CN108752243A - A kind of 1,4- naphthaquinone derivatives and its preparation method and application - Google Patents
A kind of 1,4- naphthaquinone derivatives and its preparation method and application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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Abstract
The present invention relates to one kind 1,4- naphthaquinone derivatives and its preparation method and application, the present invention synthesizes and finds that such compound has the activity of good inhibition human colon cancer cell (SW480 and HCT116) for the first time, has potential value in terms of antitumor drug development and application；The present invention has carried out alpha-glucosaccharase enzyme inhibition activity to synthesized compound simultaneously, the experimental results showed that such compound also has certain alpha-glucosaccharase enzyme inhibition activity, illustrate that such compound also has bright prospects in the exploitation for the treatment of diabetes medicament with application aspect.
Description
Technical field
The invention belongs to noval chemical compound synthesis and medicinal application fields, are related to a kind of 1,4-naphthoquinone analog derivative, including close
At, activity rating and application.
Technical background
1,4-naphthoquinone derivative has multiple biological activities, such as antitumor, antimicrobial, antibacterial, antiviral, free basic capsule
Solution, antithrombotic, trypanocidia isoreactivity have potential medical value, thus are widely used in the industries such as agricultural, medicine.Cause
This, synthesis and the activity research of 1,4-naphthoquinone derivative are concerned.
Nineteen sixty-eight, a series of 2- amido derivatives that Benjamin P. report the chloro- 1,4-naphthoquinones of 2- are lived with anti-malarial
Property, but these derivatives do not have sulfoamido side chain.2009M.Sebti et al. is found that from the screening of NCI compound libraries
1,4- naphthoquinone derivatives PI-083 (NSC-45382), which has, inhibits oophoroma T80-Hras, pancreas C7-Kras and breast cancer MCF-
7 activity, target spot may be proteasome (proteasome).The seminar reports PI-083 derivatives again within 2010
Synthesis and proteasome inhibition activity.An J. seminars research in 2017 finds that the compound also has and improves lung carcinoma cell
The activity of chemosensitivity.
Invention content
The object of the present invention is to provide the synthesis of a kind of novel 1,4- naphthoquinone derivatives to be controlled in antitumor and anti-diabetic
Application in treatment.
The purpose of the present invention is what is be achieved through the following technical solutions：
The present invention has synthesized a kind of novel 1,4-naphthoquinone derivative, and general structure I is as follows：
Wherein, R1For substituted or non-substituted aryl, alkyl or hydroxyl；R2For hydrogen or halogen；R3Replace for 5,6,7,8
Halogen, nitro, aryl, carboxyl, trifluoromethyl, ester group, alkyl or alkoxy；The integer of n=1-8.
General structure II is as follows：
Wherein, R1For acetylamino, propionamido, butyrylamino, trifluoroacetamido,R2For hydrogen or halogen；R3
Halogen, nitro, aryl, carboxyl, trifluoromethyl, ester group, alkyl or the alkoxy replaced for 5,6,7,8.WhereinN=
4, the integer of 6-8, i.e., four, six, seven, eight methylene imines.
The advantages of the present invention are：
1, reaction of the invention is not required to anhydrous and oxygen-free operation, and easy to operate, raw material is cheap and easy to get with reagent, is suitble to extensive
Production and exploitation.
2,1,4- naphthoquinone derivatives according to the present invention have preferable anti-human colon cancer cell activity.
3,1,4- naphthoquinone derivatives according to the present invention have certain alpha-glucosaccharase enzyme inhibition activity.
Description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of compound 1；
Fig. 2 is the nuclear-magnetism carbon spectrogram of compound 2；
Fig. 3 is the nucleus magnetic hydrogen spectrum figure of compound 3；
Fig. 4 is the nuclear-magnetism carbon spectrogram of compound 4；
Fig. 5 is the nucleus magnetic hydrogen spectrum figure of compound 5；
Fig. 6 is the nuclear-magnetism carbon spectrogram of compound 6；
Fig. 7 is the nucleus magnetic hydrogen spectrum figure of compound 7；
Fig. 8 is the nuclear-magnetism carbon spectrogram of compound 8；
Fig. 9 is the nucleus magnetic hydrogen spectrum figure of compound 9；
Figure 10 is the nuclear-magnetism carbon spectrogram of compound 10；
Figure 11 is the nucleus magnetic hydrogen spectrum figure of compound 11；
Figure 12 is the nuclear-magnetism carbon spectrogram of compound 12；
Figure 13 is the nuclear-magnetism carbon spectrogram of compound 13.
