CN105503687A - Multi-membered ring polyhydroxylated alkaloid compound and application thereof - Google Patents

Multi-membered ring polyhydroxylated alkaloid compound and application thereof Download PDF

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Publication number
CN105503687A
CN105503687A CN201510881994.7A CN201510881994A CN105503687A CN 105503687 A CN105503687 A CN 105503687A CN 201510881994 A CN201510881994 A CN 201510881994A CN 105503687 A CN105503687 A CN 105503687A
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acid
polyhydroxylated alkaloid
ring structures
alkaloid compounds
polyhydroxylated
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何祥久
林剑锋
王宜海
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Guangdong Pharmaceutical University
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Guangdong Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

The invention discloses a multi-membered ring polyhydroxylated alkaloid compound and application thereof. The multi-membered ring polyhydroxylated alkaloid compound is extracted from silkworm excrement, has an excellent hypoglycemic effect, can effectively improve postprandial blood glucose rise, and has a certain function in relieving and treating diabetes, adiposis and the like. The multi-membered ring polyhydroxylated alkaloid compound can be obtained via separation of cheap silkworm excrement, has the advantages of high efficiency and low toxicity, and can be used for development of new medicine and health foods used for preventing and treating diseases such as diabetes mellitus and adiposis.

Description

The polyhydroxylated alkaloid compounds of the polynary ring of tool and application thereof
Technical field
The present invention relates to a kind of natural extract, in particular to the polyhydroxylated alkaloid compounds with ring structure, this compounds has alpha-glucosaccharase enzyme inhibition activity, is expected to the medicine and the protective foods that are developed as the diseases such as prevention and therapy diabetes, obesity.
Background technology
The metabolic disease of diabetes to be caused by hypoinsulinism and/or impaired insulin action one group with hyperglycemia be feature.It shows as in blood and urine, and glucose concn is abnormal to be raised, and can occur typical " three-many-one-little " symptom when blood sugar, glucose in urine are too high, namely many drink, diuresis, eat more and lose weight, and with fatigue and weak.Diabetes are generally divided into the several types such as type i diabetes, type ii diabetes and gestational diabetes.Type ii diabetes not only can cause microvascular complication, as peripheral neuropathy, Eye disease, diabetic nephropathy etc., and can cause serious macrovascular complications, as myocardial infarction, apoplexy, lower limb vascular obstructive pulmonary disease etc.These complication are very harmful, reduce the quality of life of people, brought heavy economical load.Therefore treat diabetes, control the generation of diabetic complication and develop to have seemed more and more important.
Alpha-glucosidase inhibitor is a class reaches treatment diabetes orally-taken blood sugar reducing medicine to delay enteron aisle carbohydrate absorption.Alpha-glucosidase inhibitor is the treatment diabetes medicament of comparative maturity, has been widely used in clinical.Its mechanism of action is the various alpha-glucosidases that competitive inhibition is positioned at small intestine, and the speed making starch based be decomposed into glucose slows down, thus slows down the absorption of glucose in enteron aisle, reduces postprandial hyperglycemia.
The medicine that natural drug especially derives from plant has chemical structure diversity and diverse biological activities, is the main source of mankind's prevention and therapy disease always.The many medicines applied clinically all directly or indirectly derive from natural product, and natural product not only can as the semisynthetic precursor of medicine, and can as the template of pharmaceutical chemistry synthesis, for new drug design provides new approaches.Natural product has become one of main source finding novel drugs or lead compound.
Silkworm excrement is Chinese medicine traditional simply, is the dry ight soil of insect bombyx mori BobyxmoriL larva, is recorded in Compendium of Material Medica.Mainly be distributed in the provinces such as China Zhejiang, Sichuan, Henan, Jiangsu, Hunan, Jiangxi, Yunnan, Guangdong, Guangxi, Anhui, Gansu, Hubei, Shandong, Liaoning.Silkworm excrement have dispel rheumatism, removing heat to brighten vision, analgesic therapy of invigorating blood circulation function.Cure mainly wind-heat order pain, rheumatic heart disease, sacroiliitis, numb limbs and tense tendons, rubella cancer are itched, the diseases such as head wind of having a headache, often use in the compound of some treatment diabetes.The main active ingredient of silkworm excrement is polyhydroxylated alkaloid constituents.Modern pharmacology experimental study shows that silkworm excrement has stronger hypoglycemic, antitumor, anti-inflammatory, antibacterial, protects the liver, anti-oxidant, antiviral, promote marrow isoreactivity.Existing research is still not deep enough to silkworm excrement chemical constitution study, and thus in silkworm excrement, polyhydroxylated alkaloid class chemical composition is worth researching and developing utilization further.
