CN103275095B - 10-hydroxycamptothecine derivatives and applications thereof - Google Patents
10-hydroxycamptothecine derivatives and applications thereof Download PDFInfo
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Abstract
The invention relates to 10-hydroxycamptothecine derivatives and applications thereof and belongs to the field of pesticides. The 10-hydroxycamptothecine is spliced with active sites of a conventional chemical pesticide, namely, a pyrethroid pesticide to obtain a series of pyrethroid-10-hydroxycamptothecine derivatives, so that the pyrethroid-10-hydroxycamptothecine derivatives maintain the original excellent antifeedant activity of the 10-hydroxycamptothecine to beet armyworms, can also be endowed with the excellent contact toxicity of the pyrethroid pesticide to the beet armyworms and have important research significance for the development of new high-efficiency low-toxicity pesticides with a unique targeting effect.
Description
Technical field
The present invention relates to a kind of derivative and application thereof of 10-hydroxycamptothecine, belong to pesticide field.
Background technology
Along with improving constantly and the pursuit of the mankind to fine living environment of people's quality of life; produce green non-pollution agricultural-food and the most attention destroying and be subject to countries in the world that protects the environment from pollution; as the important production means-agricultural chemicals in agricultural-food production link, being therefore faced with should to the harmless environment amenable demand again of agricultural-food while control harmful organism.Thus, initiative has that efficient, low toxicity, pollution are little, selectivity advantages of higher " harmonious environment agricultural chemicals " or " biorational agricultural chemicals " has become the general trend of events of pesticide industry development in recent years, and Plant source active substances receives much concern because meeting this trend.In plant and the long-term coevolution course of insect, plant also defines a set of chemical, biological defense system gradually.Especially its secondary metabolite; of a great variety; active high-effect single-minded; the preference such as to breed in order to regulate the perch that takes food to plant of around insect; to ensure that plant population can keep out the invasion of insect destructiveness; thus complete whole life course normally in order, and as caused larva food refusal, behavior such as protection such as interference of growing grade.Confirm very strong anti-insect activity by the material extracted in many different types of plant origins, can regulate energetically or the normal physiological activity of interference insect, thus controlled harmful organism population quantity, have effectively achieved the chemical protection of plant to crop.
Insecticide active substance in natural phant is extremely abundant, can be divided into following a few class according to its chemical structure: alkaloids, terpene, Anthraquinones and flavonoid, essential oil class, steroid, light-activated toxin class.
In addition, the Plant source active substances such as pyrethrin (carboxylic acid esters), ether acyl Tuberculate Speranskia Herb element (lignin), Inokosterone (steroid), kind fennel glycosides (glucosides class) various insects is shown tag, food refusal and growth inhibitory activity.
Vegetative insecticidal substance classes is various, make it also varied to the mode of action of insect, be mainly manifested in Behavioral interference, tag, stomach toxicity, growth-inhibiting, anesthesia, the aspect such as stifling and photoactivation.
So far, had a large amount of reports about camptothecine control harmful organism, such as leaf of Common Camptotheca extract missible oil has good prevention effect to false eye leafhopper, may be used for the green prevention and control system of tea place leafhopper; The camptothecine missible oil of 0.2% all has higher prevention effect to cabbage aphid, rice hoppers and striped rice borer; Camptothecine acetone soln has a certain impact to citrus fruit fly adult reproductivity, grow etc.; Camptothecine has stronger stomach poison function to small cabbage moth, and grows to it, to lay eggs and egg hatching all has obvious restraining effect; Camptothecine also shows obvious growth-inhibiting and sterile effect to beet armyworm.In addition, there are some researches show that camptothecine also has good inhibition to the growth of some phytopathogens.But the camptothecine limitation that solubleness is neither good in organic solvent and water, makes camptothecine be restricted in the direct application of agriculture field.So some investigator starts research sight to turn on the camptothecin derivative that exploitation solubleness is good.Introduce the L-amino acid containing nitroxyl radicals by esterification camptothecine 20-hydroxyl in existing report, and it is water-soluble with it to wish to improve compound biological activity.According to this thinking, they have carried out structural modification to camptothecine and obtain a series of new compound and determine these compounds to the antifeedant activity of mythimna separata third-instar larvae and insecticidal activity.But the food refusal of the compound of new synthesis and insecticidal activity are all lower than camptothecine.
