CN102453036A - Camptothecin compound, preparation method thereof and application thereof in pesticide - Google Patents
Camptothecin compound, preparation method thereof and application thereof in pesticide Download PDFInfo
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Abstract
The invention relates to a novel camptothecin compound, a preparation method of the compound and application of the compound in pesticides. The preparation method of the compound is thatN- (1 ' -oxy-2 ',2',5',5' -tetramethylpyrrole-amide) -3-LReacting amino acid and 5-hydroxyethyl oxy camptothecin under the action of a proper amount of catalyst and dehydrating agent, and purifying and separating to obtain the compound. Tests on insecticidal, bacteriostatic and herbicidal activities of the compounds prove that the compounds have better poisoning activities on agricultural pests (such as brontispa longissima and spodoptera litura) and plant germs (such as mango anthracnose and mango stalk rot) and farmland weeds (such as crab grass and mustard) compared with camptothecin and DRF-1042Vegetable and amaranth) has better inhibition effect.
Description
Technical field
The present invention relates to a kind of new camptothecine compounds, and the preparation method of this compound and the purposes in the preparation agricultural chemicals thereof.Belong to pesticide field.
Background technology
NSC 94600 (Camptothecin) be Wall equal 1966 at first from the distinctive Nyssaceae plant camptotheca acuminata of China (
Camptotheca acuminata) in separate a kind of quinoline alkaloid obtain, its have anticancer, antiviral, desinsection and multiple biological activity such as antibacterial (
J. Nat. Prod. 2004, 67,129-135).The domestic and international major side of the research of NSC 94600 is overweighted anti-tumor aspect; Further investigate at aspects such as its chemosynthesis and structural modification, anticancer structure activity relationship, the mechanisms of action, wherein a plurality of active compounds such as irinotecan, TPT, 9-aminocamptothecin, 9-nitrocamptothecin, DX-8951f, GG-211 and CKD-602 etc. are by FDA approval listing or be in the clinical study stage (1.
Bioorg. Med.Chem.
2004,
12, 1585 – 1604; 2.
Phytochem. 2004,
65, 2735 – 2749).
In recent years, NSC 94600 crude extract and simple derivatives be used to prepare sterilant or fungistat (
J. Agric. Food Chem. 2005, 53, 32-37, US20020018762 (2002), CN100384329 (2005), CN101518250 (2009), CN1843128 (2006), CN100579372 (2006)).Be easy to decompose but exist when NSC 94600 crude extract and simple derivatives are used for preparing sterilant or fungistat, the lasting period of losing efficacy is short, poorly water-soluble be difficult for processing shortcoming such as preparation.
The present invention utilizes principle of hybridization that NO free radical is passed through
L-amino acid connects in 5 of NSC 94600 and forms camptothecin ester; Design has been synthesized a series of structures and has been difficult for decomposing; The inefficacy lasting period prolongs; The new camptothecine compounds of water-soluble raising has also improved medicine agricultural (comprising desinsection, antibacterial and weeding) activity simultaneously, and has made things convenient for the preparation of this compounds on pesticide preparation.
Summary of the invention
The present invention provides one type of new camptothecine compounds.Simultaneously another object of the present invention provides the preparation method of this type new compound and in the purposes of pesticide field.
Technical scheme of the present invention is to have agricultural preferably (comprising desinsection, antibacterial and weeding) activity according to NSC 94600, but it has moderate toxicity, and NO free radical reaches
L-amino acid has advantages such as wide biological activity, can reduce its toxicity greatly obviously improving the bioactive while.Therefore, the present invention passes through NO free radical
L-amino acid connects in 5 of NSC 94600 and forms camptothecin ester; Synthetic a series of difficult decomposition; The inefficacy lasting period prolongs; The camptothecine compounds of water-soluble raising improves agricultural (comprising desinsection, antibacterial and weeding) activity of this compounds simultaneously, makes things convenient for the preparation of this compounds on pesticide preparation simultaneously.
