CN103275095A - 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 human pursuit to fine living environment of people's quality of life; produce the green non-pollution agricultural-food and protect the environment from pollution and destroy the generally attention that is subjected to countries in the world; as the important production means-agricultural chemicals in the agricultural-food production link, therefore being faced with should be to the harmless environment amenable demand again of agricultural-food in the control harmful organism.Thereby the general trend of events that initiative has is efficient, low toxicity, pollution are little, " the harmonious agricultural chemicals of environment " or " biorational agricultural chemicals " the selectivity advantages of higher become pesticide industry development in recent years, the plant-sourced active substance receives much concern because meeting this trend.In the long-term coevolution course of plant and insect, plant has also formed a cover chemical, biological defense system gradually.Especially its secondary metabolite; of a great variety; active high-effect single-minded; in order to insect around regulating the food perch of getting of plant such as is bred at preference; to guarantee that plant population can keep out the crushing invasion of insect; thereby the normal orderly whole life course of finishing is as causing the larva food refusal, behavior such as protection such as interferences of growing grade.Confirmed very strong anti-insect activity by the material that extracts in many different types of plant origins, can regulate energetically or the normal physiological activity of interference insect, thereby control harmful organism population quantity has realized the chemical protection of plant to crop effectively.
Insecticide active substance in the natural phant is extremely abundant, can be divided into following a few class according to its chemical structure: alkaloids, terpene, anthraquinone class and flavonoid, essential oil class, steroid, photoactivation endotoxin.
In addition, pyrethrin (carboxylic acid esters), ether acyl Tuberculate Speranskia Herb element (lignin), Inokosterone (steroidal class), kind fennel glycosides plant-sourced active substances such as (glucosides classes) various insects is shown tag, food refusal and growth inhibitory activity.
The vegetative insecticidal substance classes is various, makes its mode of action to insect also varied, aspects such as the behavior that mainly shows is disturbed, tagged, stomach toxicity, growth-inhibiting, anesthesia, stifling and photoactivation.
So far, a large amount of reports has been arranged about camptothecine control harmful organism, for example leaf of Common Camptotheca extract missible oil has the better prevention effect to false eye leafhopper, can be used for the green prevention and control system of tea place leafhopper; 0.2% camptothecine missible oil all has higher prevention effect to cabbage aphid, rice hoppers and striped rice borer; The camptothecine acetone soln has certain influence to citrus fruit fly adult reproductivity, grow etc.; Camptothecine has stronger stomach poison function to small cabbage moth, and it is grown, lays eggs and ovum hatching all has the obvious suppression effect; Camptothecine also shows obvious growth to beet armyworm and suppresses and sterile effect.In addition, there are some researches show that camptothecine also has the good restraining effect to the growth of some phytopathogens.But the neither good limitation of camptothecine solubleness in organic solvent and water makes camptothecine be restricted in the direct application of agriculture field.So some investigator begins research sight has been turned on the good camptothecin derivative of exploitation solubleness.Introduce the L-amino acid that contains nitroxyl radicals by esterification camptothecine 20-hydroxyl in the existing report, and it is water-soluble with it to wish to improve the compound biological activity.They have carried out structural modification to camptothecine and obtain a series of new compounds and measured antifeedant activity and the insecticidal activity of these compounds to the mythimna separata third-instar larvae according to this thinking.But food refusal and the insecticidal activity of the new compound that synthesizes all are lower than camptothecine.
Beet armyworm (Spodoptera exigua H ü bner) belongs to lepidopteran (Lepidoptera) Noctuidae (Noctuidae), is a kind of worldwide distribution, intermittent big polyphagous pest-insect of taking place.The plant of larval feeding has 35 sections, 108 belong to, 138 kinds, not only endanger food crop such as corn, Chinese sorghum, cotton, soybean, peanut, go back cash crop such as danger to vegetables, flowers, fruit tree, tobacco, beet, cause heavy losses, and its distribution is very uneven, is spot film and takes place, and the part is injured seriously, be difficult to prediction, also do not have effective Forecasting Methodology so far.For the control of beet armyworm, chemical prevention accounts for critical role at present.But for a long time, owing to use chemical pesticide in a large number and unreasonably, beet armyworm is very fast to its resistance development speed, and resistance level is also in continuous enhancing.It is reported, at present beet armyworm has produced resistance in various degree to number of chemical agricultural chemicals such as organochlorine, carbamate, organophosphorus, pyrethroid and Bacillus thuringiensis, Avrmectin etc., cause the peasant in the process of preventing and treating, to continue to increase dosage, natural control ability influence to natural enemy, agroecosystem is very big, make environment threatened by pollution, HUMAN HEALTH, the eubiosis is destroyed.
