3- dimethylamino-propyl) -3- ethyl carbon
The molar ratio of diimmonium salt hydrochlorate, the I-hydroxybenzotriazole and the triethylamine can for 1:1~2:0.9~1.2:1.5~
2.5；Concretely 1:1.5:1:2；
The molar ratio of compound shown in compound shown in the formula II and the formula III can be 1:1~1.5, concretely 1:
1。
In above-mentioned preparation method, the organic solvent is at least one of methylene chloride, acetone and chloroform；
The temperature of the hybrid reaction can be -10~5 DEG C, and concretely 0 DEG C, the time can be 0.5~2.5h, concretely
1h；
The temperature of the amidation process is room temperature, and the time can be 1.5~3h, concretely 2h.
In above-mentioned preparation method, the step of preparing compound shown in the formula II, is as follows:
1) in methanesulfonic acid, by compound shown in formula IV and 3, the mixing of 3- methyl methacrylate is reacted, is obtained
Compound shown in formula V；
2) in polar solvent, compound shown in the formula V reacts to arrive the formula with N-bromosuccinimide
Compound shown in II；
In formula IV and formula V, R1、R2、R3The alkyl for being 1~4 for H or C.
In above-mentioned preparation method step 1), the temperature of the reaction can be 50~90 DEG C, concretely 70 DEG C, 50~70
DEG C, 70~90 DEG C or 60~80 DEG C, the time can be 2~5h, concretely 3h, 3~5h, 2~3h or 2~4h；
The molar ratio of compound shown in the formula IV and the 3,3- methyl methacrylate can be 1:1~2；
In step 2), the temperature of the reaction is room temperature, and the time can be 1~3h, concretely 2.5h, 1~2.5h or 2.5
~3h；
The polar solvent is the mixture of acetonitrile and water；
The molar ratio of compound shown in the formula V and the N-bromosuccinimide can be 1:1~3.
In the present invention, the room temperature is common sense well known in the art, refers to 10~30 DEG C.
In above-mentioned preparation method, the step of preparing compound shown in the formula III, is as follows:
A) in organic solvent 1, compound shown in formula VI and N- crassitude hybrid reaction obtain chemical combination shown in formula VII
Object；
B) in organic solvent 2,3- aminomethyl phenyl methanol and Trifluoroacetic Acid Ethyl Ester hybrid reaction obtain chemical combination shown in formula VIII
Object；
C) in an inert atmosphere, by compound hybrid reaction shown in compound shown in the formula VII and the formula VIII, obtain
Compound shown in formula Ⅸ；
D) in polar solvent 1, compound shown in the formula Ⅸ is reacted under the conditions of base catalysis to get the formula III is arrived
Shown compound.
In above-mentioned preparation method step a), the molar ratio of compound shown in the formula VI and N- crassitude is 1:1
~2, concretely 1:1；The temperature of the reaction can be 15~40 DEG C, concretely 25 DEG C, the time can for 18~for 24 hours, specifically
It can be 20h, 18~20h or 20~for 24 hours；
The organic solvent 1 is n,N-Dimethylformamide or dimethyl sulfoxide；
In step b), the molar ratio of the 3- aminomethyl phenyl methanol and the Trifluoroacetic Acid Ethyl Ester can be 1:0.5~1.5,
Concretely 1:1；The temperature of the reaction can be room temperature, and the time can be 1~3h, concretely 2h, 1~2h, 2~3h or 1.5
~2.5h；It is carried out under the conditions of the reaction is existing for the triethylamine；
The organic solvent 2 is dry methanol or dry acetonitrile；
In step c), the molar ratio of compound shown in compound shown in the formula VII and the formula VIII can be 1:1~2, tool
Body can be 1:1；The temperature of the reaction is room temperature, and the time can be 1~4h, concretely 2.5h, 1~2.5h, 2.5~4h or 2
~3h；The reaction dissolvent is n,N-Dimethylformamide or dimethyl sulfoxide, and the reaction carries out under potassium tert-butoxide catalysis；
The inert atmosphere is nitrogen, argon gas or helium；
In step d), the polar solvent 1 be volume ratio can be 17:1 first alcohol and water mixed liquor；The reaction is in carbon
It is carried out under sour potassium or sodium carbonate existence condition.