Specific embodiment
In order to understand the present invention, with reference to embodiment, the invention will be further described：Following embodiments are illustrative
, it is not restrictive, protection scope of the present invention cannot be limited with following embodiments.
A kind of 1,4-naphthoquinone derivative, is synthesized by the following way what route obtained：
It wherein prepares above-mentioned 1,4- naphthoquinone derivatives I and specifically includes following step：
(1) diamines list (Boc)2O is protected：By (Boc)2O (0.2eq.) is dissolved in anhydrous methylene chloride (50mL), at 0 DEG C
It is lower by (Boc)2The solution of O is added drop-wise in the anhydrous methylene chloride solution of diamines (1.0eq.) under protection of argon gas, will be reacted
Mixture stirs 1h at 0 DEG C, then reacts 10h at room temperature.Reaction solution is washed with saturation NaCl aqueous solutions (30mL), will be had
Machine layer Na2SO4Dry, solvent evaporated after filtering obtains intermediate III, is colorless oil.
(2) by step (1) gained desciccate III (1.0eq.) dichloromethane (10mL) solution, be added triethylamine
(3.0eq.) and sulfonic acid chloride (1.2eq.), reacts about 4h at room temperature, after the reaction was complete, is diluted, is used with dichloromethane (10mL)
Water washing, organic layer Na2SO4Dry, solvent evaporated after filtering, silica gel chromatography obtains product IV, is white powder.
(3) acid condition removes Boc protecting groups：(2) step is obtained to desciccate IV be dissolved in dichloromethane, into solution
Trifluoroacetic acid (1.5eq.) is added, reaction mixture is concentrated under reduced pressure after complete reaction by reaction about 2-4h, obtains product V.
(4) step product V (1.0eq.) (3) is added in 95% ethyl alcohol (15mL), be added triethylamine (1.5eq.) with
The chloro- 1,4-naphthoquinones of 2- or derivatives thereof (1.1eq.), 100-120 DEG C is heated 2-3 days, and red precipitate is obtained.Reaction is mixed
Object is cooled to room temperature, and solid is obtained by filtration, and is washed 3-5 times with ethyl alcohol.Silica gel column chromatogram separating purification obtains product I.
Specific preparation embodiment provided by the invention is as follows：
Embodiment 1
A kind of preparation method of 1,4-naphthoquinone derivative described in claim 1, steps are as follows：
Diamines list (Boc)2III is obtained after O protections, IV is obtained by the reaction with sulfonic acid chloride, acid condition removes Boc protecting groups
V is obtained, obtains a kind of 1,4-naphthoquinone derivative with 1,4-naphthoquinone and its derivatives reaction, reaction equation is
More particularly to the synthesis of compound 1.
By (Boc)2O (3.6g, 0.1eq.) is dissolved in anhydrous methylene chloride (50mL), by (Boc) at 0 DEG C2The solution of O
It is added drop-wise in the anhydrous methylene chloride solution of ethylenediamine (0.2mol/L, 1.0eq.) under protection of argon gas.By reaction mixture
1h is stirred at 0 DEG C, then reacts 10h at room temperature.It is saturated NaCl aqueous solutions (30mL) to wash, by organic layer Na2SO4It is dry
Dry, solvent evaporated after filtering obtains product III, is colorless oil.
Triethylamine (3.0eq.) and sulphonyl are added into dichloromethane (10mL) solution of above-mentioned product III (1.0eq.)
