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István Ujváry Chemical Research Center Hungarian Academy of Sciences Budapest, Hungary Chemical Research Center Hungarian Academy of Sciences Budapest,

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Presentation on theme: "István Ujváry Chemical Research Center Hungarian Academy of Sciences Budapest, Hungary Chemical Research Center Hungarian Academy of Sciences Budapest,"— Presentation transcript:

1 István Ujváry Chemical Research Center Hungarian Academy of Sciences Budapest, Hungary Chemical Research Center Hungarian Academy of Sciences Budapest, Hungary T HE I MPORTANCE OF N ATURAL P RODUCTS IN I NSECT C ONTROL T HE I MPORTANCE OF N ATURAL P RODUCTS IN I NSECT C ONTROL IV th International Conference on Arthopods Chemical, Physiological & Environmental Aspects Białka Tatrzańska, Poland, September , 2005 IV th International Conference on Arthopods Chemical, Physiological & Environmental Aspects Białka Tatrzańska, Poland, September , 2005

2 World Pesticide Market HerbicidesHerbicides 45.4% OthersOthers 5.4% FungicidesFungicides InsecticidesInsecticides 27.5% 21.7% Pesticide Pesticide Sales: 32,665 Million USD ~420 Million USD ~1,3% Biopesticides:Biopesticides: Natural products?? ~4,700 Million USD ~15% Biotech / GM crops:

3 Sources of Pest Control Agents Semi-syntheticSynthetic Inorganic Natural Organic Botanical MicrobialAnimal MarineMarine OF HUMAN ORIGIN ??

4 Why Natural Products? For historical reasons: have been used for milennia  For historical reasons: have been used for milennia  Proven “ track record ” : evolved to bind biomacromolecules  Abundant & renewable  Unique structure (diversity!)  As template exploitable for biochemical modifications  Environmentally acceptable / degradable  etc.

5 Synthetics versus Natural Products Natural products tend to have larger molecular mass  larger molecular mass  more O atoms (e.g., ring-connected alcohol, ether or ester)  less N atoms (except alkaloids)  less halogens  larger polar surfaces  less aromatic systems, but more non-aromatic C=C bonds  more sp 3 -bridgehead C atoms  more chiral centers  unique scaffold larger molecular mass  larger molecular mass  more O atoms (e.g., ring-connected alcohol, ether or ester)  less N atoms (except alkaloids)  less halogens  larger polar surfaces  less aromatic systems, but more non-aromatic C=C bonds  more sp 3 -bridgehead C atoms  more chiral centers  unique scaffold

6 Production of Natural Products Use of the living or killed organism (or part of it) directly  Use of the living or killed organism (or part of it) directly  Extract: crude or enriched  Fermentation (microbials!)  Plant tissue & cell culture Use of the living or killed organism (or part of it) directly  Use of the living or killed organism (or part of it) directly  Extract: crude or enriched  Fermentation (microbials!)  Plant tissue & cell culture Conventional breeding Mutation Genetically modified organisms Conventional breeding – Mutation – Genetically modified organisms or Directed biosynthesis or Directed biosynthesis  Chemical synthesis PROBLEMS: Low yields, impurities, need of large amounts of natural resources SOLUTIONS:

7 Chemical Origin of Insect Control Agents   276 organophosphates carbamates carbamates organohalogens organohalogens acylureas, etc. acylureas, etc.organophosphates carbamates carbamates organohalogens organohalogens acylureas, etc. acylureas, etc. HCN, PH 3 pyrethrins nicotine nicotine avermectins avermectins spinosad spinosad pheromones, etc pheromones, etcpyrethrins nicotine nicotine avermectins avermectins spinosad spinosad pheromones, etc pheromones, etc pyrethroids pyrethroids neonicotinoids neonicotinoidsjuvenoids pyrethroids pyrethroids neonicotinoids neonicotinoidsjuvenoids Ujváry I: Phytoparasitica 30, 439 (2002) Based on: The Pesticide Manual and The BioPesticide Manual

8 azadirachtin Selected Botanical Insecticides sabadilla ryanodine 21 9 R = pyrrole-2-CO 2 H Major bioactive components of multicomponent mixtures pyrethrin I Ujváry I: In Handbook of Pesticide Toxicology (Krieger RI, ed.) Academic Press, p. 109 (2001) phosphinothricin

9 Nicotine and Selected Neonicotinoid Insecticides nithiazinenithiazine nicotinenicotineimidacloprid dinotefuranacetamiprid thiamethoxam 1992