The present invention also provides a kind of targets neoplastic cells DNA repair enzyme MGMT inhibitor, are chemical combination shown in above-mentioned Formulas I
Object；
Preferably, the targets neoplastic cells DNA repair enzyme MGMT inhibitor, refers under hypoxia condition, target tumor is thin
Born of the same parents.
The present invention also provides a kind of hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor, are above-mentioned Formulas I shownization
Close object.
Compound shown in Formulas I of the present invention is applied in drug of the preparation for treating tumour.The tumour is entity
Tumor, including nervous system neoplasm, digestive system tumor, genital system；The nervous system neoplasm specifically includes human brain mind
Through glioma, the digestive system tumor specifically includes colon cancer, and the genital system specifically includes breast cancer or uterine neck
Cancer.
Mechanism of the compound shown in Formulas I of the present invention as hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor
Process is as follows:
By above-mentioned reaction mechanism it is found that hypoxemia activation group is to change shown in the formula II in compound shown in the Formulas I
The group for closing object, is easy to leave away, generates MGMT inhibitor compound shown in the formula III.
The invention has the following advantages that
The compounds of this invention can be used as hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor, and there is hypoxemia to activate base
Group can decompose to obtain the MGMT inhibitor of high activity in the low oxygen area of solid tumor as pro-drug, can specificity gram
The drug resistance that DNA repair enzyme MGMT is mediated in tumour cell is taken, while reducing the toxic side effect of normal tissue, and its preparation side
Method is simple, and raw material is readily synthesized.
Detailed description of the invention
Fig. 1 is the mechanism flow chart of the compounds of this invention hypoxemia activation.
Fig. 2 is HPLC-UV and the MS figure of compound 2 in the embodiment of the present invention 1.
Fig. 3 is the mass spectrogram of compound 2 in the embodiment of the present invention 1.
Fig. 4 is HPLC-UV and the MS figure of compound 3 in the embodiment of the present invention 1.
Fig. 5 is the mass spectrogram of compound 3 in the embodiment of the present invention 1.
Fig. 6 is HPLC-UV and the MS figure of target compound in the embodiment of the present invention 1.
Fig. 7 is the mass spectrogram of target compound in the embodiment of the present invention 1.
Fig. 8 is the hydrogen spectrogram of target compound in the embodiment of the present invention 1.
Specific embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
The materials, reagents and the like used in the following examples is commercially available unless otherwise specified.
Embodiment 1,
1, according to R in compound shown in following reaction process compounds 1 synthesis formula V1、R2、R3For the compound 2 of methyl:
It takes 20.0mL methanesulfonic acid in 100mL volumetric flask, after being heated to 70 DEG C, 2.0g trimethylhydroquinone is added
(13.14mmol) and 1.7g 3,3- methyl methacrylate (14.9mmol) continue to be stirred to react 3h in 70 DEG C, backward
The ethyl acetate of water and 75mL that 250mL is added in reaction mixture extracts (3 times), combines organic phase water, is saturated NaHCO3,
Saturation NaCl is washed one time, anhydrous MgSO4It is dry, it is concentrated under reduced pressure, obtains crude product white-yellowish solid.Re-crystallizing in ethyl acetate obtains
2 2.5g of white crystal (10.67mmol, yield 81.2%).TLC monitoring reaction: hexamethylene: ethyl acetate=1:1.
The structural identification of compound 2: as shown in Figures 2 and 3.