Beet armyworm (Spodoptera exigua H ü bner), belongs to lepidopteran (Lepidoptera) Noctuidae (Noctuidae), is a kind of worldwide distribution, the intermittent large polyphagous pest-insect occurred.The plant of larval feeding has 35 sections, 108 belong to, 138 kinds, not only endanger the food crop such as corn, Chinese sorghum, cotton, soybean, peanut, go back the cash crop such as danger to vegetables, flowers, fruit tree, tobacco, beet, cause heavy losses, and its distribution is very uneven, occur in spot film, local is injured serious, be difficult to prediction, also there is no effective Forecasting Methodology so far.At present for the control of beet armyworm, chemical prevention accounts for critical role.But for a long time, due in a large number and use chemical pesticide unreasonably, beet armyworm is very fast to its resistance development speed, and resistance level is also in continuous enhancing.It is reported, current beet armyworm creates resistance in various degree to the number of chemical agricultural chemicals such as organochlorine, carbamate, organophosphorus, pyrethroid and Bacillus thuringiensis, Avrmectin etc., peasant is caused to continue to increase dosage in the process of preventing and treating, very big on the natural control ability impact of natural enemy, agroecosystem, make environment suffer to pollute, HUMAN HEALTH threatened, the eubiosis is destroyed.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of derivative and application thereof of 10-hydroxycamptothecine, the reactive site of 10-hydroxycamptothecine and traditional chemical agricultural chemicals pyrethroid insecticides splices by the present invention, obtain a series of pyrethroid-10-hydroxycamptothecine derivative, make it that 10-hydroxycamptothecine can be kept the original outstanding antifeedant activity of beet armyworm, the contact toxicity that pyrethroid insecticides is outstanding to beet armyworm can be obtained again, this has the efficient of unique effect target to exploitation, low toxicity novel pesticide has important Research Significance.
The technical scheme that the present invention solves the problems of the technologies described above is as follows: a kind of derivative of 10-hydroxycamptothecine, and general structure is as follows:
Wherein, R is the one in having structure:
On the basis of technique scheme, the present invention can also do following improvement.
Further, structural formula is as follows:
Further, structural formula is as follows:
Further, structural formula is as follows:
Further, structural formula is as follows:
Further, structural formula e is as follows:
According to the derivative of above-mentioned a kind of 10-hydroxycamptothecine for the preparation of the agricultural chemicals killing beet armyworm.
The invention has the beneficial effects as follows:
The reactive site of 10-hydroxycamptothecine and traditional chemical agricultural chemicals pyrethroid insecticides splices by the present invention, obtain a series of pyrethroid-10-hydroxycamptothecine derivative, make it that 10-hydroxycamptothecine can be kept the original outstanding antifeedant activity of beet armyworm, can obtain again the contact toxicity that pyrethroid insecticides is outstanding to beet armyworm, this has important Research Significance to efficient, the low toxicity novel pesticide that exploitation has unique effect target.
Accompanying drawing explanation
Fig. 1 be experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine (1) 6,24,48 and 72h after cytotoxicity figure;
Fig. 2 be experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (a) 6,24,48 and 72h after cytotoxicity figure;
Fig. 3 be experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (b) 6,24,48 and 72h after cytotoxicity figure;
Fig. 4 be experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (c) 6,24,48 and 72h after cytotoxicity figure;
Fig. 5 be experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (d) 6,24,48 and 72h after cytotoxicity figure;
Fig. 6 be experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (e) 6,24,48 and 72h after cytotoxicity figure;
Embodiment
Be described principle of the present invention and feature below, example, only for explaining the present invention, is not intended to limit scope of the present invention.
The present invention introduces chrysanthemumic acid part beet armyworm to the pyrethroid insecticides of outstanding contact toxicity at 10 of 10-hydroxycamptothecine, obtains 5 pyrethroid-10-camptothecin derivatives (a-e).The reaction expression of this experiment is as follows:
Wherein, R is the one in having structure:
Be below the derivative compound experiment of 10-hydroxycamptothecine laboratory apparatus used:
(1) X-4 type numerical monitor melting point detector: Yuhua Instrument Co., Ltd., Gongyi City, thermometer does not correct
(2) 300MHz type NMR spectrometer with superconducting magnet (Bruker DRX FT-NMR300MHz): Brooker dalton company of the U.S.
(3) Wzz-2B automatic polarimeter: Shanghai Yi Ce plant and instrument company limited
(4) fourier transformation high-resolution mass spectrometer (Bruker Apex IV FTMS): Brooker dalton company of the U.S.
(5) the multiplex vacuum pump of circulating water type (SHB-III): Great Wall, Shanghai science, industry and trade company limited
(6) Rotary Evaporators (RE-2000): Shanghai Yarong Biochemical Instrument Plant
(7) regulating temp. electrothermal cover (DZTW): Beijing is bright Medical Instruments factory forever
(8) electronic balance (JA12002): Shanghai Yue Ping scientific instrument company limited
(9) various glassware: Beijing Glass Implement Factory
Be below derivative compound experiment experiment reagent used and the explanation of 10-hydroxycamptothecine:
(1) 10-hydroxycamptothecine: 98.92%, Shanghai Longxiang Biomedicine Development Co., Ltd., lot number LX-HT-110502
(2) 2,2,3,3-Tetramethylcycloprop-ne-ne carboxylic acid acyl chlorides (first cyanogen chrysanthemum acyl chlorides): 98%, Tianjin method Moses medical sci-tech company
(3) 3-(2,2-dichloroethylene)-2,2-dimethylcyclopropane formyl chloride (dichloro chrysanthemum acyl chlorides): >=98%, Kaifeng rel Chemical Co., Ltd.