Summary of the invention
The object of the invention is to the polyhydroxylated alkaloid compounds with ring structure, this compounds has alpha-glucosaccharase enzyme inhibition activity, is expected to the medicine and the protective foods that are developed as the diseases such as prevention and therapy diabetes, obesity.
The technical solution used in the present invention is:
The polyhydroxylated alkaloid compounds of tool more ring structures, its general structure is:
Or above-claimed cpd and C2 ~ C4 unit acid or diprotic acid react the monoesters or polynary ester that generate.
Preferably, C2 ~ C4 unit acid, diprotic acid are saturated acid.Further, unit acid is acetic acid, n Propanoic acid; Diprotic acid is oxalic acid or propanedioic acid.
Improve medicine or the protective foods of postprandial blood sugar, its activeconstituents contains the polyhydroxylated alkaloid compounds of above-mentioned tool more ring structures.
A kind of alpha-glucosidase inhibitor, its activeconstituents contains the polyhydroxylated alkaloid compounds of above-mentioned tool more ring structures.
Be used for the treatment of or prevent medicine or the healthcare products of hyperglycemia relative disease, its activeconstituents contains the polyhydroxylated alkaloid compounds of above-mentioned tool more ring structures.Hyperglycemia relative disease is selected from diabetes, obesity.
The polyhydroxylated alkaloid compounds of tool more ring structures is as the application of alpha-glucosidase inhibitor, and wherein, the polyhydroxylated alkaloid compounds of tool more ring structures is as above-mentioned.
The polyhydroxylated alkaloid compounds of tool more ring structures is as treatment or the application preventing hyperglycemia relative disease medicine or healthcare products, and wherein, the polyhydroxylated alkaloid compounds of tool more ring structures is as above-mentioned.Hyperglycemia relative disease is selected from diabetes, obesity.
The invention has the beneficial effects as follows:
The polyhydroxylated alkaloid compounds of tool more ring structures of the present invention has good hypoglycemic activity, alleviation and tool such as treatment diabetes and obesity etc. are had certain effect, this compound can be separated and obtain from the silkworm excrement of cheapness, there is advantage that is efficient, low toxicity, be expected to the medicine and the protective foods that are developed as the new disease such as prevention and therapy diabetes, obesity.
Accompanying drawing explanation
Fig. 1 is the compounds of this invention 1 1h-NMR collection of illustrative plates;
Fig. 2 is the compounds of this invention 1 13c-NMR collection of illustrative plates;
Fig. 3 is the HSQC collection of illustrative plates of the compounds of this invention 1;
Fig. 4 is the HMBC collection of illustrative plates of the compounds of this invention 1;
Fig. 5 is the NOESY collection of illustrative plates of the compounds of this invention 1.
Embodiment
Below in conjunction with experiment, further illustrate technical scheme of the present invention.
The extraction of silkworm excrement total alkaloid
Get dry silkworm excrement 30kg, with aqueous solution refluxing extraction 72h, alcohol precipitation removal of impurities is carried out to extracting solution, concentrating under reduced pressure with 70% ethanol is molten, obtain brown thick paste and be about 1.4kg.
The enrichment of silkworm excrement total alkaloid
The centrifugal rear thin up of thick paste, heating, ultrasonic rear filtered on buchner funnel, rear upper 732 strong-acid type cation exchange columns.Then use 0.5mol/L ammonia soln wash-out, track to alkaloid with chloro-o-tolidine reagent colour development and elute completely, concentrated evaporate to dryness obtains silkworm excrement total alkaloid 150g.By the silkworm excrement total alkaloid medicinal extract dilute with water obtained, heating, ultrasonic rear filtered on buchner funnel, rear upper 717 strong base anion exchange columns, use deionized water wash-out, collection elutriant, concentrate to obtain the silkworm excrement total alkaloid after 92g purifying.
The further separation and purification of silkworm excrement total alkaloid
By the silkworm excrement total alkaloid medicinal extract dilute with water obtained, heating, ultrasonic rear filtered on buchner funnel, rear upper 717 strong base anion exchange columns, use deionized water wash-out, collection elutriant, concentrate to obtain the silkworm excrement total alkaloid after 92g purifying.Silkworm excrement total alkaloid after purifying is crossed D152 weak-type cationic exchange coloum, first use deionized water wash-out, then use 0.5mol/L ammonia soln wash-out, according to thin-layer chromatography colour developing situation, being divided into 5 parts, is FB-1 to FB-4, and ammoniacal liquor elution fraction.