Chlorine (1.2eq.), is stirred at room temperature reaction mixture 4-8h.After stirring, solution is concentrated, is washed with water, Na is used2SO4It is dry
And solvent is removed under reduced pressure, pass through silica gel column chromatography (ethyl acetate:N-hexane=2:3) purifying obtains white powder product
IV。
Product IV is dissolved in dichloromethane, trifluoroacetic acid (1.5eq.) is added dropwise into solution, about 2-4h is reacted, waits having reacted
Reaction mixture is concentrated under reduced pressure Quan Hou, obtains product V.
Product V (1.0eq.) is added in 95% ethyl alcohol (15mL), triethylamine (1.5eq.) and the chloro- Isosorbide-5-Nitrae-naphthalenes of 2- is added
Quinone (1.1eq.), 100 DEG C are heated 3 days, and red precipitate is obtained.Reaction mixture is cooled to room temperature, solid is obtained by filtration, is used
Ethyl alcohol washs 3-5 times.Silica gel column chromatogram separating purification obtains red solid product I.Yield 92%.Structural parameters:1H NMR
(400MHz,DMSO-d6) δ 8.32 (d, J=8.8 Hz, 2H), 8.02 (s, 2H), 7.95 (dd, J=1.6Hz, 2H), 7.83 (t,
J=7.6Hz, 1H), 7.75 (t, J=7.6Hz, 1H), 7.31 (s, 1H), 3.81-3.76 (m, 2H), 3.16-3.12 (m, 2H)；
HRMS (ESI-TOF)m/z calcd.for C18H14N3O6SClNa+[(M+Na)+]:458.0170,found 458.0184.
Embodiment 2
The synthesis of compound 2.
Synthetic method of the synthetic method of embodiment 2 with above compound 1.
Yield：89%；Structural parameters:1H NMR(400MHz,DMSO-d6) δ 7.95 (d, J=7.6Hz, 3H), 7.83-
7.72 (m, 4H), 7.58 (d, J=8.4Hz, 2H), 7.30 (s, 1H), 3.80-3.75 (m, 2H), 3.10-3.07 (m, 2H)；13C
NMR(100MHz,DMSO-d6)δ180.3,175.9,145.5, 139.6,137.8,135.3,133.2,132.2,130.3,
129.7,128.8,126.9,126.3,43.5.HRMS (ESI-TOF)m/z calcd.for C18H14N2O4SCl2Na+[(M+
Na)+]:446.9932,found 446.9944.
Embodiment 3
The synthesis of compound 3.
Synthetic method of the synthetic method of embodiment 3 with above compound 1.
Yield：94%；Structural parameters:1H NMR(400MHz,DMSO-d6) δ 7.94 (t, J=7.2Hz, 2H), 7.82 (t,
J=8.4Hz, 1H), 7.76-7.71 (m, 2H), 7.64 (d, J=7.6Hz, 2H), 7.26 (d, J=8.0Hz, 3H), 3.79-
3.74(m,2H),3.07–3.02(m,2H),2.19(s,3H)；13C NMR(100MHz,DMSO-d6)δ180.2,175.8,
145.4,143.0,137.8,135.3,133.2,132.2, 130.3,130.0,1126.9,126.9,126.2,43.5,
21.2.HRMS(ESI-TOF)m/z calcd.for C19H17N2O4SClNa+[(M+Na)+]:427.0480,
found427.0490.
Embodiment 4
The synthesis of compound 4.
Synthetic method of the synthetic method of embodiment 4 with above compound 1.
Yield：90%；Structural parameters:1H NMR(400MHz,DMSO-d6) δ 7.95 (t, J=4.4Hz, 2H), 7.94-
7.81 (m, 4H), 7.74 (t, J=8.4Hz, 7.2H), 7.35 (t, J=8.4Hz, 8.8H), 3.80-3.75 (m, 2H), 3.10-
3.07(m,2H)；13C NMR(100MHz,DMSO-d6)δ180.3, 175.9,165.7,163.2,145.6,137.2,137.1,
135.3,133.1,132.2,130.3,129.9,129.8, 126.9,126.2,116.8,116.6,43.7,43.5.HRMS
(ESI-TOF)m/z calcd.for C18H14N2O4FSClNa+[(M+Na)+]:431.0240,found431.0239.
