istván ujváry chemical research center hungarian academy of sciences budapest, hungary chemical...
TRANSCRIPT
István UjváryIstván UjváryChemical Research Center
Hungarian Academy of SciencesBudapest, Hungary
Chemical Research CenterHungarian Academy of Sciences
Budapest, Hungary
THE IMPORTANCE OF NATURAL PRODUCTS
IN INSECT CONTROL
THE IMPORTANCE OF NATURAL PRODUCTS
IN INSECT CONTROL
IVth International Conference on ArthopodsChemical, Physiological & Environmental Aspects
Białka Tatrzańska, Poland, September 18 - 23, 2005
IVth International Conference on ArthopodsChemical, Physiological & Environmental Aspects
Białka Tatrzańska, Poland, September 18 - 23, 2005
World Pesticide MarketWorld Pesticide Market -- 20042004
HerbicidesHerbicidesHerbicidesHerbicides
45.4%45.4%
OthersOthersOthersOthers
5.4%5.4%FungicidesFungicidesFungicidesFungicides
InsecticidesInsecticidesInsecticidesInsecticides
27.5%27.5%
21.7%21.7%
PesticidePesticide Sales: 32,665 Million USD
~420 Million USD~420 Million USD
~1,3%~1,3%Biopesticides:Biopesticides:Biopesticides:Biopesticides:
Natural products??Natural products??Natural products??Natural products??
~4,700 Million USD~4,700 Million USD
~15%~15%BiotechBiotech // GM crops:GM crops:BiotechBiotech // GM crops:GM crops:
Sources of Pest Control AgentsSources of Pest Control Agents
Semi-syntheticSemi-synthetic SyntheticSynthetic
InorganicInorganic
NaturalNatural
OrganicOrganicBotanicalBotanical
MicrobialMicrobialAnimalAnimal
MarineMarineMarineMarine
OF HUMAN ORIGINOF HUMAN ORIGINOF HUMAN ORIGINOF HUMAN ORIGIN ????
Why Natural Products?Why Natural Products?
For historical reasons: have been For historical reasons: have been used for milenniaused for milennia
Proven Proven ““track recordtrack record””: : evolved to bind biomacromoleculesevolved to bind biomacromolecules
AbundantAbundant && renewablerenewable
Unique structure (Unique structure (diversity!diversity!))
As template exploitable for As template exploitable for biobiochemical modificationschemical modifications
Environmentally acceptableEnvironmentally acceptable // degradabledegradable
etc.etc.
Synthetics Synthetics versusversus Natural Products Natural Products
Natural products tend to haveNatural products tend to have
larger molecular masslarger molecular mass
more more OO atoms atoms ((e.g.e.g., ring-connected alcohol, ether or ester), ring-connected alcohol, ether or ester)
less less NN atoms atoms (except alkaloids)(except alkaloids)
less less halogenshalogens
larger polar surfaceslarger polar surfaces
less aromatic systems, but more non-aromatic C=C bondsless aromatic systems, but more non-aromatic C=C bonds
more more spsp33-bridgehead C atoms-bridgehead C atoms
more chiral centersmore chiral centers
unique scaffoldunique scaffold
larger molecular masslarger molecular mass
more more OO atoms atoms ((e.g.e.g., ring-connected alcohol, ether or ester), ring-connected alcohol, ether or ester)
less less NN atoms atoms (except alkaloids)(except alkaloids)
less less halogenshalogens
larger polar surfaceslarger polar surfaces
less aromatic systems, but more non-aromatic C=C bondsless aromatic systems, but more non-aromatic C=C bonds
more more spsp33-bridgehead C atoms-bridgehead C atoms
more chiral centersmore chiral centers
unique scaffoldunique scaffold
Production of Natural ProductsProduction of Natural Products
Use of the living or killed organism Use of the living or killed organism ((or part of itor part of it)) directly directly
Extract: crude or enrichedExtract: crude or enriched
Fermentation (microbials!)Fermentation (microbials!)
