CN106854223A - Mustargen quercetin derivative and its production and use - Google Patents
Mustargen quercetin derivative and its production and use Download PDFInfo
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- CN106854223A CN106854223A CN201710008376.0A CN201710008376A CN106854223A CN 106854223 A CN106854223 A CN 106854223A CN 201710008376 A CN201710008376 A CN 201710008376A CN 106854223 A CN106854223 A CN 106854223A
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- mustargen
- quercetin
- quercetin derivative
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- -1 Mustargen quercetin derivative Chemical class 0.000 title claims abstract description 40
- 229940087004 mustargen Drugs 0.000 title claims abstract description 38
- 238000004519 manufacturing process Methods 0.000 title description 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 238000006467 substitution reaction Methods 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 6
- 201000011510 cancer Diseases 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005002 aryl methyl group Chemical group 0.000 claims description 4
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 abstract description 21
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 abstract description 10
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 abstract description 10
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 abstract description 10
- 229960001285 quercetin Drugs 0.000 abstract description 10
- 235000005875 quercetin Nutrition 0.000 abstract description 10
- 125000003963 dichloro group Chemical group Cl* 0.000 abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 150000003244 quercetin derivatives Chemical class 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical group ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 210000004088 microvessel Anatomy 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 240000002853 Nelumbo nucifera Species 0.000 description 2
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 2
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 1
- 241001480055 Quercus mongolica Species 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000037308 hair color Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012109 statistical procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
- C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
- C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Include its stereoisomer or dynamic isomer and preparation method thereof, and the pharmaceutical composition with the analog derivative as active component, and application of the medicine in treating cancer the present invention relates to mustargen quercetin derivative.The preparation method of the analog derivative is obtained the Mannich base of Quercetin with Quercetin with formaldehyde and chlorethamin first, and the then amino phosphinylidyne dichloro reaction again with substitution is obtained mustargen quercetin derivative.Mustargen quercetin derivative has antitumor action.
Description
Technical field
Application the present invention relates to mustargen quercetin derivative and its in pharmacy, belongs to pharmaceutical technology field.
Background technology
Quercetin is the important component of flavone compound, such as anti-with extensive pharmacological action and bioactivity
Oxidation and scavenging activated oxygen, hypotensive, Ischemic myocardium, avoid ischemia-reperfusion damage funeral, enhancing immunologic function and anticancer,
Antiviral and analgesic activity etc..In recent years, Quercetin to HOC, breast cancer, leucocyte, gastroenteric tumor cell propagation
Inhibitory action, receive much concern.With Quercetin as parent, structural modification is carried out to it, improve its pharmaceutical activity, it is new to finding
Medicine, there is important meaning.
Chlormethine series pharmaceuticals are the important antineoplastics that a class directly acts on DNA, and its antitumor spectra is wide, is widely used in
It is clinical.But it has the disadvantage that its metabolin has toxicity.In order to reduce its toxic and side effect, its active anticancer, this hair are further improved
A person of good sense enters in Quercetin structure mustargen structure fragment, and having obtained a class has the mustargen quercetin derivative of active anticancer.
The content of the invention
It is an object of the invention to provide mustargen quercetin derivative, including its stereoisomer or dynamic isomer, its
Effect with anticancer.
Another object of the present invention is to provide above-mentioned mustargen quercetin derivative, including its stereoisomer or mutually variation
The preparation method of structure body.
It is still another object of the present invention to provide above-mentioned mustargen quercetin derivative, including its stereoisomer or mutually variation
The purposes of structure body.
The present invention will be described in detail below.
The present invention provides a kind of mustargen quercetin derivative, including its stereoisomer or dynamic isomer, and structure is as follows
Shown in formula：
In formula：R is selected from substituents：H, saturated hydrocarbyl, unsaturated alkyl, aryl, heterocyclic radical, substitution aryl, substitution
Heterocyclic radical, the alkyl of substitution include chloroethyl, 1- carboxylics（Ester）Base alkyl, 2- hydroxy alkylenes, aryl methyl, heterocyclyl methyl, virtue
Base ethyl, heterocyclylethyl, the aryl methyl of substitution, the heterocyclyl methyl of substitution, aryl ethyl, the heterocyclylethyl of substitution.
Described mustargen quercetin derivative, including the structure of its stereoisomer or dynamic isomer includes：
Present invention also offers described mustargen quercetin derivative, including its stereoisomer or dynamic isomer preparation side
Method, comprises the following steps：
Mustargen quercetin derivative of the invention, including its stereoisomer or dynamic isomer, with active anticancer.
Beneficial effect：There is provided a kind of mustargen quercetin derivative with active anticancer.
The present invention is further illustrated by following examples, but should be noted that the scope of the present invention is not implemented by these
Any limitation of example.