(4) 3-(chloro-3,3, the 3-tri-fluoro-1-propenyl of 2-)-2,2-dimethyl cyclopropane carboxylic acids (time acid): >=98%, Chunjiang Agricultural Chemical Co., Ltd., Jiangsu
(5) 2-(4-chloro-phenyl-)-3-Methylbutanoyl chloride (cyanogen penta chrysanthemum acyl chlorides): >=96%, this reagent of Adama
(6) 3-(2,2-dibromo vinyl)-2,2-dimethylcyclopropane formyl chloride (dibromo chrysanthemum acyl chlorides): >=98%, Kaifeng rel Chemical Co., Ltd.
(7) agents useful for same, comprise methylene dichloride, tetrahydrofuran (THF), methyl alcohol, sherwood oil, ethyl acetate, methyl alcohol etc. and be commercially available AR level reagent, reaction reagent is not purified further, and part has the reagent of particular requirement through Non-aqueous processing.
All melting point compounds are not calibrated.
Nuclear magnetic resonance spectrum
1h-NMR, frequency is 300MHz, and be interior mark with TMS, chemical shift represents with (ppm), and solvent is DMSO-d
6or CDCl
3.S(is unimodal), d(doublet), t(triplet) and, q(quartet), m(multiplet) and, br s(is wide unimodal).
Nuclear magnetic resonance spectrum
13c-NMR, frequency is 75MHz, and be interior mark with TMS, chemical shift represents with (ppm), and solvent is DMSO-d
6or CDCl
3.
High resolution mass spectrum detector used is ESI.
Embodiment 1
10-[(2,2,3,3-tetramethyl-ring propyl) formic acid ester group]-(20S)-camptothecine (a) synthetic route: in 250mL flask, add 10-hydroxycamptothecine (0.364g, 1mmol), reaction flask vacuumizing is passed into N
2after, add tetrahydrofuran (THF) (THF) 120mL, first cyanogen chrysanthemum acyl chlorides (0.96g, 6mmol) and triethylamine (Et
3n) 0.9mL.N
2stopped reaction after the lower back flow reaction 4h of protection.Reaction solution moves in 500mL separating funnel, and add 180mL ethyl acetate, vibration mixes.Add 40mL distilled water again, vibration mixing completely, leaves standstill separatory, gets upper organic phase, in triplicate.Organic phase proceeds in 500mL Erlenmeyer flask, and add anhydrous sodium sulphate vibration, leave standstill, filter, solution revolves steaming and obtains faint yellow solid.This solid adds anhydrous diethyl ether 20mL, magnetic agitation 10h, suction filtration, and anhydrous diethyl ether washs, and gained solid is dry 0.5h in stink cupboard, obtains white solid 0.415g.Yield 84.7%.
1H NMR(DMSO-d
6,300MHz)δ0.89(3H,t,J=7.3Hz,H-18),1.27(12H,s,4CH
3),1.66(1H,s,OCOCH),1.87(2H,m,H-19),5.30(2H,s,H-5),5.43(2H,s,H-17),6.54(1H,s,OH),7.34(1H,s,H-14),7.64(1H,dd,J=2.6,2.6Hz,H-9),7.91(1H,d,J=2.6Hz,H-11),8.19(1H,d,J=9.2Hz,H-12),8.67(1H,s,H-7);
13C NMR(DMSO-d
6,75MHz)δ7.9(CH
3,C-18),16.6(CH
3,2CH
3),23.2(CH
3,2CH
3),30.5(CH
2,CH
2),31.2(C,2C(CH
3)
2),34.9(CH,CHCOO),50.4(CH
2,C-5),65.4(CH
2,C-17),72.5(C,C-20),96.8(CH,C-14),119.3(CH,C-9),126.5(CH,C-11),128.5(CH,C-12),130.4(C,C-6),131.3(CH,C-7),145.5(C,C-3),146.0(C,C-13),149.2(CH,C-10),150.2(C,C-15),152.6(C,C-2),156.9(C,C-16a),169.9(C,C-21),172.6(C,COOCH)。
Embodiment 2
10-[[3-(2,2-dichloroethylene)-2,2-dimethylcyclopropane bases] formic acid ester group]-(20S)-camptothecine (b) synthetic route: in 250mL flask, add 10-hydroxycamptothecine (0.36g, 1mmol), reaction flask vacuumizing is passed into N
2after, add tetrahydrofuran (THF) 120mL, dichloro chrysanthemum acyl chlorides (1.35g, 6mmol) and triethylamine 0.9mL.N
2stopped reaction after the lower back flow reaction 6h of protection.Reaction solution moves in 500mL separating funnel, and add 180mL ethyl acetate, vibration mixes.Add 40mL distilled water again, vibration mixing completely, leaves standstill separatory, gets upper organic phase, in triplicate.Organic phase proceeds in 500mL Erlenmeyer flask, adds anhydrous sodium sulphate and dewaters, and crosses silicagel column (methylene chloride/methanol/sherwood oil=70/0.5/30), obtain faint yellow solid 0.28g after filtering evaporate to dryness.Yield 50.3%.