[0007]The objective of the invention is to realize through following measures:
Camptothecine compounds of the present invention is meant to have the compound shown in the following general formula (I):
（I）
(I) R is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl in the formula.
The preparation method of compound according to the invention be with 5-hydroxyethyl oxygen NSC 94600 with
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-amino acid is dissolved in the exsiccant methylene dichloride, under nitrogen protection, stirs, and adds NSC 57182 (DCC) then; Stirring reaction under nitrogen protection; Refilter after question response is accomplished and remove white precipitate, remove solvent under reduced pressure after, crude product is through column chromatography purification; The use volume ratio is 40: 1 a chloroform-methanol wash-out, gets product.
The best preparation method of compound according to the invention is dissolved in 5-hydroxyethyl oxygen NSC 94600 1mmol in the 50mL methylene dichloride, adds 1mmol's
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-amino-acid compound, with N, the N-lutidine is as catalyzer under nitrogen protection, and the NSC 57182 (DCC) that adds equivalent is dewatering agent, is reflected at room temperature condition and carries out.
Desinsection, antibacterial and weeding activity detect and show that the compound of formula (I) has desinsection, antibacterial and weeding activity, therefore the invention provides the purposes of camptothecine compounds aspect preparation control plant disease pest and weed medicine.
Beneficial effect of the present invention:
Camptothecine compounds novel structure according to the invention, be easy to synthesize; Have and be difficult for decomposing the lasting period prolongation of losing efficacy, the characteristics of water-soluble raising; With respect to NSC 94600 and DRF-1042; Phytopathogen, Agricultural pests and farmland weed are all shown good inhibitory effect, be easy to process all kinds of pesticide preparation, can utilize stable, efficient, the nontoxic environment friendly agricultural of its exploitation.Have broad application prospects.
Below, foregoing of the present invention is done further detailed description through embodiment.But should this be interpreted as limitation of the present invention.
Embodiment
Embodiment 1
Camptothecine compounds prepares process
Preparing method of the present invention be with 5-hydroxyethyl oxygen NSC 94600 (compound 2) with
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-amino acid (3a-3h) is dissolved in the exsiccant methylene dichloride, the adding catalytic amount
N, N-lutidine stirred 5 minutes under nitrogen protection, added NSC 57182 (DCC) then; Stirring reaction is 2 hours under nitrogen protection; Remove by filter white precipitate, remove solvent under reduced pressure after, crude product is through column chromatography purification; The use volume ratio is 40: 1 a chloroform-methanol wash-out, gets formula I compound (4a-4h).
Relevant reaction is referring to reaction formula 1.
Reaction formula 1
R in the formula 1 is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl.
The used intermediate feed 5-hydroxyethyl of the present invention oxygen NSC 94600 (compound 2) be by NSC 94600 (compound 1) for raw material at FeCl
3/ H
2SO
4/ OHCH
2CH
2The OH reaction system obtains, and its method therefor is referring to (Subrahmanyam, D. et al, US6177439 (2001)), and correlated response is seen formula 1.
?