Summary of the invention
Technical problem to be solved by this invention provides a kind of derivative and application thereof of 10-hydroxycamptothecine, the reactive site of 10-hydroxycamptothecine and traditional chemical agricultural chemicals pyrethroid insecticides is spliced in the present invention, obtain a series of pyrethroids-10-hydroxycamptothecine derivative, make it can keep 10-hydroxycamptothecine to the original outstanding antifeedant activity of beet armyworm, can obtain the pyrethroid insecticides contact toxicity outstanding to beet armyworm again, this has the efficient of unique effect target to exploitation, the 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, a kind of in the following array structure of R:
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 of killing beet armyworm.
The invention has the beneficial effects as follows:
The reactive site of 10-hydroxycamptothecine and traditional chemical agricultural chemicals pyrethroid insecticides is spliced in the present invention, obtain a series of pyrethroids-10-hydroxycamptothecine derivative, make it can keep 10-hydroxycamptothecine to the original outstanding antifeedant activity of beet armyworm, can obtain the pyrethroid insecticides contact toxicity outstanding to beet armyworm again, this has important Research Significance to efficient, the low toxicity novel pesticide that exploitation has the unique effect target.
Description of drawings
Fig. 1 for experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine (1) 6,24,48 and 72h after cytotoxicity figure;
Fig. 2 for experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (a) 6,24,48 and 72h after cytotoxicity figure;
Fig. 3 for experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (b) 6,24,48 and 72h after cytotoxicity figure;
Fig. 4 for experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (c) 6,24,48 and 72h after cytotoxicity figure;
Fig. 5 for experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (d) 6,24,48 and 72h after cytotoxicity figure;
Fig. 6 for experimental example 3MTT method of the present invention measure 10-hydroxycamptothecine derivative (e) 6,24,48 and 72h after cytotoxicity figure;
Embodiment
Below principle of the present invention and feature are described, institute only gives an actual example and to be used for explaining the present invention, is not for restriction scope of the present invention.
The present invention has the chrysanthemumic acid part of the pyrethroid insecticides of outstanding contact toxicity in 10 introducings of 10-hydroxycamptothecine to beet armyworm, obtain 5 pyrethroids-10-camptothecin derivative (a-e).The reaction expression of this experiment is as follows:
Wherein, a kind of in the following array structure of R:
Below be the used laboratory apparatus of derivative compound experiment of 10-hydroxycamptothecine:
(1) X-4 type numeral shows melting point detector: Yuhua Instrument Co., Ltd., Gongyi City, thermometer is not proofreaied and correct
(2) 300MHz type NMR spectrometer with superconducting magnet (Bruker DRX FT-NMR300MHz): U.S. Brooker dalton company
(3) the automatic polarimeter of Wzz-2B: plant and instrument company limited is easily surveyed in Shanghai
(4) fourier transformation high-resolution mass spectrometer (Bruker Apex IV FTMS): U.S. Brooker dalton company
(5) the circulation ability of swimming is used vacuum pump (SHB-III) more: Great Wall, Shanghai science, industry and trade company limited
(6) Rotary Evaporators (RE-2000): Shanghai Yarong Biochemical Instrument Plant
(7) temperature adjustable electrically heated cover (DZTW): Beijing is bright Medical Instruments factory forever
(8) electronic balance (JA12002): the more flat scientific instrument in Shanghai company limited
(9) various glassware: Beijing Glass Implement Factory
Below be the used experiment reagent of derivative compound experiment 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 chemistry company limited
(4) 3-(2-chloro-3,3,3-three fluoro-1-propenyl)-2,2-dimethyl cyclopropane carboxylic acid (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 chemistry company limited
(7) agents useful for same comprises that methylene dichloride, tetrahydrofuran (THF), methyl alcohol, sherwood oil, ethyl acetate, methyl alcohol etc. are commercially available AR level reagent, and reaction reagent is not further purified, and part has the reagent of particular requirement through no water treatment.