1H NMR(DMSO-d
6,300MHz)δ0.90(3H,t,J=7.3Hz,H-18),1.31(3H,s,CH
3),1.36(3H,s,CH
3),1.88(2H,m,H-18),2.32(2H,m,CHCOO,CHCHCCl
2),5.24(2H,s,H-5),5.42(2H,s,H-17),6.20(1H,dd,J=0.9,8.4Hz,CHCHCCl
2),6.30(1H,s,OH),7.32(1H,d,J=1.9Hz,H-14),7.63(1H,dd,J=2.5,2.5Hz,H-9),7.89(1H,t,J=2.2Hz,H-11),8.18(1H,d,J=9.1Hz,H-12),8.63(1H,s,H-7);
13C NMR(DMSO-d
6,75MHz)δ7.9(CH
3,C-18),20.2,21.8(CH
3,2CH
3),27.4(C,C(CH
3)
2),28.7(CH,CHCHCCl
2),30.5(CH
2,C-19),32.6(CH,CHCOO),50.3(CH
2,C-5),65.4(CH
2,C-17),72.5(C,C-20),96.8(CH,C-14),119.4(CH,C-9),120.0(C,C-16),125.5(C,CHCCl
2),126.1(CH,C-11),128.3(CH,CHCCl
2),128.4(CH,C-12),130.4(C,C-6),130.5(CH,C-7),131.3(C,C-8),145.4(C,C-3),146.0(C,C-13),149.0(C,C-10),150.1(C,C-15),152.6(C,C-2),156.9(C,C-16a),169.5(C,C-21),172.5(C,CHCOO)。The structural formula of 10-[[3-(2,2-dichloroethylene)-2,2-dimethylcyclopropane base] formic acid ester group]-(20S)-camptothecine (b) is as follows:
Embodiment 3
10-[[3-(2-chloro-2-trifluoromethyl vinyl)-2,2-dimethylcyclopropane base] formic acid ester group]-similar the b of (20S)-camptothecine (c) synthetic route, column chromatography developping agent is methylene chloride/methanol/sherwood oil=100/0.5/80), finally obtain faint yellow solid 0.32g, yield 55.1%.
1H NMR(CDCl
3,300MHz)δ1.00(3H,t,J=7.4Hz,H-18),1.42,1.46(each3H,s,CH
3),1.89(2H,m,H-19),2.32(1H,d,J=8.3Hz,CHCOO),2.41(1H,t,J=8.7Hz,CHCHC(CF
3)Cl),4.39(1H,s,OH),5.26(2H,s,H-5),5.30(2H,s,H-17),5.70(1H,d,CHC(CF
3)Cl),6.95(1H,d,H-14),7.63(1H,s,H-11),7.71(1H,s,H-9),8.23(1H,d,J=9.2Hz,H-12),8.30(1H,d,J=2.9Hz,H-7);
13C NMR(CDCl
3,75MHz)δ7.7(CH
3,C-18),14.8(CH
3,2CH
3),28.3(C,C(CH
3)
2),28.8(CH
2,C-19),31.7(CH,CHCHC(CF
3)Cl),32.6(CH,CHCOO),50.0(CH
2,C-5),66.2(CH
2,C-17),72.8(C,C-20),98.3(CH,C-14),114.9(CH,C-9),122.6(C,C-16,CHC(CF
3)Cl),125.8,128.4,129.2,130.5(CH,C-7,11,12,CHC(CF
3)Cl;C,C-6,8,CHC(CF
3)Cl),146.0(C,C-3),146.7(C,C-13),150.2(CH,C-10),152.3(C,C-15),157.5(C,C-2),162.3(C,C-16a),168.6(C,C-21),173.7(C,CHCOO)。The structural formula of 10-[[3-(2-chloro-2-trifluoromethyl vinyl)-2,2-dimethylcyclopropane bases] formic acid ester group]-(20S)-camptothecine (c) is as follows:
Embodiment 4
The similar b of 10-[3-methyl-2-(4-chloro-phenyl-) butyric acid ester group]-20 (S)-camptothecine (d) synthetic route, column chromatography developping agent is methylene chloride/methanol/sherwood oil=80/0.5/60), finally obtain faint yellow solid 0.81g, yield 72.5%.