Embodiment 2
The present invention is used
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-amino acid (
3a-3h) obtain through following method:
With 3-carboxyl-2,2,5,5-tetramethyl-pyrroles-NO free radical (compound 5,9.2g, 0.05mol) and triethylamine (5.05g 0.05mol) is dissolved in the 100mL anhydrous diethyl ether, under agitation mixture is cooled to 0 ℃.(5.42g 0.05mol), at room temperature stirs 3h with mixture after dropwising, and filters, and the evaporate to dryness of will filtrating is used the sherwood oil recrystallization, gets the glassy yellow needle-like crystal slowly to drip Vinyl chloroformate
6, productive rate 90%.With the gained compound
6(10.25g, (3.88g is in 75mL acetone 0.06mol) and the mixing solutions of water 0.04mol) to join the sodiumazide that is dissolved with of stirring immediately; Under ice bath, stir 30min; Use n-hexane extraction then, extraction liquid is used anhydrous sodium sulfate drying, removal of solvent under reduced pressure; Debris is cooled to-20 ℃, gets yellow crystals
7, productive rate 93%.With the above-mentioned triazo-compound that is prepared into
7(2.09g 0.01mol) is dissolved in the 20mL diox, it is joined be dissolved with in the 0.01mol amino acid and the magnesian 10mL aqueous solution of 0.8g; Temperature is controlled under 40 ℃; Stir 24h, also use anhydrous sodium sulfate drying with chloroform extraction then, steaming desolventizes purifying and obtains
N-(1-oxygen base-2,2,5,5-tetramethyl-pyrroles-acid amides)-
L-amino acid (
3a-3h), productive rate: 50 ~ 60%.Method therefor referring to literature method (Hideg, K. et al,
Synthesis,
1978, 914-916).
Its reaction is referring to following formula (reaction formula 2)
Reaction formula 2
R in its reaction formula is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl.
Best preparation method of the present invention is dissolved in 5-hydroxyethyl oxygen NSC 94600 1mmol in the 20mL methylene dichloride, adds 1mmol's
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-amino-acid compound, under nitrogen protection with
N, N-lutidine is as catalyzer, and the NSC 57182 (DCC) that adds equivalent is dewatering agent, is reflected at room temperature condition and carries out.
The embodiment of the invention below is provided
Embodiment 3
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-Glycocoll] camptothecin ester (
4a) synthetic
With 3-carboxyl-2,2,5,5-tetramethyl-pyrroles-NO free radical
(compound 5)(9.2g, 0.05mol) and triethylamine (5.05g 0.05mol) is dissolved in the 100mL anhydrous diethyl ether, under agitation mixture is cooled to 0 ℃.(5.42g 0.05mol), at room temperature stirs 3h with mixture after dropwising, and filters, and the evaporate to dryness of will filtrating is used the sherwood oil recrystallization, gets slowly to drip Vinyl chloroformate
Compound 6, forThe glassy yellow needle-like crystal, 11.6g, productive rate 90%, fusing point: 63-65 ℃.
With compound
6(10.25g, (3.88g is in 75mL acetone 0.06mol) and the mixing solutions of water 0.04mol) to join the sodiumazide that is dissolved with of stirring immediately; Under ice bath, stir 30min; Use n-hexane extraction then, extraction liquid is used anhydrous sodium sulfate drying, removal of solvent under reduced pressure; Debris is cooled to-20 ℃, gets compound
7, forYellow crystals, 7.8g, productive rate 93%, fusing point: 62-63 ℃.
With the above-mentioned compound that is prepared into 7 (2.09g; 0.01mol) be dissolved in the 20mL diox; It is joined be dissolved with in the 0.01mol amino acid and the magnesian 10mL aqueous solution of 0.8g, temperature is controlled under 40 ℃, stirs 24h; Also use anhydrous sodium sulfate drying with chloroform extraction then, steaming desolventizes purifying and obtains
N-(1-oxygen base-2,2,5,5-tetramethyl-pyrroles-acid amides)-
L-amino acid (compound 3a-3h), productive rate: 50 ~ 60%.This reactions step is with reference to Hideg, K. et al,
Synthesis,
1978, 914-916 institute reported method.
The used intermediate feed 5-hydroxyethyl of the present invention oxygen NSC 94600 is to be that raw material is at FeCl by NSC 94600
3/ H
2SO
4/ OHCH
2CH
2The OH reaction system obtains, and its method therefor is referring to (Subrahmanyam, D. et al, US6177439 (2001).