Specific embodiment
Embodiment 1
Mustargen quercetin derivative（1）Preparation
N2Under protection, by the formalin of 97.6mg (1.2mmol), 94.8mg (1.2mmol) 2- chloro ethamine, 302mg
(1.0mmol) Quercetin and 5 mL ethanol are added in closed reactor, plus 4 and are dripped hydrochloric acid, are heated to 75-80 DEG C of reaction 3h, nature
Cooling, separates out solid, and suction filtration, crude product is separated through chromatoplate（V（N-butanol）：V (water）：V(HOAc）= 4:1:1, methyl alcohol wash-out,
Obtain Quercetin Mannich base yellow solid 129mg, yield 33.0%.
393mg (1mmol) above-mentioned Mannich base is taken, 431mg (2.2mmol) 2- chloroethene amino phosphinylidyne dichloros use 5mL
Dry DMF dissolvings, are stirred at room temperature lower dropwise addition 0.6mL Et3The mixed liquor of the N and dry DMF of 4mL, 30min is dripped off, and room temperature is anti-
After answering 2h, 60 DEG C are then heated to, TLC monitoring reactions are complete, and it is 3-4 to adjust the pH value of solution with 10% HCl solution, is added
50mL water, filtering, obtains crude product, is separated through chromatoplate（V（N-butanol）：V (water）：V(HOAc）= 4:1:1, methyl alcohol wash-out obtains Mongolian oak
Skin element derivative（1）.MS (EIS)[M+H]+ = 640.0。
Embodiment 2
Mustargen quercetin derivative（2）Preparation
With 462mg (2.2mmol)（N-2- chloroethyls-N '-methyl) amino phosphinylidyne dichloro- is for the 431mg in embodiment 1
(2.2mmol) 2- chloroethene amino phosphinylidyne dichloros, other operations are same as Example 1, obtain quercetin derivative（2）, yield
72.5%。MS (EIS)[M+H]+ = 668.0。
Embodiment 3
Mustargen quercetin derivative（3）Preparation
With 696mg (2.2mmol) L-（N-2- chloroethyls-N '-hydroxymethylbenzyl）Amino phosphinylidyne dichloro- is in embodiment 1
431mg (2.2mmol) 2- chloroethene amino phosphinylidyne dichloros, other operations are same as Example 1, obtain quercetin derivative（3）,
Yield 71%.MS (EIS) [M+H]+ = 880.1。
Embodiment 4
Mustargen quercetin derivative（4）Preparation
Replace 431mg (2.2mmol) the 2- chloroethene amino phosphinylidyne two in embodiment 1 with 520mg (2mmol) phosphinylidyne dichloro mustargen
Chlorine, other operations are same as Example 1, obtain quercetin derivative（4）, yield 76%.MS (EIS) [M+H]+ = 764.0。
Embodiment 5
Mustargen quercetin derivative（5）Preparation
Embodiment 1 is replaced with 565mg (2mmol) L- [N-2- chloroethyls-N '-(2- carboxylate methyl esters base) ethyl] amino phosphinylidyne dichloro-
In 431mg (2.2mmol) 2- chloroethene amino phosphinylidyne dichloros, other operations are same as Example 1, obtain quercetin derivative
（5）, yield 72%.MS (EIS) [M+H]+ = 812.0。
Embodiment 6
Mustargen quercetin derivative（6）Preparation
Replaced with 597mg (2mmol) L- [N-2- chloroethyls-N '-(1- hydroxyl -2- carboxylate methyl esters base) ethyl] amino phosphinylidyne dichloro-
431mg (2.2mmol) 2- chloroethene amino phosphinylidyne dichloros in embodiment 1, other operations are same as Example 1, obtain Quercetin
Derivative（6）, yield 67%.MS (EIS)[M+H]+ = 842.1。
Embodiment 7
Mustargen quercetin derivative（7）Preparation
With 247mg (2mmol)（N-2- chloroethyl-N ' -4- pyridine radicals）Amino phosphinylidyne dichloro- is for the 431mg in embodiment 1
(2.2mmol) 2- chloroethene amino phosphinylidyne dichloros, other operations are same as Example 1, obtain quercetin derivative（7）, yield
69.1%。MS (EIS) [M+H]+ = 794.0。
Embodiment 8
Mustargen quercetin derivative（8）Preparation
With 573mg (2mmol)（N-2- chloroethyls-N '-benzyl）Amino phosphinylidyne dichloro- is for the 431mg in embodiment 1
(2.2mmol) 2- chloroethene amino phosphinylidyne dichloros, other operations are same as Example 1, obtain quercetin derivative（8）, yield
73.2%。MS (EIS) [M+H]+ = 820.1。
Embodiment 9
Mustargen quercetin derivative antitumor activity
Suppression of one, to ascitic type S180 tumours
To be inoculated with 7 days, the de- vertebra of well-grown lotus S180 tumour cells mouse is put to death, in clean workbench belly iodine disinfection,
Ascites tumor is extracted after the de- iodine of alcohol, with physiological saline with l：4 (ascites：Physiological saline) dilution proportion be cell suspension（Cell
Density 2 × 109/L）.Subcutaneous vaccination tumour cell liquid 0.2ml after every right armpit iodine disinfection of mouse.Will in inoculation next day
Mouse is randomly divided into negative control group, ifosfamide group, 5 FU 5 fluorouracil group, Quercetin positive controls and mustargen Quercetin
Derivative group.The equal continuous gavage of each group is administered 10 days.The de- vertebra of mouse is put to death in next day after last dose, strips tumor tissue, claimed
Knurl weight and body weight (after except knurl).Experimental result is carried out into statistical procedures, tumour inhibiting rate is calculated（Table 1）.Result shows, right with the positive
According to condition ratio, mustargen quercetin derivative has significant inhibitory action to lotus ascitic type S180 mice with tumor.Mice Body after medication
Weight is suitable with Quercetin group weightening, obvious compared with ifosfamide group and the weightening of 5 FU 5 fluorouracil group, and hair color is good, and knurl body is small, and dynamic
Thing illustrates that mustargen quercetin derivative toxicity is smaller without death.