2, according to R in compound shown in following reaction process compounds 2 synthesis formula II1、R2、R3For the compound 3 of methyl:
2.5g compound 2 (10.67mmol) is weighed, (130mL) is suspended from 15% acetonitrile solution.Then in solution by
It is added dropwise to the acetonitrile solution 40mL (v/v, 40%) of N-bromosuccinimide containing 2.6g (14.6mmol), dropwise addition is stirred to react >
1h (specially 25 DEG C of room temperature reacts 2.5h).After adding, continue to be stirred to react 30min, it is rear that 330mL water dilute reaction solution is added,
Ether extracts 3 times, each 75mL.Joint organic phase is washed with water 2 times (each 100mL), anhydrous MgSO4It is dry, after reduced pressure
Obtain crude product yellow solid.Re-crystallizing in ethyl acetate obtains 2.15g yellow crystals 3 (8.59mmol, yield 80.5%).TLC
Monitor reaction product: hexamethylene: ethyl acetate=1:1.
The structural identification of compound 3: as shown in Figure 4 and Figure 5.
3, the preparation of compound shown in formula III:
A) in n,N-Dimethylformamide, compound shown in formula VI and N- crassitude molar ratio are 1:1；Reaction
Temperature can be 25 DEG C of room temperature, and reaction 20h is mixed, obtains compound shown in formula VII；
B) in dry methanol, 3- aminomethyl phenyl methanol and Trifluoroacetic Acid Ethyl Ester molar ratio are 1:1, and triethylamine is added and stirs
Mix hybrid reaction；25 DEG C of room temperature, reaction time 2h；Obtain compound shown in formula VIII；
C) in nitrogen atmosphere, the molar ratio of compound shown in compound shown in formula VII and formula VIII is mixed and is added for 1:1
Potassium tert-butoxide, 25 DEG C of room temperature are stirred to react 2.5h, obtain compound shown in formula Ⅸ；
D) in the mixed liquor for the first alcohol and water that volume ratio is 17:1, compound shown in formula Ⅸ is anti-under the conditions of potassium carbonate
It should be to get to compound shown in the formula III.
4, according to R after the reaction of following reaction process compounds 3 and in compound shown in compound synthesis Formulas I shown in formula III1、
R2、R3Compound shown in Formulas I -1 for methyl (target compound):
It accurately weighs 100mg compound 3 (Mr=250.29g/mol, 0.4mmol) and is dissolved in 5mL CH2Cl2, it is added
115.02mg EDCHCl (Chinese 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, Mr=191.7g/
Mol, 0.6mmol), 54mg HOBT (Chinese I-hydroxybenzotriazole, Mr=135.1mg/mol, 0.4mmol), 110 μ L
TEA (Chinese triethylamine, Mr=101.19g/mol, ρ=0.73g/cm3, 0.8mmol), 1h is reacted under the conditions of 0 DEG C, then
It is added 100mg compound 15 (270g/mol, 0.37mmol), is restored to room temperature reaction, TLC, which is monitored to raw material point, to disappear, and stops
Reaction.30mL water and the extraction of 30mL ethyl acetate is added, joint organic phase water, saturation NaCl wash one time, anhydrous Na2SO4It is dry
Overnight.(raw material ratio is acid: EDCHCl:HOBT:TEA: amine=1:1.5:1:2:1).Filtering, mixes silica gel, and column chromatography purifies (first
Alcohol: methylene chloride=1:50~1:10) to get arrive target compound, 60mg (Mr=502.56g/mol, 0.12mmol, yield
30%).
The structural identification of target compound: as shown in Fig. 6, Fig. 7 and Fig. 8.