With 1mmol 5-hydroxyethyl oxygen NSC 94600 and 1mmol
N-(1-oxygen base-2,2,5,5-tetramethyl-pyrroles-acid amides)-
L-glycocoll is dissolved in the 20mL exsiccant methylene dichloride, adds 0.1 gram N of catalytic amount, the N-lutidine; Under nitrogen protection, stirred 5 minutes, add 0.21 gram NSC 57182 (DCC) then, stirring reaction is 2 hours under nitrogen protection; Remove by filter white precipitate, remove solvent under reduced pressure after, crude product is through column chromatography purification; Using volume ratio is 40: 1 chloroform-methanol wash-out, 5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-glycocoll] camptothecin ester (compound 4a).
The detection data of product (compound 4a) are following:
Productive rate: 90%; M.p. 115-117; IR (KBr) υ cm
-1: 3346 (NH), 1715 (NHCO), 3062,1626,1490 (ArH), 1662 (C=O), 1242,1155,1090 (C-O), 1364 (NO
. ); MS (EI) m/z: 632 (M+1); HRMS C
33H
35N
4O
9: theoretical value (M+H): 632.2477, measured value: 632.2481; ESR:g
0=2.0055, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
?
Embodiment 4
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-L-Ala] camptothecin ester (compound
4b) synthetic:
Experimental procedure and embodiment 1 only replace glycocoll with L-Ala together.The reaction products therefrom is a compound
4b,The detection data are following:
Productive rate: 86%; M.p. 120-122 ℃; IR (KBr) υ cm
-1: 3429 (NH), 1743 (NHCO), 3056,1624,1552 (ArH), 1662 (C=O), 1087,1156,1231 (C-O), 1362 (NO
. ); MS (EI) m/z: 646 (M+1); HRMS C
34H
37N
4O
9: theoretical value (M+H): 646.2633, measured value: 646.2625; ESR:g
0=2.0058, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
?
Embodiment 5
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-Methionine(Met)] camptothecin ester (compound
4c) synthetic
Experimental procedure and embodiment 1 only replace the glycocoll of embodiment 1 together with methionine(Met).Reaction products therefrom (compound
4c) to detect data following:
Productive rate: 82%; M.p. 155-157; IR (KBr) υ cm
-1: 3423 (NH), 1711 (NHCO), 3060,1625,1563 (ArH), 1663 (C=O), 1088,1153,1236 (C-O), 1362 (NO
. ); MS (EI) m/z: 706 (M+1); HRMS C
36H
41N
4O
9S: theoretical value (M+H): 706.2267, measured value: 706.2656; ESR:g
0=2.0055, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
?
Embodiment 6
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-Isoleucine] camptothecin ester (compound 4d) synthetic
Experimental procedure and embodiment 1 only replace the glycocoll of embodiment 1 together with Isoleucine.It is following that reaction products therefrom (compound 4d) detects data:
Productive rate: 75%; M.p. 160-162; IR (KBr) υ cm
-1: 3423 (NH), 1746 (NHCO), 3091,1621,1562 (ArH), 1664 (C=O), 1114,1155,1228 (C-O), 1359 (NO
. ); MS (EI) m/z: 688 (M+1); HRMS C
37H
43N
4O
9: theoretical value (M+H): 688.3103, measured value: 688.3098; ESR:g
0=2.0055, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
?
Embodiment 7
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-Phenylalanine(Phe)] camptothecin ester (compound
4e) synthetic
Experimental procedure and embodiment 1 only replace the glycocoll of embodiment 1 together with phenylalanine(Phe).Reaction products therefrom (compound
4e) to detect data following:
Productive rate: 87%; 142-144 ℃; IR (KBr) υ cm
-1: 3425 (NH), 1744 (NHCO), 3093,1623,1564 (ArH), 1664 (C=O), 1113,1153,1234 (C-O), 1361 (NO
. ); MS (EI) m/z: 722 (M+1); HRMS C
40H
41N
4O
9: theoretical value (M+H): 722.2946, measured value: 722.2944; ESR:g
0=2.0055, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
?
