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1. N-Alkylamides
1.1. Structure
1.2. Occurrence
1.3. Objective
2. Database
CHEMICAL-FUNCTIONAL SPACE EXPLORATION
OF PLANT N-ALKYLAMIDES
3. Clustering
4. Conclusions
Jente Boonen1, Vikas Sharma2, Vinot Dixit2 and Bart De Spiegeleer1*
1
Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences,
Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium
2 Department of Pharmaceutical Sciences, Dr. H.S. Gour University, Sagar 470003 M.P. India.
*Corresponding author: Tel.: +32 9 264 8100; Fax: +32 9 264 8193,
E-mail: [email protected]
2011-240b
1. N-Alkylamides
1.1. Structure
1.2. Occurrence
1.3. Objective
2. Database
R1=
3. Clustering
Aliphatic, often
unsaturated
units, w/wo
substutients (N,
O, S, cyclic,…)
or in cyclic
system with R2.
4. Conclusions
O
R
1
R
2
N
R
3
R2=
Aliphatic, often
isobutylamide,
methylbutylamide,
phenylethylamide,
tyramide, piperidide or
pyrrolidide derivative,
w/wo substituents (N,
O, S, cyclic,…) or in
cyclic system with R1.
R3=
Mostly H, Me,
MeO, OH
function.
New group of potential drugs related to lipoid peptides (antiinflammatory, immunostimulant, anti-hepatotoxic, anti-oxidant, tingling, CB2
endocannabinomimetic, anti-microbial,…)
May 2011
Now: 9 different plant families
CH3
CH3
O
O
O
NH
CH3
CH3
O
H3C
O
H3C
1. N-Alkylamides
1.1. Structure
CH3
NH
CH3
N
1.2. Occurrence
1.3. Objective
2. Database
CH3
O
Ceramides
OH
Ergopeptides
3. Clustering
NH
N
CH3
4. Conclusions
R= aliphatic chain
HN
May 2011
1. N-Alkylamides
1.1. Structure
1.2. Occurrence
1.3. Objective
2. Database
Plant species
?
?
N-alkylamide
Functionality
?
Interdisciplinary
3. Clustering
4. Conclusions
No structured overview of plant N-alkylamides
DATABASE
CHEMICAL CLUSTERING
May 2011
Relational database, now containing ± 300 plant N-alkylamides
O
H3C
CH3
NH
CH3
CC(C)CNC(=O)\C=C\CC/C=C\C=C\C
C14H23NO
deca-2E,6Z,8E-trienoic acid isobutylamide
(2E,4E,8E)-N-butan-2-yldeca-2,4,8-trienamide
spilanthol or affinin
1. N-Alkylamides
2. Database
3. Clustering
4. Conclusions
Asteraceae
Helianthea
Spilanthes
acmella
Anti-oxidant
EC50=1.38 µmol
May 2011
1. N-Alkylamides
3D structure optimization
2. Database
- Calculation and selection of 141 descriptors
 Constitutional descriptors
 WHIM descriptors
 Molecular properties
3. Clustering
4. Conclusions
- Data-scaling transformation: zi = (хi – x)/SD
- Multivariate analysis:
 Hierarchical cluster analysis (HCA)
 Principal compontent analysis (PCA)
May 2011
1. N-Alkylamides
2. Database
3. Clustering
4. Conclusions
HCA => Dendrogram
PCA => PC1_PC2
(4 PCs for >70% Q²)
May 2011
1. N-Alkylamides
4. Conclusions
Loading plot
3. Clustering
Scoring plot
2. Database
N
1. N-Alkylamides
«228»
QUALITY ATTRIBUTES FOR CLUSTER:
O
2. Database
3. Clustering
4. Conclusions
CH3
OH
(1) Constitutional
 AMW => molecular weight
 nAB, nBnZ, nCIC, nRO6 => aromatic ring structures
(2) WHIM
 P2: shape
 L2: size
 E2: accessibility
H3C
CH3
O
«220»
N
O
CH3
(3) Molecular properties
 Ui => unsaturation index
O
H3C
O
CH3
N
H
O
«193»
May 2011
1. N-Alkylamides
DATABASE => EXPLORATORY MINING
2. Database
Chemical/functional overview of plant N-alkylamides
3. Clustering
4. Conclusions
CLUSTERING
Chemical similarities =>
 Functionality
 Toxicity
 PK e.g. transdermal/transmucosal
 Justified choice of model compounds
May 2011
Thank you for your attention
May 2011