All melting point compounds are not calibrated.
Nuclear magnetic resonance spectrum
1H-NMR, frequency is 300MHz, is interior mark with TMS, chemical shift represents that with (ppm) solvent is DMSO-d
6Or CDCl
3S(is unimodal), the d(doublet), the t(triplet) and, the q(quartet), the m(multiplet) and, br s(is wide unimodal).
Nuclear magnetic resonance spectrum
13C-NMR, frequency is 75MHz, is interior mark with TMS, chemical shift represents that with (ppm) solvent is DMSO-d
6Or CDCl
3
The used detector of high resolution mass spectrum is ESI.
10-[(2,2,3,3-tetramethyl-ring propyl) the formic acid ester group]-(20S)-and camptothecine (a) synthetic route: in the 250mL flask, (0.364g 1mmol), feeds N with the reaction flask vacuumizing to add 10-hydroxycamptothecine
2After, add tetrahydrofuran (THF) (THF) 120mL, first cyanogen chrysanthemum acyl chlorides (0.96g, 6mmol) and triethylamine (Et
3N) 0.9mL.N
2Stopped reaction behind the back flow reaction 4h under the protection.Reaction solution moves in the 500mL separating funnel, adds the 180mL ethyl acetate, and vibration mixes.Add 40mL distilled water again, vibration mixes fully, leaves standstill separatory, gets upper organic phase, triplicate.Organic phase changes in the 500mL Erlenmeyer flask, adds the anhydrous sodium sulphate vibration, leaves standstill, and filters, and solution revolves to steam and obtains faint yellow solid.This solid adds anhydrous diethyl ether 20mL, magnetic agitation 10h, and suction filtration, the anhydrous diethyl ether washing, the gained solid is dry 0.5h in stink cupboard, gets 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)。
10-[[3-(2,2-dichloroethylene)-2,2-dimethylcyclopropane base] the formic acid ester group]-(20S)-and camptothecine (b) synthetic route: in the 250mL flask, (0.36g 1mmol), feeds N with the reaction flask vacuumizing to add 10-hydroxycamptothecine
2After, (1.35g is 6mmol) with triethylamine 0.9mL for adding tetrahydrofuran (THF) 120mL, dichloro chrysanthemum acyl chlorides.N
2Stopped reaction behind the back flow reaction 6h under the protection.Reaction solution moves in the 500mL separating funnel, adds the 180mL ethyl acetate, and vibration mixes.Add 40mL distilled water again, vibration mixes fully, leaves standstill separatory, gets upper organic phase, triplicate.Organic phase changes in the 500mL Erlenmeyer flask, adds anhydrous sodium sulphate and dewaters, and crosses silicagel column (methylene chloride/sherwood oil=70/0.5/30) behind the filtration evaporate to dryness, obtains faint yellow solid 0.28g.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)。10-[[3-(2,2-dichloroethylene)-2,2-dimethylcyclopropane base] the formic acid ester group]-(20S)-structural formula of camptothecine (b) is as follows:
Embodiment 3
10-[[3-(2-chloro-2-trifluoromethyl vinyl)-2,2-dimethylcyclopropane base] the formic acid ester group]-(20S)-the similar b of camptothecine (c) synthetic route, the column chromatography developping agent is methylene chloride/sherwood oil=100/0.5/80), obtain faint yellow solid 0.32g at last, 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)。10-[[3-(2-chloro-2-trifluoromethyl vinyl)-2,2-dimethylcyclopropane base] the formic acid ester group]-(20S)-structural formula of camptothecine (c) is as follows:
Embodiment 4
10-[3-methyl-2-(4-chloro-phenyl-) butyric acid ester group] the similar b of-20 (S)-camptothecine (d) synthetic routes, the column chromatography developping agent is methylene chloride/sherwood oil=80/0.5/60), obtain faint yellow solid 0.81g at last, 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)。10-[3-methyl-2-(4-chloro-phenyl-) butyric acid ester group] structural formula of-20 (S)-camptothecine (d) is as follows:
Embodiment 5
10-[[3-(2, the 2-dibromo vinyl)-2,2-dimethylcyclopropane base] the formic acid ester group-(20S)-the similar b of camptothecine (e) synthetic route, the column chromatography developping agent is methylene chloride/sherwood oil=70/0.5/40), obtain faint yellow solid 0.18g at last, 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-[[3-(2,2-dibromo vinyl)-2,2-dimethylcyclopropane base] structural formula of formic acid ester group-(20S)-camptothecine (e) is as follows:
The present invention is by 10 the chrysanthemumic acid parts of introducing different pyrethroid insecticideses of esterification at 10-hydroxycamptothecine, synthesized 5 new 10-hydroxycamptothecine derivatives, table 1 is molecular formula, fusing point, specific rotation and the high resolution mass spectrum data of the derivative of test implementation example 1～embodiment 5 preparations.