For compound shown in the Formulas I -1 that synthesizes of the present invention, in order to prove that the present invention under hypoxemia and normoxic condition synthesizes
Compound shown in Formulas I -1 has differences the inhibitory activity of MGMT, determines drug-treated using HPLC-ESI-MS/MS method
The MGMT in cell is active (J.Chromatogr.B 2016,1033,138-146.) afterwards.This method is based on O6Benzyl bird is fast
Purine (O6- BG) substrate as MGMT, there is high affinity with MGMT.Specific determination step is as follows: SF767 and SF763 are thin
Born of the same parents' (SF767 and SF763 are that MGMT high expresses human brain neuroglial cytoma) are respectively under normal oxygen or hypoxia condition through 100 μM of sheets
After inventing the processing of compound (abbreviation drug) shown in the Formulas I -1 of synthesis 1h, the culture medium containing drug is discarded, with PBS (NaCl
137mmol/L, KCl 2.7mM, Na2HPO410mM, KH2PO42mM, no calcium and magnesium) washing 3 times, the digestion of 0.25% pancreatin is added,
Cell is collected by centrifugation.Then be added 0.7mL buffer (50mM Tris pH 8.0,0.1mM EDTA-2Na, 1mM DTT, 5%
Glycerol, 0.1mM PMSF) washing 2 times, it is centrifuged spare after abandoning supernatant or puts to -80 DEG C of preservations.Then cell is hanged again
In above-mentioned buffer, until ultrasonication on ice 5 times, persistently 30s, every minor tick 1min, subsequent 13000rpm are centrifuged 15min every time
Remove cell fragment, collect protein-contg supernatant to spare on ice or be rapidly frozen in liquid nitrogen, -80 DEG C save it is stand-by.Carefully
Protein concentration in born of the same parents' protein extract is measured with Bradford method.
Take the O of 1.0 μ L 200nM6The buffer that 99 μ L contain 100 μ g cell protein extracts is added in-BG (200fmol)
(50mM Tris-HCl, pH 7.5,0.1mM EDTApH 8.0,1mM dithiothreitol (DTT), percent by volume are 5% glycerol,
0.1mM phenylmethylsulfonyl fluoride) in, 37 DEG C of reaction 1h.After reaction, the cold acetonitrile precipitation albumen of half volume, 4 DEG C of items are added
12000rpm is centrifuged 5min under part, takes supernatant.This step is repeated 1 times, and 2 supernatants are merged.Then to being added 1.0 in supernatant
The D of μ L 1000nM6-O6- BG is used as Isotopic Internal Standard (final concentration of 5nM), by Microcon YM-10 micropore centrifugal filtration
After pipe filtering, collects filtrate and analyzed for HPLC-ESI-MS/MS.The blank control of acellular albumen extract is set simultaneously.Instead
Answer O in system6The amount of-BG is 200fmol.
- 1 institute of Formulas I that human brain neuroglial cytoma SF767 and SF763 is synthesized under hypoxemia and normoxic condition through the present invention
Show MGMT activity change after compound processing, experimental result is as shown in table 1:
Table 1SF767 and SF763 cell treated MGMT activity change (fmol/mg protein extract)
As result in table 1 it is found that the MGMT activity of compound hypoxemia processing group shown in formula I-1 is substantially less than normal oxygen
Control group, illustrates the drug resistance that the compounds of this invention is activated with hypoxemia, and MGMT in tumour cell can effectively be inhibited to mediate, therefore energy
As hypoxemia targets neoplastic cells DNA repair enzyme MGMT inhibitor, and it is used to prepare the drug for treating tumour.
Claims (10)
1. a kind of compound, structural formula are shown in formula I:
In Formulas I, R1、R2、R3The alkyl for being 1~4 for H or C.
2. the preparation method of compound according to claim 1 includes the following steps: in organic solvent, by II institute of formula
Show that compound is mixed with 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, I-hydroxybenzotriazole and triethylamine
Reaction, obtained reaction system mix progress amidation process with compound shown in formula III to get to compound shown in Formulas I；
In formula II, R1、R2、R3The alkyl for being 1~4 for H or C.
3. preparation method according to claim 2, it is characterised in that: compound shown in the formula II and the 1- (3- bis-
Methylaminopropyl) -3- ethyl-carbodiimide hydrochloride, the I-hydroxybenzotriazole and the triethylamine molar ratio be 1:1
~2:0.9~1.2:1.5~2.5；
The molar ratio of compound shown in compound shown in the formula II and the formula III is 1:1~1.5.
4. preparation method according to claim 2 or 3, it is characterised in that: the organic solvent be methylene chloride, acetone and
At least one of chloroform；
The temperature of the hybrid reaction is -10~5 DEG C, and the time is 0.5~2.5h；
The temperature of the amidation process is room temperature, and the time is 1.5~3h.