Plant tissue & cell culturePlant tissue & cell culture
Use of the living or killed organism Use of the living or killed organism ((or part of itor part of it)) directly directly
Extract: crude or enrichedExtract: crude or enriched
Fermentation (microbials!)Fermentation (microbials!)
Plant tissue & cell culturePlant tissue & cell culture
ConventionalConventional breedingbreeding – MutationMutation – GeneticallyGenetically modifiedmodified organismsorganisms
or or DirectedDirected biosynthesisbiosynthesis
Chemical synthesisChemical synthesis Chemical synthesisChemical synthesis
PROBLEMS:PROBLEMS:
Low yields, impurities, need of large amounts of natural resourcesLow yields, impurities, need of large amounts of natural resourcesLow yields, impurities, need of large amounts of natural resourcesLow yields, impurities, need of large amounts of natural resources
SOLUTIONS:SOLUTIONS:
Natural productsNatural product analoguesOther organics ('synthetics')Inorganics
Natural productsNatural product analoguesOther organics ('synthetics')Inorganics
Chemical Origin of Insect Control AgentsChemical Origin of Insect Control Agents
276276276276
organophosphatesorganophosphates carbamatescarbamates organohalogensorganohalogens acylureas, acylureas, etc.etc.
organophosphatesorganophosphates carbamatescarbamates organohalogensorganohalogens acylureas, acylureas, etc.etc.
HCN, PHHCN, PH33HCN, PHHCN, PH33
pyrethrinspyrethrins nicotinenicotine avermectinsavermectins spinosadspinosad pheromones, etcpheromones, etc
pyrethrinspyrethrins nicotinenicotine avermectinsavermectins spinosadspinosad pheromones, etcpheromones, etc
pyrethroidspyrethroids neonicotinoidsneonicotinoidsjuvenoidsjuvenoids
pyrethroidspyrethroids neonicotinoidsneonicotinoidsjuvenoidsjuvenoids
Ujváry I: Phytoparasitica 30, 439 (2002)Ujváry I: Phytoparasitica 30, 439 (2002)
Based on: Based on: The Pesticide ManualThe Pesticide Manual and and The BioPesticide ManualThe BioPesticide Manual
azadirachtinazadirachtin
O
O
O
OH
H
OO
AcO
O
OH
OH
O
H
CO2Me
MeO2C
O
O
O
OH
H
OO
AcO
O
OH
OH
O
H
CO2Me
MeO2C
Selected Botanical InsecticidesSelected Botanical Insecticides
N
OH
OH
OH
OH
OH
OO
OH
H H
H
HR
N
OH
OH
OH
OH
OH
OO
OH
H H
H
HR
sabadillasabadilla
3
22
23
ryanodineryanodine
219
R = pyrrole-2-CO2HR = pyrrole-2-CO2H
OHOH OH
OH
ORO
OH
OH
H
OHOH OH
OH
ORO
OH
OH
H
Major bioactive components of multicomponent mixturesMajor bioactive components of multicomponent mixtures
OO
O
HOO
O
H
pyrethrin Ipyrethrin I
Ujváry I: In Handbook of Pesticide Toxicology (Krieger RI, ed.) Academic Press, p. 109 (2001)Ujváry I: In Handbook of Pesticide Toxicology (Krieger RI, ed.) Academic Press, p. 109 (2001)
POH
O O
NH2
OH
POH
O O
NH2
OH
phosphinothricinphosphinothricin
Nicotine and Selected Neonicotinoid InsecticidesNicotine and Selected Neonicotinoid Insecticides
nithiazinenithiazinenithiazinenithiazinenicotinenicotinenicotinenicotine
NH S
NO2
NH S
NO2
imidaclopridimidacloprid
ONH
N
NH
NO2
MeO
NH
N
NH
NO2
Me
dinotefurandinotefuran
S
N N N
O
NNO2
Me
ClS
N N N
O
NNO2
Me
Cl
acetamipridacetamiprid
1979197919911991
1997199719981998
N
NMe
N
NMe
18931893
NCl
N NH
NNO2
NCl
N NH
NNO2
thiamethoxamthiamethoxam
N
NCl
Me
N Me
CN
N
NCl
Me
N Me
CN
19921992
Avermectin-Type Insecticides & ParasiticidesAvermectin-Type Insecticides & Parasiticides
Avermectin BAvermectin B1a-b1a-b RR == secsec-Bu-Bu // isoiso-Pr, -Pr, XX–YY == CH CH=CHCH (abamectin)(abamectin)
Ivermectin B Ivermectin B RR == secsec-Bu-Bu // isoiso-Pr, -Pr, XX–YY == CH CH22–CHCH22
O
YX
O
O
R
O
O
OH
HOH
OO
O
OOH
OMe
MeO
O
YX
O
O
R
O
O
OH
HOH
OO
O
OOH
OMe
MeO
EmamectinEmamectinEmamectinEmamectinNH
Me
EprinomectinEprinomectinEprinomectinEprinomectinNH
Ac
4’’4’’
2223
25
5
Selamectin Selamectin RR = cyclohexyl= cyclohexyl directed biosynthesis!directed biosynthesis!