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 measured the antifeedant activity of beet armyworm third-instar larvae
For trying the worm source: beet armyworm is provided by Plant Protection institute, Chinese Academy of Agricultral Sciences 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 sample configuration: the sample that takes by weighing embodiment 1～embodiment 5 preparations respectively is dissolved in the mother liquor that is made into 100mg/mL in the acetone, is diluted to the experimental concentration of 5mg/mL then, tests.With 10-hydroxycamptothecine medicine in contrast, collocation method is the same.
Test method: adopt leaf dish method to measure the pyrethroid camptothecin derivative to the antifeedant activity of beet armyworm third-instar larvae.With punch tool cabbage leaves is broken into the leaf dish (diameter 2.0cm) of specification unanimity earlier, the 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 treating that acetone volatilizees naturally, chemicals treatment leaf dish and acetone are contrasted each 5 cross arrangement of leaf dish in culture dish (diameter 9.0cm), filled up the clean filter paper of one deck in the culture dish in advance, and adding distil water is preserved moisture.Every culture dish place 10 hungry 2h of uniform size 3 the initial stage in age larva as a processing, every processing repeats 3 times, places the insectary to raise, and measures 24h with the squared paper method, 48h posterior lobe dish is got the food area, calculates the food refusal rate.
Test-results: pyrethroid-10-hydroxycamptothecine derivative the results are shown in Table 2 and table 3 to the antifeedant activity of beet armyworm third-instar larvae.
Table 210-hydroxycamptothecine (1) and derivative (a-e) thereof are to the 24h antifeedant activity of beet armyworm third-instar larvae
| Numbering | Food refusal rate (%) |
| 1 | 67.6abc |
| a | 86.7a |
| b | 80.8ab |
| c | 62.9abc |
| d | 56.5bc |
| e | 46.4c |
aExpression adopts the LSD method that testing data is carried out variance analysis (P=0.05).
Table 310-hydroxycamptothecine (1) and derivative (a-e) thereof are to the 48h antifeedant activity of beet armyworm third-instar larvae
| Numbering | Food refusal rate (%) |
| 1 | 68.5a |
| a | 82.5a |
| b | 62.2ab |
| c | 39.4c |
| d | 43.0bc |
| e | 40.8bc |
aExpression adopts the LSD method that testing data is carried out variance analysis (P=0.05).
By table 2 and table 3 as can be known, along with the difference of the active group of the pyrethroid insecticides of new introducing, new synthetic compound has very big difference to the antifeedant activity of beet armyworm third-instar larvae.By 24h result relatively, target compound a is significantly improved than 10-hydroxycamptothecine (1) activity;
The present application people further studies, at 20 splicings of (20S)-camptothecine and 10 groups that splicing is identical of 10-hydroxycamptothecine, repeat to do above-mentioned experiment, experiment purpose relatively 10-hydroxycamptothecine derivative (a-e) and (20S)-antifeedant activity of the derivative (A-E) of camptothecine, result such as table 4, table 5 are that to be better than with (20S)-camptothecine be the synthetic series compound (A-E) of raw material to synthetic series compound (a-e) activity of raw material with the 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
| |
24h food refusal rate (%) | |
24h food refusal 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 |
aExpression adopts the LSD method that testing data is carried out variance analysis (P=0.05).