Embodiment 8
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-Leucine] camptothecin ester (compound
4f) synthetic
Experimental procedure and embodiment 1 with, only with the glycocoll of leucine in place embodiment 1.Reaction products therefrom (compound
4f) to detect data following:
Productive rate: 68%; M.p.117-119; IR (KBr) υ cm
-1: 3418 (NH), 1747 (NHCO), 3065,1621,1562 (ArH), 1664 (C=O), 1114,1157,1227 (C-O), 1359 (NO
. ); MS (EI) m/z: 688 (M+1); HRMS C
37H
43N
4O
9: theoretical value (M+H): 688.3103, measured value: 688.3110; ESR:g
0=2.0055, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
?
Embodiment 9
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-Xie Ansuan] camptothecin ester (compound
4g) synthetic
Experimental procedure and embodiment 1 only replace the glycocoll of embodiment 1 together with Xie Ansuan.Reaction products therefrom (compound
4g) to detect data following:
Productive rate: 76%; M.p.120-122; IR (KBr) υ cm
-1: 3416 (NH), 1750 (NHCO), 3092,1620,1538 (ArH), 1665 (C=O), 1106,1157,1231 (C-O), 1359 (NO
. ); MS (EI) m/z: 674 (M+1); HRMS C
36H
41N
4O
9 :Theoretical value (M+H): 674.2946, measured value: 674.2956; ESR:g
0=2.0055, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
?
Embodiment 10
5-O-second hydroxyl-[
N-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'-
L-Tryptophane] camptothecin ester (compound
4h) synthetic
Experimental procedure and embodiment 1 only replace the glycocoll of embodiment 1 together with tryptophane.Reaction products therefrom (compound
4h) to detect data following:
Productive rate: 54%; M.p.127-129; IR (KBr) υ cm
-1: 3413 (NH), 1745 (NHCO), 3061,1619,1522 (ArH), 1663 (C=O), 1086,1158,1229 (C-O), 1356 (NO
. ); MS (EI) m/z: 761 (M+1); HRMS C
42H
42N
5O
9 :Theoretical value (M+H): 761.3055, measured value: 761.3040; ESR:g
0=2.0055, A
N=14.62Gs (triplet peak in 1 * 10
-4M, DMF).
Embodiment 11
Camptothecine compounds 4a-4h is active to the inhibition of phytopathogen
Supply the examination bacterial classification:Mango blossom-end rot bacterium
Botryodiplodia theobromaePat., mango anthracnose bacterium
Colletotrichum gloeosporioidesPenz, Glorosprium musarum Cookeet Mass
Colletotrichum musae(Berk. et Curt.) Arx provides by Research Institute of Environment and Plant Protection, Chinese Academy of Tropi.
Supply the reagent agent:Medicine is a compound
4a-4h(according to embodiment 1 preparation), NSC 94600 and 5-hydroxyethyl oxygen NSC 94600 are as reference substance.
TP: test employing growth rate method (Mu Liyi. the chemical protection of plant research method. Chinese agriculture press. 1987:79-81).Concrete operations are following:
1. bacterial classification is prepared: in petridish, pour 10mL PDA substratum (or the capsicum epidemic disease is used the Radix Dauci Sativae substratum) into; Under the aseptic condition, get a mycelia piece, be placed in the middle of the petridish from supplying examination germ inclined-plane; The cultured continuously several generations; Test inoculating once in preceding 3 days, the darkroom is cultivated subsequent usely under the thermophilic, guarantees the vigor of bacterial classification.
2. supply reagent liquid: the acetone that test compound is dissolved in, the acetone soln that is mixed with 1 mg/mL supplies examination.
3. make the bacterium cake: under the aseptic condition, it is subsequent use to supply the examination bacterial classification to get an amount of bacterium cake with the 0.4cm punch tool.