There is in silkworm excrement total alkaloid extract the separation and purification to alpha-glucosaccharase enzyme inhibition activity material
By adopting spent ion exchange resin (OH -form, NH 4+form), the separation method such as gel SephadexLH-20, be separated and obtain the compounds of this invention 1 and 2.By the chemical structure of physicochemical constant and the Modern spectroscopy section of learning to do (ESIMS, 1D-NMR, 2D-NMR) authenticating compound 1 and 2.
The Structural Identification process of compound 1 is as follows:
(2R, 3R, 4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine-N-glyoxylamide (compound 1): white amorphous powder, IR (KBr) ν max3458,1638,1384cm -1, molecular formula is C 7h 12n 2o 5.
? 1h-NMR (D 2o, 400MHz) spectrum in, containing 7 hydrogen signals: δ: 3.20 (1H, dd, J=11.6,4.3Hz, H-2), 3.65 (1H, dd, J=8.6,4.9Hz, H-5), 3.72 (1H, d, J=5.8Hz, H-5 '), 3.75 (1H, d, J=5.4Hz, H-6), 3.80 (1H, dd, J=11.2,5.5Hz, H-6 '), 4.02 (1H, t, J=3.6Hz, H-3), δ 4.12 (1H, dd, J=10.0,4.3Hz, H-4).
? 13c-NMR (D 2o, 100MHz) spectrum in, containing 7 carbon signals, comprise two carbonyl carbon signals (δ 163.6,164.6), three methylene signals (δ 52.1,62.6,65.2) and two methine carbon signals (δ 74.1,77.7).The connection C determined between skeleton C and H signal is composed in connection between C and H signal by HSQC and HMBC 5h 2-C 4h-C 3h-C 2h-C 6h 2-OH.C-2 (δ 65.2) methine signals and the C-5 (δ 52.1) that are connected with methylol carbon C-6 (δ 62.6) are connected to ring with the nitrogen on nitrogen heterocyclic respectively.Methine carbon signal δ 74.1 and δ 77.7 belongs to C-4 and C-3 being connected with hydroxyl respectively.Carbonyl carbon signals δ 163.6 and δ 164.6 belongs to acid amides carbon (CONH2) and carbonyl carbon (CO) signal respectively.The steric configuration of tetramethyleneimine is composed by NOESY and is determined, C-6 (CH 2oH) atom and the NOE effect between H-2, H-3, H-4 illustrate that H-2, H-3 and H-4 are α, β and α configuration respectively.Therefore, compound 1 is inferred as (2R, 3R, 4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine-N-glyoxylamide.
The chemical structure of compound 1 and 2 in table 1, 1h and 13cNMR data are in table 2.
Table 1: the structure of the compounds of this invention
Table 2: the compounds of this invention 1 and compound 2 1h-and 13c-NMR data (D 2o)
Alpha-glucosaccharase enzyme inhibition activity is tested:
Experiment be divided into blank group, control group, sample blank group and sample sets, each reactant carries out application of sample by dosage in table 3 in 96 orifice plates, often organize 3 parallel.Add PBS damping fluid, enzyme solution and inhibitor solution successively by table, mix, in 37 DEG C of water bath heat preservation 5min, after terminating, take out, add PNPG substrate solution, fully mix, in 37 DEG C of water-bath 15min, after terminating, add the Na of 80 μ L0.2mol/L 2cO 3solution stopped reaction.Produce glucose and PNP, PNP and have maximum absorption because PNPG can be hydrolyzed under the effect of alpha-glucosidase at 405nm place, it measures its absorbancy, just can calculate inhibiting rate and the IC of each sample alpha-glucosidase according to formula 50value.
Inhibiting rate by following formulae discovery, and with the half-inhibition concentration (IC of the tested sample of CalcuSyn computed in software 50)
Inhibiting rate (%)=[(A s– A sB)/(A c– A cB)] × 100.
The each reagent dosage of table 3 and order (unit: μ L)
。
Experimental result is in table 4.
Table 4: the compounds of this invention is to the restraining effect of alpha-glucosidase
From the experimental data of table 4, compound 1 and 2 pairs of alpha-glucosidases all have significant restraining effect, and its restraining effect is 93.4 times and 29.6 times of acarbose respectively, effectively can improve postprandial blood sugar and raise.Polyhydroxylated alkaloid compounds of the present invention, particularly compound 1 and 2 has good hypoglycemic activity, alleviation and tool such as treatment diabetes and obesity etc. are had certain effect, this compound can be separated and obtain from the silkworm excrement of cheapness, there is advantage that is efficient, low toxicity, be expected to the medicine and the protective foods that are developed as the new disease such as prevention and therapy diabetes, obesity.
Compound of the present invention and the acid of C2 ~ C4 unit, diprotic acid react the monoesters or polynary ester that generate, compound 1 or 2 can be dissociateed in vivo, there is identical or close physiologically active, also there is good hypoglycemic activity, alleviation and tool such as treatment diabetes and obesity etc. are had certain effect, there is advantage that is efficient, low toxicity, be expected to the medicine and the protective foods that are developed as the new disease such as prevention and therapy diabetes, obesity.