Table 5(20S)-derivative of hydroxycamptothecinederivatives derivatives (A-E) and 10-hydroxycamptothecine is to the 48h antifeedant activity of beet armyworm third-instar larvae
| |
48h food refusal rate (%) | |
48h food refusal 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 |
aExpression adopts the LSD method that testing data is carried out variance analysis (P=0.05).
Experimental example 2 pyrethroids-10-hydroxycamptothecine derivative is measured the contact toxicity of beet armyworm third-instar larvae
For trying the worm source: beet armyworm is provided by Plant Protection institute, Chinese Academy of Agricultral Sciences 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): the U.S. auspicious peaceful RAININ company
The sample configuration: the sample that takes by weighing embodiment 1～embodiment 5 preparations respectively is dissolved in the mother liquor that is made into 100mg/mL in the acetone, is diluted to the experimental concentration of 10mg/mL then, tests.With lead compound 10-hydroxycamptothecine medicine in contrast, collocation method is the same.
Test method: adopt micro-topical application method pyrethroid camptothecin derivative to the antifeedant activity of beet armyworm third-instar larvae.Be the acetone soln of 10mg/mL with the concentration of 10-hydroxycamptothecine and derivative thereof, with micro-dropper o'clock in the pronotum of 3 instar larvaes, every point 1.0 μ L, 10 of every processing drops, repeat 3 times, contrast is done same the processing with acetone, after the processing beet armyworm is received on fresh host's blade immediately, puts into insect box.Insect box places 25 ± 2 ° of C, relative humidity 70%, and under the photoperiod 16L:8D condition, 24h, the dead borer population of statistics calculates mortality ratio and corrected mortality behind 48h and the 72h.
Test-results: corrected mortality such as the table 6 of each compound after to beet armyworm third-instar larvae effect 72h.
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 |
aExpression adopts the LSD method that testing data is carried out variance analysis (P=0.05).
By the result of table 6 as can be seen, all the other compounds are compared all the same 10-hydroxycamptothecine of the contact toxicity of beet armyworm third-instar larvae (1) and are improved a lot except e.Especially a, its 72h corrected mortality under 10mg/mL concentration reaches 95.4%, so on this basis, has measured the median lethal concentration(LC﹠-{50}) LC of a
50Table 7 has been listed the LC of 10-hydroxycamptothecine (1), camptothecine (2) and compound a
50Value.By the result of table 7 as can be seen, the LC of a
50Almost be 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 also is best in the new synthetic compound, so compound a has meaning and the value of further research and development.
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 |
The present application people further studies, at 20 splicings of (20S)-camptothecine and 10 groups that splicing is identical of 10-hydroxycamptothecine, repeat to do above-mentioned experiment, experiment purpose relatively 10-hydroxycamptothecine derivative (a-e) and (20S)-derivative (A-E) of camptothecine is to the 72h contact toxicity of beet armyworm third-instar larvae, result such as table 8 are that the contact toxicity of the synthetic series compound (a-e) of raw material will be significantly better than being the synthetic compound (A-E) of raw material with the 10-hydroxycamptothecine with (20S)-camptothecine.Table 810-hydroxycamptothecinederivatives derivatives (a-e) and (20S)-hydroxycamptothecinederivatives derivatives (A-E) is 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 |
aExpression adopts the LSD method that testing data is carried out variance analysis (P=0.05).
Embodiment 3 pyrethroids-10-camptothecin derivative is to the cytotoxic assay of IOZCAS-Spex-II
In order to verify that the beet armyworm of new synthetic compound a has good insecticidal activity, further having measured 10-hydroxycamptothecine and derivative thereof is the toxicity of Spex-II to the beet armyworm midgut epithelial cells.
For trying cell: beet armyworm midgut fatty body cell IOZCAS-Spex-II is by this laboratory culture (Institute of Zoology, Academia Sinica gives).Cell cultures is in Grace insect substratum (GIBCO company), substratum add 10% foetal calf serum (Invitrogen, USA), 100U penicillin and 100U Streptomycin sulphate.Culture condition is (26 ± 1) ℃, RH70%-80%, and every 6d goes down to posterity once.