Embodiment 5
The synthesis of compound 5.
Synthetic method of the synthetic method of embodiment 5 with above compound 1.
Yield：88%；Structural parameters:1H NMR(400MHz,DMSO-d6) δ 8.41 (d, J=8.0Hz, 2H), 8.09
(dd, J=8.0,4.4Hz, 5H), 7.84 (t, J=6.8Hz, 1H), 7.75 (t, J=8.0Hz, 1H), 3.67 (d, J=
6.0Hz,2H),2.86(s,2H),1.58(s,2H),1.44(s,2H)；13C NMR (100MHz,DMSO-d6)δ180.6,
175.8,149.9,146.7,146.6,135.4,133.0,132.5,130.3, 128.4,126.9,126.2,125.0,
125.0,43.7,42.8,28.4,26.6.HRMS(ESI-TOF)m/z calcd. for C20H18N3O6SClNa+[(M+Na)+]:
462.0519,found462.0532.
Embodiment 6
The synthesis of compound 6.
Synthetic method of the synthetic method of embodiment 6 with above compound 1.
Yield：92%；Structural parameters:1H NMR(400MHz,CDCl3) δ 7.96 (d, J=3.6Hz, 2H), 7.84-7.72
(m, 5H), 7.65 (d, J=8.0Hz, 2H), 7.46 (s, 1H), 3.67 (d, J=6.4Hz, 2H), 2.79 (d, J=6.0Hz,
2H), 1.57 (d, J=6.4Hz, 2H), 1.44 (d, J=6.4Hz, 2H)；13C NMR(100MHz,DMSO-d6)δ180.5,
175.8,145.5,139.9,137.6,135.3,133.0,132.5, 130.2,129.7,128.8,126.9,126.2,
43.8,42.8,28.4,26.6.HRMS(ESI-TOF)m/z calcd. for C20H18N2O4SCl2Na+[(M+Na)+]:
475.0248,found 475.0257.
Embodiment 7
The synthesis of compound 7.
Synthetic method of the synthetic method of embodiment 7 with above compound 1.
Yield：96%；Structural parameters:1H NMR(400MHz,CDCl3) δ 7.97 (t, J=5.6Hz, 2H), 7.84 (t, J
=7.2Hz, 1H), 7.75 (t, J=7.6Hz, 1H), 7.69 (d, J=8.0Hz, 2H), 7.53 (t, J=6.0Hz, 1H), 7.47
(s, 1H), 7.39 (d, J=8.0Hz, 2H), 3.71-3.66 (m, 2H), 2.79-2.74 (m, 2H), 1.63-1.56 (m, 2H),
1.48-1.40(m,2H),2.38(s,3H)；13C NMR (100MHz,DMSO-d6)δ180.5,175.8,145.5,142.9,
137.6,138.1,135.3,133.0,132.5, 120.2,120.0,126.9,126.2,43.8,42.8,28.5,26.6,
21.3.HRMS(ESI-TOF)m/z calcd.for C21H21N2O4SClNa+[(M+Na)+]:455.0797,
found455.0803.
Embodiment 8
The synthesis of compound 8.
Synthetic method of the synthetic method of embodiment 8 with above compound 1.
Yield：91%；Structural parameters:1H NMR(400MHz,DMSO-d6) δ 7.97 (t, J=7.2Hz, 2H), 7.83 (t,
J=8.4Hz, 3H), 7.74 (t, J=9.2Hz, 1H), 7.63 (t, J=5.6Hz, 1H), 7.48 (s, 1H), 7.40 (t, J=
8.8Hz,2H),3.69-3.64(m,2H),2.78-2.74(m,2H), 1.60-1.53(m,2H),1.44-1.37(m,2H)；13C
NMR(100MHz,DMSO-d6)δ180.6, 175.8,165.7,163.2,137.4,137.3,135.4,133.1,132.5,
130.3,129.9,129.8,126.9, 126.2,116.8,116.6,43.8,42.7,28.4,26.6.HRMS(ESI-TOF)
m/z calcd.for C20H18N2O4FSClNa+[(M+Na)+]:459.0541,found459.0552.