10 Avermectin-Type Insecticides & Parasiticides Avermectin B 1a-b R = sec-Bu / iso-Pr, XY = CHCH Avermectin B 1a-b R = sec-Bu / iso-Pr, X–Y = CH=CH (abamectin) (abamectin) Ivermectin B R = sec-Bu / iso-Pr, XY = CH 2 CH 2 Ivermectin B R = sec-Bu / iso-Pr, X–Y = CH 2 – CH 2EmamectinEmamectin EprinomectinEprinomectin 4’’ Selamectin R = cyclohexyl directed biosynthesis! directed biosynthesis! XY = CH 2 CH 2 X–Y = CH 2 –CH 2 Selamectin R = cyclohexyl directed biosynthesis! directed biosynthesis! XY = CH 2 CH 2 X–Y = CH 2 –CH 25 produced by: Streptomyces avermitilis Streptomyces avermitilis produced by: Streptomyces avermitilis Streptomyces avermitilis semisynthetic ! * Complete genome sequence: Ikeda H et al.: Nature Biotechnology 21, 526 (2003) *

11 Spinosyn Insecticides Spinosad: spinosyn A / D R R = H / Me produced by: Saccharopolyspora spinosa Saccharopolyspora spinosa produced by: Saccharopolyspora spinosa Saccharopolyspora spinosa 2’  analogues using chemistry and / or combinatorial biosynthesis “unnatural natural products”  analogues using chemistry and / or combinatorial biosynthesis “unnatural natural products” 17 9

12 dioxapyrrolomycin nominine F4265 (benzhydrolpiperidine) Selected Microbial Insecticides & Analogues chlorfenapyr from Streptomyces from Aspergillus

13 Analogues of Stemona Alkaloids stemofoline cyanotropane Lind RJ et al.: BCPC Conference - Pests & Diseases, 145 (2002) Dr. Shen’s No More Lice Soak Stemona collinsae

14 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 -NH 2 ) From insects: From microorganisms: Photorhabdus luminescens Cyt2Aa Peptides as Insect Control Agents? toxin A

15 Non-Steroidal Ecdysteroid Hormone “Analogues” The past… (serendipity) 20-OH-ecdysone tebufenozide chromafenozide 2020 B e s t f i t - w r o n g h i t ?B e s t f i t - w r o n g h i t ?B e s t f i t - w r o n g h i t ?B e s t f i t - w r o n g h i t ? B e s t f i t - w r o n g h i t ?B e s t f i t - w r o n g h i t ?B e s t f i t - w r o n g h i t ?B e s t f i t - w r o n g h i t ? Maximizing overlap (1954) (from 1986)

16 X-Ray Structure of Heliothis virescens Ecdysone Receptor + Ponasterone A Billas I.M.L. et al.: Nature 426, 91 (2003) heterodimerheterodimer USPUSP EcREcR Ponasterone A

17 Ecdysteroid Hormone Analogues. The future: Computer-Aided Molecular Design ? ponasterone A BYI Billas I et al.: Nature 426, 91 (2003) overlay of ligands from X-ray structures:

18 Botanicals or Semi-Natural Products? Semi-natural product: Semi-natural product: a man-made substance (re)isolated from natural sources. a man-made substance (re)isolated from natural sources. fenvalerate in Mushigie cypermethrin in Musikoro terbufos from Paeonia suffruticosa ? terbufos from Paeonia suffruticosa ? fenoxycarb on mulberry trees ? fenoxycarb on mulberry trees ? Ujváry I: Pest Manag Sci 56, 703 (2000)

19 All is not gold that glitters!

20 Natural products Semi-synthetics Synthetics Environmental Cycle of Chemicals Semi-naturalproducts Biochemistry Chemistry Genetics Agricultural biology

21

22 Crossword puzzle question What is a nine-letter word for “ biotechnology ” ? CHEMISTRY from a Sidney Harris cartoon 1

23 Global Area of Transgenic Crops by Trait James C: Global Status of Commercialized Biotech/GM Crops: ISAAA (2004) million ha In 2004, 5% of the 1.5 billion ha of all global cultivable crop land was occupied by biotech crops

24 Insecticide + Fagostimulant Semiochemicals: Feeding to Death in a Corn Field ? Carbaryl Metcalf RL et al.: J Econ Entomol 80, 870 (1987) rootworm (Diabrotica) species (Coleoptera: Chrysomelidae) + Cucurbitacin A (e.g., in buffalo gourd) (e.g., in buffalo gourd) S LAM ® others : I NVITE EC C IDETRAK WP C IDETRAK WP Parimi S et al.: Crop Protection 22, 781 (2003) reduction to <10%

25 Dendrogram of Bacillus thuringiensis toxins ~150 Bt Cry proteins known

26 Selected Natural PGRs & Herbicides bilanafosbilanafosphosphinothricin Sglufosinate (S)-glufosinatephosphinothricin From microorganisms hydrolysis P ROHERBICIDE ! From plants brassinolidebrassinolide CH 3 (CH 2 ) 29 OH triacontanoltriacontanol  -terthienyl 1,8-cineole1,8-cineole


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