Cancer suppressing ratio (%)=(the average average knurl weight of knurl weight-treatment group of control group) average knurl weight × 100% of/control group
Suppression of two, to microvessel growth in S180 tumor tissues
Mouse is put to death in above-mentioned experiment anesthesia in the 21st day, and excised tumor tissue, 40g/L formalins are fixed, and FFPE is routinely cut
Piece, piece is thick 3-5 μm, respectively row HE dyeing and SABC inspection.SABC inspection uses SABC methods, and primary antibody is rabbit-anti mouse
CD31 antibody, is replaced with PBS, and used as negative control, peri- tumorous normal tissues are used as positive control.Method of counting：Selection tumor group
The vascular endothelial cell or cell cluster or lumen of vessels internal diameter for knitting the isolated yellowish-brown of cytoplasm Inner are represented less than 8 red blood cell persons
One single capilary.In 200 times of visuals field（0.7386mm3）5 capilary numbers in the visual field of lower counting, average.Meter
Calculate microvessel density（Table 2）.
Result shows that mustargen quercetin derivative significantly inhibits effect to microvessel growth in S180 tumor tissues.
Embodiment 10
Mustargen quercetin derivative is to TRAMP-C2 prostate gland cancer cell inhibitory action
Take 77 C57BL/6 male mices, 6-8 week old, body weight 18-20g/ only, after adaptability feeds 2d, in every under aseptic condition
Right side of mice dorsal sc injection is in the TRAMP-C2 single cell suspensions 0.2mL of exponential phase, 5.0 × 106Individual cell,
After inoculation 2 days, negative control group, Quercetin control group, ifosfamide control group and mustargen quercetin derivative are randomly divided into
Group.Negative control group with propane diols 0.1mL/ only, intraperitoneal injection, 3 times a week, totally 3 weeks 10 times.Quercetin control group, different ring phosphorus
Acid amides control group and mustargen quercetin derivative group are dissolved in 0.1ml propane diols with 50mg/kg body weight respectively, intraperitoneal injection, often
Week 3 times, totally 3 weeks 10 times administrations.The daily spirit for noting observation mouse, diet and active situation, in after inoculation 5 weeks, draw at neck
Dead mouse, takes out tumour, weighs tumor weight, calculates tumour inhibiting rate（Table 3）.Result shows that mustargen quercetin derivative has significantly
Suppression TRAMP-C2 prostate gland cancer cells effect, during experiment the treatment group mouse state of mind, diet and active situation with
Control group illustrates that mustargen quercetin derivative does not produce obvious toxic-side effects in dosage range to mouse without significantly different.
Claims (4)
1. mustargen quercetin derivative includes its stereoisomer or dynamic isomer, it is characterised in that general structure is as follows：
In formula：R is selected from substituents：H, saturated hydrocarbyl, unsaturated alkyl, aryl, heterocyclic radical, substitution aryl, substitution
Heterocyclic radical, the alkyl of substitution include chloroethyl, 1- carboxylics（Ester）Base alkyl, 2- hydroxy alkylenes, arylmethyl, heterocyclic methyl, fragrant ethyl,
Heterocycle ethyl, the arylmethyl of substitution, the heterocyclic methyl of substitution, fragrant ethyl, the heterocycle ethyl of substitution.
2. mustargen quercetin derivative according to claim 1, including its stereoisomer or dynamic isomer, its feature
It is that instantiation includes following structural formula：
3. mustargen quercetin derivative according to claim 1, including its stereoisomer or dynamic isomer, its preparation
Method is comprised the following steps：
4. the mustargen quercetin derivative according to right 1, including its stereoisomer or dynamic isomer, and such medicine
Compositions, the application in terms for the treatment of cancer medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047271A (en) * | 2017-12-06 | 2018-05-18 | 石家庄学院 | A kind of quercetin dimer derivative and its preparation method and application |
| CN109810142A (en) * | 2019-03-12 | 2019-05-28 | 石家庄学院 | One kind matrine derivative of ligustrazine containing mustargen and its preparation method and application |
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