THE IMPORTANCE OF NATURAL PRODUCTS
IN INSECT CONTROL
István Ujváry
Chemical Research Center
Hungarian Academy of Sciences
Budapest, Hungary
IVth International Conference on Arthopods
Chemical, Physiological & Environmental Aspects
Białka Tatrzańska, Poland, September 18 - 23, 2005
World Pesticide Market - 2004
Pesticide Sales:
32,665 Million USD
Others
5.4%
Fungicides
Herbicides
Biopesticides: ~1,3%
~420 Million USD
Natural products??
21.7%
45.4%
27.5%
Insecticides
Biotech/GM crops: ~15%
~4,700 Million USD
Sources of Pest Control Agents
Natural
Semi-synthetic
Synthetic
Botanical
Organic
Animal
Microbial
Marine
OF HUMAN ORIGIN ?
Inorganic
Why Natural Products?







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.
Synthetics versus Natural Products
Natural products tend to have









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 sp3-bridgehead C atoms
more chiral centers
unique scaffold
Production of Natural Products





Use of the living or killed organism (or part of it) directly
Extract: crude or enriched
Fermentation (microbials!)
Plant tissue & cell culture
Chemical synthesis
PROBLEMS:
Low yields, impurities, need of large amounts of natural resources
SOLUTIONS:
Conventional breeding – Mutation – Genetically modified organisms
or Directed biosynthesis
Chemical Origin of Insect Control Agents
Based on: The Pesticide Manual and The BioPesticide Manual
Natural products
Natural product analogues
Other organics ('synthetics')
Inorganics
HCN, PH3
organophosphates
carbamates
organohalogens
acylureas, etc.
S 276
pyrethrins
nicotine
avermectins
spinosad
pheromones, etc
pyrethroids
neonicotinoids
juvenoids
Ujváry I: Phytoparasitica 30, 439 (2002)
Selected Botanical Insecticides
Major bioactive components of multicomponent mixtures
O
O
CO2Me
O
OH O
O
O
H
O
O
AcO
MeO2C
H
pyrethrin I
H
OH
O
azadirachtin
O
P
OH
22
23
O
O
OH
N
OH
HO
OH
NH2
phosphinothricin
H
3
RO
H
O
H
OH
H
OH sabadilla
OH
OH
OH
HO
HO HO
H
OH 21
9
O
RO
OH
ryanodine R = pyrrole-2-CO2H
Ujváry I: In Handbook of Pesticide Toxicology (Krieger RI, ed.) Academic Press, p. 109 (2001)
Nicotine and Selected Neonicotinoid Insecticides
1979
1893
HN
N
Me
N
Me
NH
H
N
Cl
nithiazine
1998
Cl
N
N
dinotefuran
NO2
N
N
NO2
imidacloprid
O
S
1991
NH
N
NO2
nicotine
O
S
N
N
N
thiamethoxam
N
1997
Me
Cl
N
N
CN
NO2
acetamiprid
Me 1992
Me
Avermectin-Type Insecticides & Parasiticides
HO
produced by:
Streptomyces avermitilis*
O
4’’
MeO
OMe
O
O
O
O
H
Me N
Y
X22 23
25
O
R
Emamectin
O
Eprinomectin
H
AcN
O
Selamectin R = cyclohexyl
directed biosynthesis!
OH
X–Y = CH2–CH2
5
O
5
H
N
OH
OH
Avermectin B1a-b R = sec-Bu / iso-Pr, X–Y = CH=CH
(abamectin)
Ivermectin B
R = sec-Bu / iso-Pr, X–Y = CH2–CH2
semisynthetic !
*Complete genome sequence: Ikeda H et al.: Nature Biotechnology 21, 526 (2003)
Spinosyn Insecticides
produced by:
Saccharopolyspora spinosa
Me2N
OMe
O
O
OMe
17
H
O
O
O
2’
O
O
H
H
OMe
9
H
H
R
Spinosad: spinosyn A / D R = H / Me
 analogues using chemistry and / or combinatorial biosynthesis
“unnatural natural products”
Selected Microbial Insecticides & Analogues
from Streptomyces
Cl