The preparation method of 1,4- naphthoquinone derivatives II is as follows：
It wherein prepares above-mentioned 1,4- naphthoquinone derivatives II and specifically includes following step：
(1) by primary amine or dichloromethane (10mL) solution of secondary amine raw material (1.0eq.), be added triethylamine (3.0eq.) and
Sulfonic acid chloride (1.2eq.), reacts about 4-8h at room temperature, after the reaction was complete, is diluted with dichloromethane (10mL), is washed with water, has
Machine layer Na2SO4Dry, solvent evaporated after filtering, silica gel chromatography obtains product VI.
(2) it by the above-mentioned product VI (1) of step, is dissolved in methanol, sodium hydrate aqueous solution (5M, 3 eq.), reflux is added
Reaction mixture is concentrated under reduced pressure after complete reaction by reaction about 2-4h, is diluted, is washed with water with dichloromethane (10mL),
Organic layer Na2SO4Dry, solvent evaporated after filtering, silica gel chromatography obtains product VII.
(3) step product VII (1.0eq.) (2) is added in 95% ethyl alcohol (15mL), be added triethylamine (1.5eq.) with
The chloro- 1,4-naphthoquinones of 2- (1.1eq.), 100 DEG C are heated 3 days, and red precipitate is obtained.Reaction mixture is cooled to room temperature, is filtered
Solid is obtained, is washed 3 times with ethyl alcohol.Silica gel column chromatogram separating purification obtains product II.
Specific preparation embodiment provided by the invention is as follows：
Embodiment 9
The synthesis of compound 9.
The synthetic method of embodiment 9 leads to method with the synthesis of above compound.
Yield：74%；Structural parameters：1H NMR(400MHz,DMSO-d6) δ 9.529 (s, 1H), 8.04 (t, J=
7.6Hz, 2H), 7.91-7.81 (m, 3H), 7.73 (d, J=8.4Hz, 2H), 7.31 (s, 1H), 7.23 (d, J=8.4Hz,
2H)；13C NMR(100MHz,DMSO-d6)δ180.2,177.5,169.2,143.2, 142.7,139.0,135.2,135.1,
133.9,132.2,132.0,130.9,130.3,127.0,126.7,126.6,126.2, 122.8,118.3.HRMS(ESI-
TOF)m/z calcd.for C18H10ClF3N2O5SNa+[(M+Na)+]: 457.9951,found 480.8874.
Embodiment 10
The synthesis of compound 10.
The synthetic method of embodiment 10 leads to method with the synthesis of above compound.
Yield：93%；Structural parameters:1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),9.61(s, 1H),8.07
(s, 1H), 7.90-7.80 (m, 4H), 7.25 (d, J=8.0Hz, 2H), 1.93 (d, J=7.2Hz, 3H)；13C NMR
(100MHz,DMSO-d6)δ180.2,177.5,169.2,144.6,143.0,135.2, 134.1,133.2,132.1,
131.0,128.30,127.1,126.7,122.0,120.3,23.7.HRMS(ESI-TOF) m/z calcd.for
C18H13ClN2O5SNa+[(M+Na)+]:404.0234,found 427.0144.
Embodiment 11
The synthesis of compound 11.
The synthetic method of embodiment 11 leads to method with the synthesis of above compound.
Yield：95%；Structural parameters:1H NMR(400MHz,DMSO-d6) δ 8.21 (dd, J=1.2,0.8Hz, 1H),
8.15 (dd, J=0.8,0.8Hz, 1H), 7.83-7.72 (m, 4H), 7.11 (d, J=8.8Hz, 1H), 3.30 (t, J=
6.0Hz,4H),1.72(s,4H),1.60-1.58(m,6H)；13C NMR(100MHz,DMSO-d6) δ180.3,177.4,
143.5,143.1,135.2,134.0,133.5,132.2,130.9,127.2,126.6,122.9, 118.9,48.1,28.9,
26.8.HRMS(ESI-TOF)m/z calcd.for C22H21ClN2O4SNa+ [(M+Na)+]:444.0911,found
467.0825.