1H NMR(CDCl
3,300MHz)δ0.99(3H,t,J=7.4Hz,H-18),1.25(6H,d,2CH
3),1.87(2H,m,H-19),2.48(1H,m,CH(CH
3)
2),3.47(1H,d,CHCOO),4.39(1H,s,OH),5.26(2H,d,H-5),5.69(2H,d,H-17),7.39(5H,m,H-14,4H-phenyl),7.51(1H,s,H-11),7.68(1H,s,H-9),8.18(1H,d,J=9.2Hz,H-12),8.24(1H,s,H-7);
13C NMR(CDCl
3,75MHz)δ7.8(CH
3,C-18),20.1(CH
3,CH
3),21.4(CH
3,CH
3),29.6(CH
2,C-19),32.1(CH,CH(CH
3)
2),49.9(CH
2,C-5),59.3(CH,CHCOO),66.1(CH
2,C-17),72.8(C,C-20),98.2(CH,C-14),118.5(CH,C-9),118.9(C,C-16),125.6(CH,C-11),128.3,128.9,129.2,129.9,130.6(CH,C-7,12,4C-phenyl;C,C-6),131.2(C,C-Cl),133.6(C,CCHCOO),135.9(C,C-8),145.9(C,C-3),146.7(C,C-13),149.5(CH,C-10),150.1(C,C-15),152.4(C,C-2),157.5(C,C-16a),171.9(C,C-21),173.6(CHCOO)。The structural formula of 10-[3-methyl-2-(4-chloro-phenyl-) butyric acid ester group]-20 (S)-camptothecine (d) is as follows:
Embodiment 5
10-[[3-(2,2-dibromo vinyl)-2,2-dimethylcyclopropane base] formic acid ester group-similar b of (20S)-camptothecine (e) synthetic route, column chromatography developping agent is methylene chloride/methanol/sherwood oil=70/0.5/40), finally obtain faint yellow solid 0.18g, yield 27.2%.
1H NMR(CDCl
3,300MHz)δ1.02(3H,t,J=7.4Hz,H-18),1.39(6H,each3H,s,CH
3),1.90(2H,m,H-19),2.19(2H,m,CHCOO,CHCHCBr
2),4.18(1H,s,H-20),5.28,5.72(each2H,d,H-5,H-17),6.79(1H,dd,J=3.4,3.4Hz,CHCBr
2),7.55(1H,dd,J=2.5,2.5Hz,H-14),7.67(2H,t,J=8.7,2.5Hz,H-9,H-11),8.23(1H,d,J=9.2Hz,H-12),8.31(1H,s,H-7);
13C NMR(CDCl
3,75MHz)δ7.9(CH
3,C-18),20.2,21.8(CH
3,2CH
3),27.4(C,C(CH
3)
2),28.7(CH,CHCHCBr
2),30.5(CH
2,C-19),32.6(CH,CHCOO),50.3(CH
2,C-5),65.4(CH
2,C-17),72.5(C,C-20),96.8(CH,C-14),119.4(CH,C-9),120.0(C,C-16),125.5(C,CHCBr
2),126.1(C,C-11),128.34(CH,CHCBr
2),128.4(CH,C-12),130.4(C,C-6),130.5(CH,C-7),131.3(C,C-8),145.4(C,C-3),146.0(C,C-13),149.0(C,C-10),150.1(C,C-15),152.6(C,C-2),156.9(C,C-16a),169.5(C,C-21),172.5(C,CHCOO)。10-[structural formula of [3-(2,2-dibromo vinyl)-2,2-dimethylcyclopropane base] formic acid ester group-(20S)-camptothecine (e) is as follows:
The present invention is by the chrysanthemumic acid part of esterification at 10 different pyrethroid insecticideses of introducing of 10-hydroxycamptothecine, synthesized 5 new 10-hydroxycamptothecine derivatives, table 1 is the molecular formula of derivative prepared by testing example 1 ~ embodiment 5, fusing point, specific rotation and high resolution mass spectrum data.
The molecular formula of table 1 new compound, fusing point, specific rotation and high resolution mass spectrum data
Experimental example 1 pyrethroid-10-hydroxycamptothecine derivative is to its Antifeedant Effect Against of beet armyworm third-instar larvae
For examination worm source: beet armyworm is provided by Plant Protection institute, Chinese Academy of Agricultral Sciences's agricultural chemicals resistance laboratory, and with the artificial breeding of Brassica oleracea L.var.capitata leaf, raising temperature is 25 ± 2 ° of C, photoperiod 16L:8D.
Sample configures: the sample taking embodiment 1 ~ embodiment 5 preparation is respectively dissolved in acetone the mother liquor being made into 100mg/mL, is then diluted to the experimental concentration of 5mg/mL, tests.With 10-hydroxycamptothecine medicine in contrast, collocation method is the same.