XX–YY == CH CH22–CHCH22
Selamectin Selamectin RR = cyclohexyl= cyclohexyl directed biosynthesis!directed biosynthesis!
XX–YY == CH CH22–CHCH22
NOH
55
produced by:produced by: Streptomyces avermitilisStreptomyces avermitilisproduced by:produced by: Streptomyces avermitilisStreptomyces avermitilis
semisyntheticsemisynthetic !!semisyntheticsemisynthetic !!
*Complete genome sequence: Ikeda H et al.: Nature Biotechnology 21, 526 (2003)*Complete genome sequence: Ikeda H et al.: Nature Biotechnology 21, 526 (2003)
*
Spinosyn InsecticidesSpinosyn Insecticides
Spinosad: spinosyn A / DSpinosad: spinosyn A / D RR = H / MeRR = H / Me
produced by:produced by: Saccharopolyspora spinosaSaccharopolyspora spinosaproduced by:produced by: Saccharopolyspora spinosaSaccharopolyspora spinosa
2’
O
O
O
OO
H
H
H
H
H
R
OOMe
OMe
OMe
O
Me2N
O
O
O
OO
H
H
H
H
H
R
OOMe
OMe
OMe
O
Me2N
analogues using chemistry andanalogues using chemistry and // or combinatorial biosynthesisor combinatorial biosynthesis““unnatural natural productsunnatural natural products””
analogues using chemistry andanalogues using chemistry and // or combinatorial biosynthesisor combinatorial biosynthesis““unnatural natural productsunnatural natural products””
17
9
NH O O
H
Cl
Cl
Cl
Cl
NO2
NH O O
H
Cl
Cl
Cl
Cl
NO2
dioxapyrrolomycindioxapyrrolomycin
OH
NH
OH
NH
nomininenominine
N+
MeOCONH
OH
CF3O
OCF3
O
N+
MeOCONH
OH
CF3O
OCF3
O
F4265 (benzhydrolpiperidine)F4265 (benzhydrolpiperidine)
Selected Microbial Insecticides & AnaloguesSelected Microbial Insecticides & Analogues
N
CNBr
F3C
O
ClN
CNBr
F3C
O
Cl
chlorfenapyrchlorfenapyr
ffromrom StreptomycesStreptomycesffromrom StreptomycesStreptomyces
from from AspergillusAspergillusfrom from AspergillusAspergillus
Analogues of Stemona AlkaloidsAnalogues of Stemona Alkaloids
N
O
O
O
O
n-Bu
OMe
N
O
O
O
O
n-Bu
OMe
stemofolinestemofoline cyanotropanecyanotropane
N
CF3
N
CN
Cl
N
CF3
N
CN
Cl
NN
Lind RJ et al.: BCPC Conference - Pests & Diseases, 145 (2002)Lind RJ et al.: BCPC Conference - Pests & Diseases, 145 (2002)
Dr.Dr. Shen’s Shen’s No More No More Lice SoakLice Soak
Dr.Dr. Shen’s Shen’s No More No More Lice SoakLice Soak
Stemona collinsae
Bacillus thuringiensis var. israelensis (Bti) -endotoxin
Trypsin modulating oostatic factor Aea-TMOF (H-YDPAPPPPPP-OH)
Proctolin (H-RYLPT-OH)
Pheromone Biosynthesis Activating Neurohormone - Hel-PBAN (H-YFSPRL-NH2)
From insects:From insects:
From microorganisms:From microorganisms:
Photorhabdus luminescens
Cyt2AaCyt2Aa
Peptides as Insect Control AgentsPeptides as Insect Control Agents??