Embodiment 12
The synthesis of compound 12.
1- tert-butoxycarbonyl-piperazines (0.51g, 2.80mmol) are dissolved in tetrahydrofuran (1.5mL), 4- nitrobenzenes are added
Sulfonic acid chloride (0.30mL, 3.70mmol) and triethylamine (0.24mL, 1.74mmol) are heated to 60 DEG C of reaction 2h, after the reaction was complete
Be cooled to room temperature, with ethyl acetate (10mL) dilute and be saturated NaHCO3(10mL) is washed.It is extracted with ethyl acetate, with nothing
Water MgSO4It is dry, obtain sterling by silica gel column chromatography (0-30%v/v ethyl acetate/hexanes) purifies and separates.
4- [4- nitrobenzophenones] -1- tert-butoxycarbonyl-piperazines (0.38g, 1.98mmol) are suspended in second alcohol and water (10
ML) 5:In 1 mixed liquor, iron powder (0.22g, 4.0mmol) is added into the solution, saturated ammonium chloride solution is then added
(1mL), and heat the mixture to 80 DEG C of reaction 3h.Then, reaction mixture is cooled to room temperature, pad diatomite filtering.With
Ethyl alcohol (10mL) and ethyl acetate (50mL) washing, and solution is concentrated in vacuo.Gained residue dichloromethane (50mL) and
Water (20mL) extracts, by organic layer with anhydrous MgSO4It is dried, filtered and concentrated, obtains compound.
Above-mentioned product (3mmol) is suspended in 95% ethyl alcohol (15mL), be added by the chloro- 1,4-naphthoquinones of 2- (700mg,
3.08mmol), it heats 3 days for 115 DEG C, after complete reaction, obtains red precipitate.Reaction mixture is cooled to room temperature, water is used
(3 × 20mL) is washed, and uses Na2SO4It dries and solvent is removed under reduced pressure.Pass through silica gel chromatography (ethyl acetate:Hexane=2:3) pure
Change obtains red powder product.Yield：85%；Structural parameters:1H NMR(400MHz,CDCl3) δ 8.22 (d, J=7.4Hz,
1H), 8.15 (d, J=7.5 Hz, 1H), 7.81 (t, J=1.2Hz, 1H), 7.76-7.68 (m, 4H), 7.13 (d, J=8.4Hz,
2H), 3.52 (t, J=4.8Hz, 4H), 3.00 (t, J=4.8Hz, 4H), 1.42 (s, 9H)；HRMS(ESI-TOF)m/z
calcd. for C25H26ClN3O6SNa+[(M+Na)+]:531.1231,found 554.1152.
Embodiment 13
The synthesis of compound 13.
Above compound 12 is dissolved in dichloromethane (15mL), trifluoroacetic acid (5mL) is then added, and stir at room temperature
Mix 2h.Organic matter is concentrated to dryness, residue is dissolved in the mixture of ethyl acetate and saturated sodium bicarbonate.By organic matter point
From dry with anhydrous magnesium sulfate and be concentrated under reduced pressure.Yield：98%；Structural parameters:1H NMR(400MHz,DMSO-d6)9.65(s,
1H), 8.63 (s, 2H), 8.06 (s, 2H), 7.87 (m, 2H), 7.68 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4Hz,
2H),3.21(s,4H),3.09(s,4H)；13C NMR(100MHz,DMSO-d6)δ180.3,177.6,144.8,143.0,
135.2,134.1,132.1,131.0, 128.4,127.8,127.1,126.7,122.5,120.4,43.4,42.6.HRMS
(ESI-TOF)m/z calcd.for C20H18ClN3O4SH+[(M+H)+]:431.0707,found432.0810.
Compound inhibits tumor cell proliferation experiment
The Pen .- Strep solution that the culture solution that cell (SW480, HCT116) culture uses is 1%, 10% tire ox
The IMDM cell culture fluids of serum, condition of culture are 37 DEG C, contain 5%CO2Constant incubator.