Test method: adopt leaf dish method to measure pyrethroid camptothecin derivative to the antifeedant activity of beet armyworm third-instar larvae.First with punch tool, cabbage leaves is broken into the consistent leaf dish of specification (diameter 2.0cm), leaf dish is flooded 3s in the acetone soln of reagent agent namely take out, control group is pure makes same treatment with acetone, after acetone volatilizees naturally, chemicals treatment leaf dish and each 5 cross arrangements of acetone control leaf dish in culture dish (diameter 9.0cm), the clean filter paper of one deck has been padded in advance in culture dish, and adding distil water moisturizing.Every culture dish place 10 hungry 2h of uniform size 3 age Initial instar larvae as a process, often process repetition 3 times, be placed in insectary and raise, measure 24h, 48h posterior lobe dish by squared paper method and taken food area, calculate anti-food rate.
Test-results: the pyrethroid-antifeedant activity of 10-hydroxycamptothecine derivative to beet armyworm third-instar larvae the results are shown in Table 2 and table 3.
Table 210-hydroxycamptothecine (1) and derivative (a-e) thereof are to the 24h antifeedant activity of beet armyworm third-instar larvae
| Numbering | Anti-food rate (%) |
| 1 | 67.6abc |
| a | 86.7a |
| b | 80.8ab |
| c | 62.9abc |
| d | 56.5bc |
| e | 46.4c |
arepresent and adopt LSD method to carry out variance analysis (P=0.05) to testing data.
Table 310-hydroxycamptothecine (1) and derivative (a-e) thereof are to the 48h antifeedant activity of beet armyworm third-instar larvae
| Numbering | Anti-food rate (%) |
| 1 | 68.5a |
| a | 82.5a |
| b | 62.2ab |
| c | 39.4c |
| d | 43.0bc |
| e | 40.8bc |
arepresent and adopt LSD method to carry out variance analysis (P=0.05) to testing data.
From table 2 and table 3, along with the difference of the active group of the new pyrethroid insecticides introduced, the antifeedant activity of compound to beet armyworm third-instar larvae of new synthesis has very large difference.By 24h results contrast, target compound a is significantly improved than 10-hydroxycamptothecine (1) activity;
Present inventor studies further, identical group is spliced with 10 of 10-hydroxycamptothecine in 20 splicings of (20S)-camptothecine, repeat to do above-mentioned experiment, experiment purpose compares the antifeedant activity of the derivative (a-e) of 10-hydroxycamptothecine and the derivative (A-E) of (20S)-camptothecine, result, as table 4, table 5, be that series compound (a-e) activity of Material synthesis is better than with (20S)-camptothecine is the series compound (A-E) of Material synthesis with 10-hydroxycamptothecine.
Table 4(20S) derivative of-hydroxycamptothecinederivatives derivatives (A-E) and 10-hydroxycamptothecine is to the 24h antifeedant activity of beet armyworm third-instar larvae
| Numbering | 24h anti-food rate (%) | Numbering | 24h anti-food rate (%) |
| A | 84.2ab | a | 86.7ab |
| B | 71.6abcd | b | 80.8abc |
| C | 57.7cdef | c | 62.9bcdef |
| D | 48.7def | d | 56.5cdef |
| E | 40.7f | e | 46.4ef |
arepresent and adopt LSD method to carry out variance analysis (P=0.05) to testing data.
Table 5(20S) derivative of-hydroxycamptothecinederivatives derivatives (A-E) and 10-hydroxycamptothecine is to the 48h antifeedant activity of beet armyworm third-instar larvae
| Numbering | 48h anti-food rate (%) | Numbering | 48h anti-food rate (%) |
| A | 53.4cd | a | 82.5a |
| B | 57.0bc | b | 62.2bc |
| C | 39.4e | c | 39.4de |
| D | 36.9e | d | 43.0de |
| E | 35.4e | e | 40.8de |
arepresent and adopt LSD method to carry out variance analysis (P=0.05) to testing data.
Experimental example 2 pyrethroids-10-hydroxycamptothecine derivative measures the contact toxicity of beet armyworm third-instar larvae
For examination worm source: beet armyworm is provided by Plant Protection institute, Chinese Academy of Agricultral Sciences's agricultural chemicals resistance laboratory, and with the artificial breeding of Brassica oleracea L.var.capitata leaf, raising temperature is 25 ± 2 ° of C, photoperiod 16L:8D.
The electronic single track pipettor of test apparatus: EDP3-Plus (1-10 μ L): Rui Ning RAININ company of the U.S.
Sample configures: the sample taking embodiment 1 ~ embodiment 5 preparation is respectively dissolved in acetone the mother liquor being made into 100mg/mL, is then diluted to the experimental concentration of 10mg/mL, tests.With lead compound 10-hydroxycamptothecine medicine in contrast, collocation method is the same.