toxin A
Non-Steroidal Ecdysteroid Hormone “Analogues”Non-Steroidal Ecdysteroid Hormone “Analogues”The past… (serendipity)The past… (serendipity)
O
NH
NO
O
NH
NO
20-OH-ecdysone20-OH-ecdysone
tebufenozidetebufenozide
chromafenozidechromafenozide
O
NH
NO
O
O
NH
NO
O
OH
OHH
O
OH
OH OH
OHOH
OHH
O
OH
OH OH
OH
20202020
BB ee ss tt ff ii tt -- ww rr oo nn gg hh ii tt ??BB ee ss tt ff ii tt -- ww rr oo nn gg hh ii tt ??Maximizing overlapMaximizing overlapMaximizing overlapMaximizing overlap
(1954)(1954)
(from 1986)(from 1986)
X-Ray Structure of X-Ray Structure of Heliothis virescensHeliothis virescens Ecdysone ReceptorEcdysone Receptor ++ Ponasterone APonasterone A
Billas I.M.L. Billas I.M.L. et al.et al.: : NatureNature 426426, 91 (2003), 91 (2003)
heterodimerheterodimerheterodimerheterodimer
USPUSPUSPUSP
EcREcREcREcR
Ponasterone APonasterone A
OH OH
H
O
OH
OH
OH
Ecdysteroid Hormone Analogues.Ecdysteroid Hormone Analogues.The future: Computer-Aided Molecular Design ?The future: Computer-Aided Molecular Design ?
ponasterone Aponasterone A
BYIBYI 0683006830
Billas I Billas I et al.et al.: : NatureNature 426426, 91 (2003), 91 (2003)
OH
OHH
O
OH
OH
OH
OH
OHH
O
OH
OH
OH
overlay of ligands overlay of ligands from X-ray structures:from X-ray structures:
Botanicals or Botanicals or SemiSemi-Natural Products?-Natural Products?Botanicals or Botanicals or SemiSemi-Natural Products?-Natural Products? Semi-natural productSemi-natural product:: a man-made substance (re)isolated from natural sources.a man-made substance (re)isolated from natural sources.
fenvalerate in fenvalerate in MushigieMushigie
O
CNO
Cl
O
O
CNO
Cl
O
O
CNO
O
Cl
Cl
O
CNO
O
Cl
Cl
cypermethrin in cypermethrin in MusikoroMusikoro
S
P
S
S(EtO)2
S
P
S
S(EtO)2
terbufos from terbufos from Paeonia suffruticosaPaeonia suffruticosa ??
terbufos from terbufos from Paeonia suffruticosaPaeonia suffruticosa ??
O
ONH
O
OEt
O
ONH
O
OEt
fenoxycarb on fenoxycarb on mulberry treesmulberry trees ??fenoxycarb on fenoxycarb on
mulberry treesmulberry trees ??
Ujváry I: Pest Manag Sci 56, 703 (2000)Ujváry I: Pest Manag Sci 56, 703 (2000)
All is not gold that glitters! All is not gold that glitters! All is not gold that glitters! All is not gold that glitters!
