StructureActivity Relationship Studies on the Arthropod Repellent Callicarpenal

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Structure-Activity Relationship Studies on the
Arthropod Repellent Callicarpenal

• Background
• Mosquito Biting Deterrency
• Mosquito Toxicity
• SAR Study on Callicarpenal

• Charles L. Cantrell, Jerome A. Klun,
• Julia Pridgeon, James Becnel, Steve Duke
• clcantr1_at_olemiss.edu

National Center for Natural Products Research
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Traditional Usage of American Beautyberry
Also used by southeastern Indian tribes as a
ceremonial plant and as a tea in sweat bath
rituals. Southerners steeped berries, roots and
leaves in a tea to treat dropsy, skin disorders,
stomach disorders and colic.
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In vitro K D Module
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C. americana Compounds at 25 nmole/cm2 vs. Aedes
aegypti and Anopheles stephensi
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Toxicities of Treatments against Female Aedes
aegypti
a Units of mg/mosquito
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Tick Repellency of C. americana Compounds

• Evaluation of repellent activity against
  host-seeking nymphs of the
• Blacklegged tick, Ixodes scapularis
• Lone star tick, Amblyomma americanum

Black-legged Tick
Lone Star Tick
Exp Appl Acarol DOI 10.1007/s10493-007-9057-2
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Black-Legged Tick (Ixodes scapularis )Bioassay
Upper Treatment Boundary
Two Layers
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Response of Ixodes scapularis nymphs in fingertip
bioassays to four concentrations of sample/control
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Percent of I. scapularis nymphs repelled - post
application of test solution at 155 nmole/cm2
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Callicarpenal Sourcing Possibilities

• Callicarpa americana
• Callicarpa sp.
• Verbenaceae species
• Methods
• Time of Year

Simple/Cheap Analog
QSAR

• Wieland-Miescher
• Sclereolide
• Labdane to Clerodane

• Smaller cpd. build-up
• Larger cpd. breakdown

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Structure-Activity Study

• Obvious sites for modifications

oxidations reductions esterifications
a-substitution
allylic substitution
oxidations reductions substitutions
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Optimization of Structure and Activity -
Repellency

• Aldehyde modifications

NaH2PO4 NaClO2 t-BuOH 2-methyl-2-butene
NaBH4, H2O
bsig. diff. from control
b
b
b
b
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Optimization of Structure and Activity -
Repellency

• Olefinic modifications

mCPBA
H2, Pd

anot different from control bsig. diff. from
control
b
b
b
a
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Optimization of Structure and Activity -
Repellency
1)H2, Pd
1)CrO3, H2SO4
2)CH2N2
2)NaBH4
1)BF3-THF 2) NaOH, H2O2
1)NaBH4
2)Ac2O, pyridine
adifferent from callicarpenal bsig. diff. from
control
b
b,a
b
b,a
b,a
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Optimization of Structure and Activity - Toxicity

• Aldehyde modifications

NaH2PO4 NaClO2 t-BuOH 2-methyl-2-butene
NaBH4, H2O
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Optimization of Structure and Activity - Toxicity

• Olefinic modifications

mCPBA
H2, Pd

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Optimization of Structure and Activity - Toxicity
1)H2, Pd
1)CrO3, H2SO4
2)CH2N2
2)NaBH4
1)NaBH4
2)Ac2O, pyridine
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Molecular Modeling Structural Differences
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Molecular Modeling Overlaid Structures
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Why Callicarpenal?
Next Steps

• Novel 13,14,15,16-tetranorclerodane
• Unusual truncated diterpenoid
• Never before isolated from natural sources
• Fragrant smell
• Natural compound
• Highly repellent
• Additional Testing Underway

• Animal Toxicity testing
• Uli Results - Humans
• Commercial Partners
• Dose-response repellency
• Continue SAR on Callicarpenal
• Collection of natural compounds
• New crude plant extracts
• SAR on intermedeol

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Acknowledgements

• Technical Support
• Solomon Green III
• Amber Callahan
• Greg Walker
• Jacob Fish
• Visiting Scientists
• Michele Fiore
• Masanori Morimoto

• USDA-ARS
• Jerry Klun
• Steve Duke
• Charles Bryson
• Jerry Klun
• John Carroll
• Jian Chen
• Julia Pridgeon
• University of Mississippi
• Ikhlas Khan
• Shabana Khan
• Funding
• USDA-ARS
• DOD
• ISTC
• Fulbright
• OECD