Test method: adopt micro intravenous drip method to measure pyrethroid camptothecin derivative to the antifeedant activity of beet armyworm third-instar larvae.Be the acetone soln of 10mg/mL by the concentration of 10-hydroxycamptothecine and derivative thereof, with micro intravenous drip device o'clock in the pronotum of 3 instar larvaes, every point 1.0 μ L, often process drop 10, repeat 3 times, contrast acetone does same process, is received immediately by beet armyworm on fresh host's blade, put into insect box after process.Insect box is placed in 25 ± 2 ° of C, relative humidity 70%, under photoperiod 16L:8D condition, adds up dead borer population after 24h, 48h and 72h, calculates mortality ratio and corrected mortality.
Test-results: each compound to the corrected mortality after beet armyworm third-instar larvae effect 72h as table 6.
Table 610-hydroxycamptothecine (1) and derivative (a-e) thereof are to the 72h contact toxicity of beet armyworm third-instar larvae
| Numbering | Corrected mortality (%) |
| 1 | 53.3bc |
| a | 95.4a |
| b | 70.6b |
| c | 56.9bc |
| d | 57.9bc |
| e | 47.8c |
arepresent and adopt LSD method to carry out variance analysis (P=0.05) to testing data.
As can be seen from the result of table 6, except e, the same 10-hydroxycamptothecine of the contact toxicity of all the other compounds to beet armyworm third-instar larvae (1) is compared and is all improved a lot.Especially a, its 72h corrected mortality under 10mg/mL concentration reaches 95.4%, so on this basis, determines the median lethal concentration(LC&-{50}) LC of a
50.Table 7 lists the LC of 10-hydroxycamptothecine (1), camptothecine (2) and compound a
50value.As can be seen from the result of table 7, the LC of a
50almost the LC of camptothecine
501/2, be 1/20 of 10-hydroxycamptothecine, this compares lead compound and improves a lot.In addition, the antifeedant activity of a is also best in new synthetic compound, so compound a has the meaning and value of research and development further.
The LC of table 710-hydroxycamptothecine (1), camptothecine (2) and compound a
50
| Compound | y=a+bx | LC 50(mg/L) | 95% fiducial interval |
| 1 | y=0.23+1.22x | 8391.5 | 7520.9-9362.9 |
| 2 | y=3.96+0.36x | 802.9 | 513.1-1256.4 |
| a | y=2.04+1.12x | 434.1 | 235.1-801.5 |
Present inventor studies further, identical group is spliced with 10 of 10-hydroxycamptothecine in 20 splicings of (20S)-camptothecine, repeat to do above-mentioned experiment, the derivative (A-E) of derivative (a-e) and (20S)-camptothecine that experiment purpose compares 10-hydroxycamptothecine is to the 72h contact toxicity of beet armyworm third-instar larvae, result, as table 8, is that the contact toxicity of the series compound (a-e) of Material synthesis will significantly better than the compound (A-E) taking (20S)-camptothecine as Material synthesis with 10-hydroxycamptothecine.Table 810-hydroxycamptothecinederivatives derivatives (a-e) and (20S)-hydroxycamptothecinederivatives derivatives (A-E) are to the 72h contact toxicity of beet armyworm third-instar larvae
| Numbering | Corrected mortality (%) | Numbering | Corrected mortality (%) |
| A | 59.6bc | a | 95.4a |
| B | 63.3bc | b | 70.6b |
| C | 47.9de | c | 56.9cde |
| D | 55.6cde | d | 57.9bcde |
| E | 32.2f | e | 47.8e |
arepresent and adopt LSD method to carry out variance analysis (P=0.05) to testing data.
Embodiment 3 pyrethroid-10-camptothecin derivative is to the cytotoxic assay of IOZCAS-Spex-II
In order to verify that new synthetic compound a has good insecticidal activity to beet armyworm, determine 10-hydroxycamptothecine and derivative thereof further to the toxicity of beet armyworm midgut epithelial cells system Spex-II.
For examination cell: in beet armyworm, intestines fat body cells IOZCAS-Spex-II is by this laboratory culture (Institute of Zoology, Academia Sinica gives).Cell cultures is in Grace Insect culture medium (GIBCO company), and substratum adds 10% foetal calf serum (Invitrogen, USA), 100U penicillin and 100U Streptomycin sulphate.Culture condition is (26 ± 1) DEG C, RH70%-80%, and every 6d goes down to posterity once.
Test reagent and instrument
Dimethyl sulfoxide (DMSO) (DMSO): 99.9%, Invitrogen company of Britain
CellTiter
aQueous One Solution cell proliferation reagent box: Promega company of the U.S.
HPS-160 incubator: Harbin Donglian Electronic & Technology Development Co., Ltd.
TECAN infinite M200pro microplate reader: Tecan company of Sweden
Sample configures: it is 5 × 10 that 10-hydroxycamptothecine and derivative (a ~ e prepared by embodiment 1 ~ embodiment 5) thereof are configured to concentration with DMSO
4the mother liquor of μm ol/L, uses liquid DMSO to be diluted to desired concn.