Natural productsNatural products
Semi-syntheticsSemi-synthetics
SyntheticsSynthetics
Environmental Cycle of ChemicalsEnvironmental Cycle of Chemicals
Semi-naturalSemi-naturalproductsproductsBiochemistryBiochemistry
ChemistryChemistry
GeneticsGenetics
Agricultural biologyAgricultural biology
Crossword puzzle questionCrossword puzzle questionCrossword puzzle questionCrossword puzzle question
What is a nine-letter word forWhat is a nine-letter word for ““biotechnologybiotechnology”” ??
CC HH EE MM II SS TT RR YY
from a Sidney Harris cartoonfrom a Sidney Harris cartoon
1
Global Area of Transgenic Crops by TraitGlobal Area of Transgenic Crops by Trait19961996 -- 20042004
James C: James C: Global Status of Commercialized Biotech/GM Crops: 2004Global Status of Commercialized Biotech/GM Crops: 2004 . ISAAA (2004). ISAAA (2004)
million hamillion ha
In 2004,In 2004, 5%5% of the 1.5 billion ha of all global cultivable crop land of the 1.5 billion ha of all global cultivable crop land was occupied by biotech cropswas occupied by biotech crops
InsecticideInsecticide ++ Fagostimulant Semiochemicals: Fagostimulant Semiochemicals: Feeding to Death in a Corn FieldFeeding to Death in a Corn Field ??
InsecticideInsecticide ++ Fagostimulant Semiochemicals: Fagostimulant Semiochemicals: Feeding to Death in a Corn FieldFeeding to Death in a Corn Field ??
CarbarylCarbaryl
O
O
NH
CH3O
O
NH
CH3
Metcalf RL Metcalf RL et al.et al.: : J Econ EntomolJ Econ Entomol 8080, 870 (1987), 870 (1987)
rootworm (rootworm (DiabroticaDiabrotica) species (Coleoptera: Chrysomelidae)) species (Coleoptera: Chrysomelidae)
++
Cucurbitacin ACucurbitacin A
OH
O
O
O
OH
OHH
OAc
HOH
O
O
O
OH
OHH
OAc
H
((e.g., e.g., in buffalo gourd)in buffalo gourd) ((e.g., e.g., in buffalo gourd)in buffalo gourd)SSLAMLAM®®
othersothers: : IINVITENVITE EC EC CCIDETRAKIDETRAK WP WP Parimi S Parimi S et al.et al.: : Crop ProtectionCrop Protection 2222, 781 (2003), 781 (2003)
reduction to <10%reduction to <10%
http://www.biols.susx.ac.uk/Home/Neil_Crickmore/Bthttp://www.biols.susx.ac.uk/Home/Neil_Crickmore/Bt
Dendrogram of Dendrogram of Bacillus thuringiensisBacillus thuringiensis toxins toxins
~150 ~150 BtBt Cry proteins known Cry proteins known~150 ~150 BtBt Cry proteins known Cry proteins known
Selected Natural PGRs Selected Natural PGRs && Herbicides Herbicides
PNH
NH
OH
O O
ONH2
O
OH
PNH
NH
OH
O O
ONH2
O
OH
POH
O O
NH2
OH
POH
O O
NH2
OH
bilanafosbilanafosbilanafosbilanafos phosphinothricinphosphinothricin(SS)-glufosinateglufosinate
phosphinothricinphosphinothricin(SS)-glufosinateglufosinate
From microorganismsFrom microorganismsFrom microorganismsFrom microorganisms
hydrolysishydrolysis
PPROHERBICIDEROHERBICIDE!!PPROHERBICIDEROHERBICIDE!!
From plantsFrom plantsFrom plantsFrom plants
brassinolidebrassinolidebrassinolidebrassinolide
O
O
H
HHH
OH
OH
OH
OH
O
O
H
HHH
OH
OH
OH
OH
CH3(CH2)29OHCH3(CH2)29OH
triacontanoltriacontanoltriacontanoltriacontanol
SSS SSS
-terthienyl-terthienyl-terthienyl-terthienyl
1,8-cineole1,8-cineole1,8-cineole1,8-cineole
OO