4. with the preparation of medicine substratum: after will supplying reagent liquid to be diluted to a series of gradient concentrations, prepare to draw a certain amount of (1mL) soup and inject correspondence markings tool plug scale test tube, pour the PDA or other substratum (9mL) that dissolve again while hot into; (this moment liquor strength diluted 10 times and do not influence solidifying of substratum), firmly shake up rapidly, pour into immediately in the correspondence markings petridish; It is evenly dull and stereotyped to process thin and thick; Three repetitions are done in each processing, and contrast is established two types, respectively pour in three petridish with pure culture base 10mL for one type and connect bacterium; Observe after three days, only for referencial use; Another kind ofly add the 9ml substratum with 1mL acetone and respectively pour in three petridish, connect three days inspection statisticses behind the bacterium.
5. will supply examination bacterium cake to place on the plate culture medium carefully with inoculating needle, mycelia faces down, three or one in every ware, and the equidistance central authorities that are put in triangular in shape add a cover mark again, put darkroom cultivation under the thermophilic.
6. result's inspection: cultivate in the dark after 72 hours (or being determined on a case-by-case basis), take out, use the kind of calliper colony diameter, two secondary data MVs are got in right-angled intersection.Notice that above-mentioned sequence of operations must be carried out under the Strict aseptic condition.
Colony growth diameter (mm)=twice diameter MV-4.0 (bacterium cake diameter)
Table 1 embodiment camptothecine compounds is at the bacteriostatic activity of 50mg/L to 3 kinds of germs
Annotate: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, NSC 94600-compound 1.
Conclusion: can know that by table 1 camptothecine compounds has good inhibitory effect to mango blossom-end rot bacterium, mango anthracnose bacterium, Glorosprium musarum Cookeet Mass, especially comparatively obvious to mango blossom-end rot bacterium restraining effect.
?
Embodiment 12
The insecticidal activity of camptothecine compounds 4a-4h
Supply the examination insect:Prodenia litura 4 instar larvaes, be from Chinese Academy of Tropical Agricultural Sciences's environment and plant protection institute test base not the Folium Ricini of dispenser adopt back, breed many generations at indoor feeding, during test the individual size of picking, solid colour 4 mid-terms in age larva supply examination.Brontispa longissima 5 instar larvaes are that coconut palm is adopted back from Danzhou, Hainan, breed many generations at indoor feeding, the larva confession examination in 5 mid-terms in age of the individual size of picking, solid colour during test.
Supply the reagent agent:Medicine is a compound
4a-4h(according to embodiment 1 preparation), NSC 94600 and 5-hydroxyethyl NSC 94600 are as reference substance.
Prodenia litura gives birth to the survey method:Test employing leaf dipping method (Mu Liyi. the chemical protection of plant research method. Chinese agriculture press. 1987:56).Earlier above sample is settled to 2 mg/mL with acetone, tests with 1 mg/mL as screening concentration.Folium Ricini put into respectively respectively supply to take out behind reagent liquid dipping 3 s, put on the thieving paper and dry, then individuality prodenia litura 4 instar larvaes of the same size are put into the petridish of handling blade is housed, be covered with filter paper at the bottom of the petridish and preserve moisture.Place incubator (T:25 ± 1 ℃, RH=70～80%) to cultivate in petridish.Compare with acetone, every concentration repeats 3 times, every repetition 10 cephalonts.The examination worm changes hello normal blade after feeding and being with malicious blade 2 d, and quantitative check examination worm is got food and death condition, touches polypide with writing brush, is regarded as death with complete motionless person.Add up dead borer population respectively at 3 d, 6 d and 9 d, calculate mortality ratio and corrected mortality, its test result is seen table 2
Table 2 embodiment camptothecine compounds at 1 mg/mL to cytotoxicity to Spodoptera litura larvae
Annotate: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, NSC 94600-compound 1.
?