It is 5 × 10 to take SW480 the and HCT116 cells in exponential phase, adjustment cell concentration4Cell/mL is inoculated with
In on 96 orifice plates, per 100 μ L of hole, while blank well and control wells are set.In 37 DEG C, 5%CO2It is cultivated in incubator for 24 hours, respectively
It is added final concentration of 0.001,0.01,0.1,1,10 μM of compound, per 0.5 μ L of hole, 3 multiple holes are arranged in each drug concentration.
Blank well is that media alone hole does not contain cell, DMSO and compound.Control wells are only to be added the DMSO's containing same concentrations
Complete medium acts on cell.37 DEG C are placed in, 5%CO2In constant incubator, respectively at 6h, 12h, for 24 hours, after 48h, per hole
The 20 μ L of MTT solution (being prepared with PBS, 0.22 μm of membrane filtration degerming) of 5mg/mL are added, are placed in 37 DEG C, 5%CO2Constant temperature incubation
Continue to be incubated 4h in case, terminates culture.Attached cell processing mode carefully removes culture supernatant in hole, and 100 μ are added per hole
LDMSO, suspension cell processing mode are exactly to continuously add 100 μ L hydrochloric acid-aqueous isopropanol in every hole to blow and beat mixing repeatedly, and 37
After DEG C placing 10min, so that purple crystal thing is fully dissolved, the absorbance (OD) in each hole is measured with microplate reader (490nm, 630nm)
Value, calculates cell inhibitory rate as follows.
Cell survival rate (%)=(experimental group OD- blank group OD)/(control group OD- blank group OD) × 100%
IC50：Drug concentration when i.e. cell survival rate is 50%, also known as half effective inhibition concentration.According to MTT results
Linear regression equation is sought, and calculates the IC of each compound50Value.
The results are shown in Table 1 for the anti tumor activity in vitro of compound 1-13 and positive control camptothecine.
The anti tumor activity in vitro of 1. compound 1-13 of table and positive control camptothecine
Table 1 the result shows that, in addition to compound 3, such compound to human colon cancer cell all have good inhibitions work
Property.
Compound inhibits alpha-glucosidase activity evaluation
Using screening micropore plate model, using p-nitrophenyl-α-D- glucopyranoses as substrate, test compound difference is dense
The inhibitory activity of alpha-glucosidase under degree.Experiment is divided into blank group, the control group of without inhibitor and sample to be tested group.Face
The alpha-glucosidase restrainer acarbose that bed uses is as positive control medicine.Inhibitor and acarbose are dissolved in DMSO,
DMSO solution content in enzyme test system is 5%；Buffer solution is phosphate buffer (pH=6.8,0.05M), p-nitrophenyl
Base-α-D- glucopyranoses are dissolved in phosphate buffer.
(1) blank group：Buffer solution, 200 μ L of total volume is added.
(2) control group：The sample to be tested (10 μ L) of buffer solution (190 μ L) and various concentration, without inhibitor is added.
(3) control group：Buffer solution (150 μ L), alpha-glucosidase (0.04U, 20 μ L) and substrate p-nitrophenyl-is added
The aqueous solution of α-D- glucopyranoses (0.5M, 30 μ L).
(4) sample to be tested group：Buffer solution (140 μ L), alpha-glucosidase (0.04U, 20 μ L) is added, sample to be tested
DMSO solution (10 μ L) and substrate p-nitrophenyl-α-D- glucopyranoses (0.5M, 30 μ L).
In 96 orifice plates, according to different experiments group, it is separately added into buffer solution, the sample to be tested of various concentration, phlorose
The DMSO solution of glycosides enzyme and sample to be tested applies 5min in 37 DEG C of temperature, adds substrate p-nitrophenyl-α-D- glucopyranoses,
The deposited 30min of temperature, absorbance is measured at microplate reader 405nm wavelength, the inhibitor is calculated to alpha-glucosaccharase according to following equation
The inhibiting rate of enzyme.
OD values are the absorbance value under microplate reader test.
The results are shown in Table 2 for the alpha-glucosaccharase enzyme inhibition activity of compound 1-13 and positive control acarbose.