Br
NO2
Cl
H
Cl
CN
F3C
N
Cl
N
H
O
Cl
O
O
dioxapyrrolomycin
chlorfenapyr
from Aspergillus
CF3O
OH
OCF3
OH
N
N
H
nominine
MeOCONH
+
O
F4265 (benzhydrolpiperidine)
Analogues of Stemona Alkaloids
Dr. Shen’s
No More
Lice Soak
Stemona collinsae
Cl
OMe
O
CF3
O
N
n-Bu
O
O
stemofoline
N
N
CN
cyanotropane
Lind RJ et al.: BCPC Conference - Pests & Diseases, 145 (2002)
Peptides as Insect Control Agents?
From microorganisms:
Bacillus thuringiensis
var. israelensis (Bti)
d-endotoxin
Photorhabdus luminescens
Cyt2Aa
toxin A
From insects:
Proctolin
(H-RYLPT-OH)
Pheromone Biosynthesis Activating
Neurohormone - Hel-PBAN (H-YFSPRL-NH2)
Trypsin modulating oostatic factor
Aea-TMOF (H-YDPAPPPPPP-OH)
Non-Steroidal Ecdysteroid Hormone “Analogues”
The past… (serendipity)
O
O
N
OH
HO
N
H
20
OH
tebufenozide
HO
(from 1986)
OH
HO
H
O
O
O
20-OH-ecdysone
N
N
H
O
(1954)
chromafenozide
Maximizing overlap
Best fit - wrong hit ?
X-Ray Structure of Heliothis virescens
Ecdysone Receptor + Ponasterone A
HO
HO
OH
O
H
HO
OH
Ponasterone A
USP
EcR
heterodimer
Billas I.M.L. et al.: Nature 426, 91 (2003)
Ecdysteroid Hormone Analogues.
The future: Computer-Aided Molecular Design ?
O
H
OH
OH
OH
overlay of ligands
from X-ray structures:
HO
OH
ponasterone A
O
H
N
O
N
O
O
BYI 06830
Billas I et al.: Nature 426, 91 (2003)
Botanicals or Semi-Natural Products?
Semi-natural product:
a man-made substance (re)isolated from natural sources.
CN
O
CN
O
O
O
Cl
O
O
Cl
Cl
fenvalerate in Mushigie
cypermethrin in Musikoro
S
O
O
(EtO)2 P
H
N
OEt
S
S
O
fenoxycarb on
mulberry trees ?
terbufos from
Paeonia suffruticosa ?
Ujváry I: Pest Manag Sci 56, 703 (2000)
All is not gold that glitters!
Environmental Cycle of Chemicals
Synthetics
Chemistry
Agricultural
Semi-synthetics
biology
Semi-natural
Biochemistry
products
Genetics
Natural
products
Crossword puzzle question
What is a nine-letter word for “biotechnology” ?
C H E M I S T R Y
1
from a Sidney Harris cartoon
Global Area of Transgenic Crops by Trait
1996 - 2004
million ha
70
In 2004, 5% of the 1.5 billion ha of all global cultivable crop land
was occupied by biotech crops
Herbicide Tolerance
60
Insect Resistance
Herbicide Tolerance + Insect resistance
50
40
30
20
10
0
1996
1997
1998
1999
2000
2001
2002
2003
2004
James C: Global Status of Commercialized Biotech/GM Crops: 2004. ISAAA (2004)
Insecticide + Fagostimulant Semiochemicals:
Feeding to Death in a Corn Field?
rootworm (Diabrotica) species (Coleoptera: Chrysomelidae)
O
HO
O
O
OAc
O
N CH3
H
HO
H
H
OH
+
O
Carbaryl
Cucurbitacin A
reduction to <10%
SLAM®
others: INVITE EC
CIDETRAK WP
(e.g., in buffalo gourd)
Metcalf RL et al.: J Econ Entomol 80, 870 (1987)
Parimi S et al.: Crop Protection 22, 781 (2003)
Dendrogram of Bacillus thuringiensis toxins
~150 Bt Cry proteins known
http://www.biols.susx.ac.uk/Home/Neil_Crickmore/Bt
Selected Natural PGRs & Herbicides
From plants
OH
S
OH
S
S
a-terthienyl
H
HO
H
CH3(CH2)29OH
H
H
O
triacontanol
O
HO
O
brassinolide
1,8-cineole
From microorganisms
O
P
OH
O
O
H
N
N
H
NH2
O
bilanafos
PROHERBICIDE!
hydrolysis
OH
O
O
P
OH
OH
NH2
phosphinothricin
(S)-glufosinate