Claims (10)

1. have a polyhydroxylated alkaloid compounds of more ring structures, its general structure is:
or ,
Or above-claimed cpd and C2 ~ C4 unit acid or diprotic acid react the monoesters or polynary ester that generate.
2. polyhydroxylated alkaloid compounds according to claim 1, is characterized in that: the acid of C2 ~ C4 unit or diprotic acid are saturated acid.
3. polyhydroxylated alkaloid compounds according to claim 1, is characterized in that: unit acid is acetic acid, n Propanoic acid; Diprotic acid is oxalic acid or propanedioic acid.
4. improve medicine or the protective foods of postprandial blood sugar, it is characterized in that: its activeconstituents contains the polyhydroxylated alkaloid compounds of the tool more ring structures described in claims 1 to 3 any one.
5. an alpha-glucosidase inhibitor, is characterized in that: its activeconstituents contains the polyhydroxylated alkaloid compounds of the tool more ring structures described in claims 1 to 3 any one.
6. be used for the treatment of or prevent medicine or the healthcare products of hyperglycemia relative disease, it is characterized in that: its activeconstituents contains the polyhydroxylated alkaloid compounds of the tool more ring structures described in claims 1 to 3 any one.
7. medicine according to claim 6, is characterized in that: hyperglycemia relative disease is selected from diabetes, obesity.
8. have the polyhydroxylated alkaloid compounds of more ring structures as the application of alpha-glucosidase inhibitor, wherein, the polyhydroxylated alkaloid compounds of tool more ring structures is as described in claims 1 to 3 any one.
9. have the polyhydroxylated alkaloid compounds of more ring structures as treatment or prevention hyperglycemia relative disease medicine or the application of healthcare products, wherein, the polyhydroxylated alkaloid compounds of tool more ring structures is as described in claims 1 to 3 any one.
10. application according to claim 9, is characterized in that: hyperglycemia relative disease is selected from diabetes, obesity.
CN201510881994.7A 2015-12-03 2015-12-03 Multi-membered ring polyhydroxylated alkaloid compound and application thereof Pending CN105503687A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116332952A (en) * 2021-12-15 2023-06-27 厦门大学 Trichothecenes, organic acids, benzodiazepines and alkaloids compounds and application thereof in preparation of hypoglycemic drugs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101671293A (en) * 2009-10-12 2010-03-17 南开大学 Alpha-glycosidase inhibitor compound in silkworm excrement total alkaloid and application thereof
WO2010049678A2 (en) * 2008-10-31 2010-05-06 Summit Corporation Plc Treatment of energy utilization diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010049678A2 (en) * 2008-10-31 2010-05-06 Summit Corporation Plc Treatment of energy utilization diseases
CN101671293A (en) * 2009-10-12 2010-03-17 南开大学 Alpha-glycosidase inhibitor compound in silkworm excrement total alkaloid and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. ALBERTO DÍEZ ET AL.: "Stereoselective synthesis and biological evaluation of D-fagomine, D-3-epi-fagomine and D-3,4-epi-fagomine analogs from D-glyceraldehyde acetonide as a common building block", 《ORG. BIOMOL. CHEM.》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116332952A (en) * 2021-12-15 2023-06-27 厦门大学 Trichothecenes, organic acids, benzodiazepines and alkaloids compounds and application thereof in preparation of hypoglycemic drugs

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