Brontispa longissima is given birth to the survey method:Test employing leaf dipping method (Mu Liyi. the chemical protection of plant research method. Chinese agriculture press. 1987:56).Earlier above sample is settled to 1 mg/mL with acetone, tests with 0.1 mg/mL as screening concentration.The coconut leaf put into respectively respectively supply to take out behind reagent liquid dipping 3 s, put on the thieving paper and dry, then individuality Brontispa longissima larva of the same size is put into the petridish of handling blade is housed, be covered with filter paper at the bottom of the petridish and preserve moisture.Place incubator (T:25 ± 1 ℃, RH=70～80%) to cultivate in petridish.Compare with acetone, every concentration repeats 3 times, every repetition 10 cephalonts.The examination worm changes hello normal blade after feeding and being with malicious blade 2 d, and quantitative check examination worm death condition is touched polypide with writing brush, is regarded as death with complete motionless person.Add up dead borer population respectively at 3 d, 6 d and 9 d, calculate mortality ratio and corrected mortality, its test result is seen table 3.
Table 3 embodiment camptothecine compounds is at the cytotoxicity of 0.1 mg/mL to Brontispa longissima 5 instar larvaes
Annotate: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, NSC 94600-compound 1.
Conclusion: can know that by table 2 and table 3 camptothecine compounds all has cytotoxicity in various degree to Brontispa longissima, prodenia litura, wherein part of compounds has significant cytotoxicity to these two types examination worms.
?
Embodiment 13
The weeding activity of camptothecine compounds 4a-4h
Supply the examination weeds:Leaf mustard
Brassica juncea(purchasing seeds company), three-coloured amaranth in the Danzhou City
Amaranthus mangostanusL. (purchase seeds company) in the Danzhou City, lady's-grass
Digitaria sanguinalis(L.) Scop. (pick up from ring and plant the institute test base).All seeds are through measuring, and seed nature germination rate is all more than 95%.
Supply the reagent agent:Medicine is a compound
4a-4h(according to embodiment 1 preparation), NSC 94600 and 5-hydroxyethyl NSC 94600 are as reference substance.
TP: with reference to agricultural chemicals indoor bioassay test rule (the People's Republic of China's agricultural industry criteria. agricultural chemicals indoor bioassay test rule. weedicide); Compound is mixed with the acetone soln that mass concentration is 1000 mg/L; Draw the 1mL soup and add and be covered with in the 90mm petridish of filter paper, treat that the acetone volatilization is done after, add the 2 mL0.1% tween-80 aqueous solution; Dilution obtains the aqueous solution of 500 mg/L (0.5mg/mL); 10 in the seed that will just sprout then fitly is arranged in the petridish, builds preservative film, and every processing repeats for 3 times; Being placed on then and cultivating (28 ℃ ± 2 ℃ of daytimes, 24 ℃ ± 2 ℃ of evenings, relative humidity 75% ± 5%) in the growth cabinet, is blank with the 0.1% tween-80 aqueous solution.Root length and the bud of measuring lady's-grass behind the 3-6 d respectively are long, and the long and plumular axis length of the root of leaf mustard and three-coloured amaranth is calculated weeding activity by following formula, and its result sees table 4.
Inhibiting rate (%)=
Table 4 embodiment camptothecine compounds is at the weeding activity of 0.5 mg/mL
Annotate: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, NSC 94600-compound 1.
Conclusion: can know that by table 4 camptothecine compounds all has weeding activity in various degree to 3 kinds of farmland weeds.。
Claims (9)
1. camptothecine compounds and preparation method thereof and the purposes in agricultural chemicals is characterized in that its chemical general formula is the compounds shown in (I) formula:
（I）
Wherein R is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl in (I) formula.