Test method: adopt mtt assay to measure.The IOZCAS-Spex-II cell of taking the logarithm vegetative period, adjustment culturing cell concentration is 10
5individual/mL.According to CellTiter
aQueous One Solution test kit specification sheets, inoculates 96 orifice plates with every hole 80 μ L, after 12h, adds 10-hydroxycamptothecine respectively and derivative makes its final concentration be 0.01,0.1,1.0,10,100 μm of ol/L, control group adds DMSO(1 μ L), each concentration establishes 3 parallel holes.After cultivating 6,24,48,72h, add CellTiter respectively
aQueous One reagent 10 μ L, after continuing to cultivate 2h, measures absorbancy by microplate reader at 490nm place, presses formulae discovery inhibitory rate of cell growth below, and adopt Excel software to carry out data analysis.
Cell proliferation inhibition rate (%)=[(A
490control group-A
490agent-feeding treatment group)/A
490control group] × 100
Test-results: each compound under each concentration and the timed interval to beet armyworm in the inhibiting rate of intestines fat body cells IOZCAS-Spex-II as shown in Fig. 1 ~ Fig. 6; Each compound concentration be 100 μm of ol/L to the inhibiting rate after IOZCAS-Spex-II effect 72h as table 9.
Table 910-hydroxycamptothecine (1) and derivative (a-e) under 100 μm of ol/L to the inhibiting rate after IOZCAS-Spex-II72h
| Compound | Inhibiting rate (%) |
| 1 | 54.3ab |
| a | 59.6a |
| b | 53.5ab |
| c | 49.7b |
| d | 34.2c |
| e | 54.4ab |
arepresent and adopt LSD method to carry out variance analysis (P=0.05) to testing data.
Present inventor studies further, identical group is spliced with 10 of 10-hydroxycamptothecine in 20 splicings of (20S)-camptothecine, repeat to do above-mentioned experiment, the derivative (A-E) of derivative (a-e) and (20S)-camptothecine that experiment purpose compares 10-hydroxycamptothecine under 100 μm of ol/L to the inhibiting rate after IOZCAS-Spex-II72h, result, as table 10, be that series compound (a-e) inhibiting rate of Material synthesis is better than with (20S)-camptothecine is the series compound (A-E) of Material synthesis with 10-hydroxycamptothecine.
Table 1010-hydroxycamptothecine (1) derivative (a-e) and (20S)-hydroxycamptothecinederivatives derivatives (A-E) under 100 μm of ol/L to the inhibiting rate after IOZCAS-Spex-II72h
| Compound | Inhibiting rate (%) | Compound | Inhibiting rate (%) |
| A | 31.8cd | a | 59.6a |
| B | 52.7ab | b | 53.5ab |
| C | 43.7bcd | c | 49.7ab |
| D | 10.3f | d | 34.2cde |
| E | 27.7e | e | 54.4ab |
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (5)
1. pair beet armyworm has the 10-hydroxycamptothecine derivative of food refusal and contact toxicity, and it is characterized in that, structural formula is as follows:
2. pair beet armyworm has the 10-hydroxycamptothecine derivative of food refusal and contact toxicity, and it is characterized in that, structural formula is as follows:
3. pair beet armyworm has the 10-hydroxycamptothecine derivative of food refusal and contact toxicity, and it is characterized in that, structural formula is as follows:
4. pair beet armyworm has the 10-hydroxycamptothecine derivative of food refusal and contact toxicity, and it is characterized in that, structural formula is as follows:
5. pair beet armyworm has the 10-hydroxycamptothecine derivative of food refusal and contact toxicity, and it is characterized in that, structural formula is as follows:
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| CN1946296A (en) * | 2004-02-10 | 2007-04-11 | 拜尔农作物科学股份公司 | Combinations of insecticide active agents based on thiacloprid and pyrethroids |
| CN101243796A (en) * | 2008-03-14 | 2008-08-20 | 浙江林学院 | Insecticide composition and its processing method |
| CN101897337A (en) * | 2010-07-23 | 2010-12-01 | 中山大学 | Microbial pesticide synergist and microbial pesticide containing same |
| CN102453036A (en) * | 2010-10-27 | 2012-05-16 | 李红玉 | Camptothecin compound and preparation method and application in pesticide thereof |
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| CN1759675A (en) * | 2005-11-08 | 2006-04-19 | 浙江林学院 | Pesticide containing comptothecin or dreivates of camptothecin, and preparation method |
| CN101243796A (en) * | 2008-03-14 | 2008-08-20 | 浙江林学院 | Insecticide composition and its processing method |
| CN101897337A (en) * | 2010-07-23 | 2010-12-01 | 中山大学 | Microbial pesticide synergist and microbial pesticide containing same |
| CN102453036A (en) * | 2010-10-27 | 2012-05-16 | 李红玉 | Camptothecin compound and preparation method and application in pesticide thereof |
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