Test reagent and instrument
Dimethyl sulfoxide (DMSO) (DMSO): 99.9%, Britain Invitrogen company
CellTiter
AQueous One Solution cell proliferation reagent box: U.S. Promega company
HPS-160 incubator: Harbin Donglian Electronic ﹠ Technology Development Co., Ltd.
TECAN infinite M200pro microplate reader: Sweden Tecan company
Sample configuration: (a of embodiment 1～embodiment 5 preparations～e) be configured to concentration with DMSO is 5 * 10 for 10-hydroxycamptothecine and derivative thereof
4The mother liquor of μ mol/L uses liquid to be diluted to desired concn with DMSO.
Test method: adopt mtt assay to measure.The IOZCAS-Spex-II cell of taking the logarithm vegetative period, adjusting culturing cell concentration is 10
5Individual/mL.According to CellTiter
AQueous One Solution test kit specification sheets is inoculated 96 orifice plates with every hole 80 μ L, and behind the 12h, adding 10-hydroxycamptothecine and derivative thereof respectively, to make its final concentration be 0.01,0.1,1.0,10,100 μ mol/L, control group add DMSO(1 μ L), each concentration is established 3 parallel holes.After cultivating 6,24,48,72h, add CellTiter respectively
AQueous One reagent 10 μ L after continuing to cultivate 2h, measure absorbancy with microplate reader at the 490nm place, calculate inhibitory rate of cell growth by following formula, and adopt Excel software to carry out data analysis.
Cell proliferation inhibition rate (%)=[(A
490Control group-A
490The dosing treatment group)/A
490Control group] * 100
Test-results: each compound under each concentration and the timed interval to the inhibiting rate of beet armyworm midgut fatty body cell IOZCAS-Spex-II such as Fig. 1～shown in Figure 6; Inhibiting rate such as the table 9 of each compound after concentration is the IOZCAS-Spex-II effect of 100 μ mol/L 72h.
Table 910-hydroxycamptothecine (1) and derivative (a-e) thereof under 100 μ mol/L to the inhibiting rate behind the IOZCAS-Spex-II72h
| Compound | Inhibiting rate (%) |
| 1 | 54.3ab |
| a | 59.6a |
| b | 53.5ab |
| c | 49.7b |
| d | 34.2c |
| e | 54.4ab |
aExpression adopts the LSD method that testing data is carried out variance analysis (P=0.05).
The present application people further studies, at 20 splicings of (20S)-camptothecine and 10 groups that splicing is identical of 10-hydroxycamptothecine, repeat to do above-mentioned experiment, experiment purpose relatively 10-hydroxycamptothecine derivative (a-e) and (20S)-derivative (A-E) of camptothecine under 100 μ mol/L to the inhibiting rate behind the IOZCAS-Spex-II72h, result such as table 10 are that to be better than with (20S)-camptothecine be the synthetic series compound (A-E) of raw material to synthetic series compound (a-e) inhibiting rate of raw material with the 10-hydroxycamptothecine.
Table 1010-hydroxycamptothecine (1) derivative (a-e) and (20S)-hydroxycamptothecinederivatives derivatives (A-E) under 100 μ mol/L to the inhibiting rate behind the 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 above only is preferred embodiment of the present invention, and is in order to limit the present invention, within the spirit and principles in the present invention not all, any modification of doing, is equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. the derivative of a 10-hydroxycamptothecine is characterized in that, general structure is as follows:
Wherein, a kind of in the following array structure of R:
2. the derivative of a kind of 10-hydroxycamptothecine according to claim 1 is characterized in that, structural formula is as follows:
3. the derivative of a kind of 10-hydroxycamptothecine according to claim 1 is characterized in that, structural formula is as follows:
4. the derivative of a kind of 10-hydroxycamptothecine according to claim 1 is characterized in that, structural formula is as follows:
5. the derivative of a kind of 10-hydroxycamptothecine according to claim 1 is characterized in that, structural formula is as follows:
6. the derivative of a kind of 10-hydroxycamptothecine according to claim 1 is characterized in that, structural formula is as follows:
7. the derivative of a kind of 10-hydroxycamptothecine according to claim 1 is for the preparation of the agricultural chemicals of killing beet armyworm.
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