2. camptothecine compounds and preparation method thereof and the purposes in agricultural chemicals is characterized in that 5-hydroxyethyl oxygen NSC 94600 and N-(1-oxygen base-2,2; 6,6-tetramethyl piperidine-oxygen-carbonyl)-L-amino acid is dissolved in the exsiccant methylene dichloride, under nitrogen protection, stirs; Add NSC 57182 (DCC) then, stirring reaction under nitrogen protection refilters after question response is accomplished and removes white precipitate; After removing solvent under reduced pressure; Crude product uses the chloroform-methanol wash-out of volume ratio as 40:1 through column chromatography purification, gets series product 4a-4h.
3. according to claim 1 and 2 described a kind of camptothecine compounds and preparation method thereof and the purposes in agricultural chemicals, it is characterized in that 5-hydroxyethyl oxygen NSC 94600 1mmol is dissolved in the 50mL methylene dichloride, add N-(the 1-oxygen base-2 of 1mmol; 2,6,6-tetramethyl piperidine-oxygen-carbonyl)-the L-amino-acid compound; Under nitrogen protection with N; The N-lutidine is as catalyzer, and the NSC 57182 (DCC) that adds equivalent is dewatering agent, is reflected at room temperature condition and carries out.
4. a kind of camptothecine compounds according to claim 1 and preparation method thereof and the purposes in agricultural chemicals is characterized in that it can use in the agricultural chemicals of preparation control fungal diseases of plants.
5. a kind of camptothecine compounds according to claim 4 and preparation method thereof and the purposes in agricultural chemicals is characterized in that said fungal diseases of plants is mango anthracnose bacterium, mango blossom-end rot bacterium and Glorosprium musarum Cookeet Mass.
6. a kind of camptothecine compounds according to claim 1 and preparation method thereof and the purposes in agricultural chemicals is characterized in that it can use in the agricultural chemicals of preparation control Agricultural pests.
7. a kind of camptothecine compounds according to claim 6 and preparation method thereof and the purposes in agricultural chemicals is characterized in that said Agricultural pests are Brontispa longissima, prodenia litura.
8. a kind of camptothecine compounds according to claim 1 and preparation method thereof and the purposes in agricultural chemicals is characterized in that it can use in the agricultural chemicals of preparation control farmland weed.
9. a kind of camptothecine compounds according to claim 8 and preparation method thereof and the purposes in agricultural chemicals is characterized in that said farmland weed is lady's-grass, leaf mustard and three-coloured amaranth.
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| CN102670820A (en) * | 2012-05-29 | 2012-09-19 | 浙江农林大学 | Camptothecin-containing external bacteriostatic medicine and preparation method and application thereof |
| CN103275094A (en) * | 2013-05-08 | 2013-09-04 | 中国农业科学院植物保护研究所 | (20S)-camptothecin derivatives and application thereof |
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| CN104725390A (en) * | 2013-12-20 | 2015-06-24 | 兰州大学 | Camptothecin compound, and preparation method and application thereof |
| CN105295016A (en) * | 2014-07-16 | 2016-02-03 | 兰州大学 | Pesticide for killing agricultural pests as well as preparation method and application of pesticide |
| CN105767018A (en) * | 2016-04-29 | 2016-07-20 | 山东胜伟园林科技有限公司 | Microbial pesticide for orange pest and disease control and preparation method thereof |
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| CN104725390A (en) * | 2013-12-20 | 2015-06-24 | 兰州大学 | Camptothecin compound, and preparation method and application thereof |
| CN104725390B (en) * | 2013-12-20 | 2017-04-05 | 兰州大学 | A kind of camptothecine compounds and preparation method thereof and the purposes in pesticide |
| CN105295016A (en) * | 2014-07-16 | 2016-02-03 | 兰州大学 | Pesticide for killing agricultural pests as well as preparation method and application of pesticide |
| CN104387401A (en) * | 2014-11-28 | 2015-03-04 | 中国农业科学院植物保护研究所 | Camptothecin derivative and preparation method thereof |
| CN105767018A (en) * | 2016-04-29 | 2016-07-20 | 山东胜伟园林科技有限公司 | Microbial pesticide for orange pest and disease control and preparation method thereof |
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