The alpha-glucosaccharase enzyme inhibition activity result of 2. compound 1-11 of table and positive control acarbose
aThe inhibiting rate when inhibiting rate of acarbose is 250 μM.
By 2 result of table it is known that such compound has centainly alpha-glucosidase under 10 μM and 1 μM of concentration
Inhibitory activity.
Claims (8)
1. a kind of 1,4-naphthoquinone analog derivative, it is characterised in that：General structure is as follows：
Wherein, R1For substituted or non-substituted aryl, alkyl or hydroxyl；R2For hydrogen or halogen；R3The halogen replaced for 5,6,7,8
Element, nitro, aryl, carboxyl, trifluoromethyl, ester group, alkyl or alkoxy；The integer of n=1-8.
2. a kind of 1,4-naphthoquinone analog derivative, it is characterised in that：General structure is as follows：
Wherein, R1For acetylamino, propionamido, butyrylamino, trifluoroacetamido,R2For hydrogen or halogen；R3It is 5,
Halogen, nitro, aryl, carboxyl, trifluoromethyl, ester group, alkyl or the alkoxy of 6,7,8 substitutions.
3. 1,4-naphthoquinone analog derivative according to claim 2, it is characterised in that：It is describedIn n=4,6-8 it is whole
Number, i.e., four, six, seven, eight methylene imines.
4. a kind of preparation method of 1,4-naphthoquinone derivative described in claim 1, it is characterised in that：Steps are as follows：
Diamines list (Boc)2III is obtained after O protections, IV is obtained by the reaction with sulfonic acid chloride, acid condition removing Boc protecting groups obtain V,
A kind of 1,4-naphthoquinone derivative is obtained with 1,4-naphthoquinone and its derivatives reaction, reaction equation is：
5. the preparation method of 1,4- naphthoquinone derivatives according to claim 2 is as follows：It is characterized in that：Steps are as follows：
VI is obtained by the reaction with sulfonic acid chloride in primary amine or secondary amine, and the Acetyl Protecting Groups that amido is removed under alkaline condition obtain VII, VII
A kind of 1,4-naphthoquinone derivative is obtained with 1,4-naphthoquinone and its derivatives reaction, reaction equation is
6. 1,4- naphthoquinone derivatives described in claim 1 are preparing the antitumor application in antidiabetic medicine for the treatment of.
7. the 1,4- naphthoquinone derivatives described in claim 2 are preparing the antitumor application in antidiabetic medicine for the treatment of.
8. a kind of 1,4-naphthoquinone analog derivative, it is characterised in that：Structural formula is as follows
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| CN111533700A (en) * | 2020-05-20 | 2020-08-14 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN111646941A (en) * | 2020-07-17 | 2020-09-11 | 天津科技大学 | Sulfonamide derivative and preparation method and application thereof |
| CN114685325A (en) * | 2020-12-29 | 2022-07-01 | 苏州瑞博生物技术股份有限公司 | Amine-containing compound and preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748809A (en) * | 2019-01-15 | 2019-05-14 | 中国科学院成都有机化学有限公司 | Method for synthesizing 2-substituted amino-1, 4-naphthoquinone derivative |
| CN109748809B (en) * | 2019-01-15 | 2022-05-13 | 中国科学院成都有机化学有限公司 | Method for synthesizing 2-substituted amino-1, 4-naphthoquinone derivative |
| CN111533700A (en) * | 2020-05-20 | 2020-08-14 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN111533700B (en) * | 2020-05-20 | 2023-03-28 | 天津科技大学 | 5-substituted uracil derivative and preparation method and application thereof |
| CN111646941A (en) * | 2020-07-17 | 2020-09-11 | 天津科技大学 | Sulfonamide derivative and preparation method and application thereof |
| CN114685325A (en) * | 2020-12-29 | 2022-07-01 | 苏州瑞博生物技术股份有限公司 | Amine-containing compound and preparation method and application thereof |
| CN114685325B (en) * | 2020-12-29 | 2024-05-28 | 苏州瑞博生物技术股份有限公司 | Amine-containing compound and preparation method and application thereof |
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