5. the preparation method according to any one of claim 2-4, it is characterised in that: prepare compound shown in the formula II
The step of it is as follows:
1) in methanesulfonic acid, by compound shown in formula IV and 3, the mixing of 3- methyl methacrylate is reacted, and obtains formula V
Shown compound；
2) in polar solvent, compound shown in the formula V reacts to arrive II institute of formula with N-bromosuccinimide
Show compound；
In formula IV and formula V, R1、R2、R3The alkyl for being 1~4 for H or C.
6. preparation method according to claim 5, it is characterised in that: in step 1), the temperature of the reaction is 50~90
DEG C, the time is 2~5h；
The molar ratio of compound shown in the formula IV and the 3,3- methyl methacrylate is 1:1~2；
In step 2), the temperature of the reaction is room temperature, and the time is 1~3h；
The polar solvent is the mixture of acetonitrile and water；
The molar ratio of compound shown in the formula V and the N-bromosuccinimide is 1:1~3.
7. the preparation method according to any one of claim 2-6, it is characterised in that: prepare compound shown in the formula III
The step of it is as follows:
A) in organic solvent 1, compound shown in formula VI and N- crassitude hybrid reaction obtain compound shown in formula VII；
B) in organic solvent 2,3- aminomethyl phenyl methanol and Trifluoroacetic Acid Ethyl Ester hybrid reaction obtain compound shown in formula VIII；
C) in an inert atmosphere, by compound hybrid reaction shown in compound shown in the formula VII and the formula VIII, formula Ⅸ is obtained
Shown compound；
D) in polar solvent 1, compound shown in the formula Ⅸ is reacted under the conditions of base catalysis to get to shown in the formula III
Compound.
8. preparation method according to claim 7, it is characterised in that: in step a), compound and N- shown in the formula VI
The molar ratio of crassitude is 1:1~2；The temperature of the reaction be 15~40 DEG C, the time be 18~for 24 hours；
The organic solvent 1 is n,N-Dimethylformamide or dimethyl sulfoxide；
In step b), the molar ratio of the 3- aminomethyl phenyl methanol and the Trifluoroacetic Acid Ethyl Ester is 1:0.5~1.5；It is described anti-
The temperature answered is room temperature, and the time is 1~3h；It is carried out under the conditions of the reaction is existing for the triethylamine；
The organic solvent 2 is dry methanol or dry acetonitrile；
In step c), the molar ratio of compound shown in compound shown in the formula VII and the formula VIII is 1:1~2；The reaction
Temperature be room temperature, the time be 1~4h；The reaction dissolvent is n,N-Dimethylformamide or dimethyl sulfoxide, the reaction
It is carried out under potassium tert-butoxide catalysis；
The inert atmosphere is nitrogen, argon gas or helium；
In step d), the polar solvent 1 is the mixed liquor for the first alcohol and water that volume ratio is 17:1；The reaction in potassium carbonate or
It is carried out under sodium carbonate existence condition.
9. a kind of targets neoplastic cells DNA repair enzyme MGMT inhibitor is compound shown in Formulas I described in claim 1；
Preferably, the targets neoplastic cells DNA repair enzyme MGMT inhibitor, refers under hypoxia condition, targets neoplastic cells.
10. compound shown in Formulas I described in claim 1 is preparing the application in the drug for treating tumour.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111925371A (en) * | 2020-03-16 | 2020-11-13 | 北京工业大学 | Nitrobenzene substituted O6-3-aminomethyl benzyl guanine and preparation method and application thereof |
| CN111925371B (en) * | 2020-03-16 | 2022-07-22 | 北京工业大学 | Nitrobenzene substituted O6-3-aminomethyl benzyl guanine and preparation method and application thereof |
| CN113717174A (en) * | 2021-08-18 | 2021-11-30 | 北京工业大学 | Tumor targeting drug resistant O6-thienylmethylguanine-indoloquinone-chloroethylnitrosourea combined molecule and preparation method thereof |
| CN113717174B (en) * | 2021-08-18 | 2022-07-12 | 北京工业大学 | Tumor targeting drug resistant O6-thienylmethylguanine-indoloquinone-chloroethylnitrosourea combined molecule and preparation method thereof |
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