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NATURAL PRODUCTS: biosynthesized by a living organism through its…
NATURAL PRODUCTS
: biosynthesized by a living organism through its metabolism
Primary metabolites
Secondary metabolites
Characteristics
They don't care about the Lipinski rules
More number of chiral centers
Lower number of rotatable bonds
The number of rings is typically higher
Heavy atom chains/substituents are smaller
HBA/D more
Synthetic compounds are more lipophilic
NP producers
Lower ->
prokaryots
and
eukaryots (yeasts, molds, mushrooms, etc.)
Higher ->
flora
,
fauna
NP Discovery
Identification of a biological activity (NP) from a specific new NP producer -
screening
Purification of the active NP(s) from the NP producer -
bio/separation/extractions
Dereplication - the deja-vu effect
Structural determination - cutting edge analyticals
EPOTHILONES
NPs from
microorganisms
Myxobacteria
Anticancer and antifungal action
Shares mechanism of action with previously discovered
taxol
Large scale production
Separation
: addition of a lipophilic absorbing resin specific in the fermentator
Extraction
: filtration of the lipophilic resin; multiple washing with water, elution with MeOH (4 x resin volume), concentration; surnatant aqueous phase (extraction with EtOAc, concentration); collected dried organic phase (46 g from 270 l of fermentation broth
Purification
: chromatography (fractionation, reverse phase, MeOH as solvent; 12 g contains two active principles structurally similar); second chromatography (MeOH:water=3:1); recrystallization from EtOAc
Dereplication
: nothing as potent with these MWs, thus novel
Structure determination
: epothilone A epothilone B. 7 chiral centers. Structural features: epoxide, thiazole and ketone. Difference in a CH3 (epoB), epoB 10-fold higher potency than epoA
TAXOL
NPs from
plants
Taxus Brevifolia
Production
Extraction
: 95% EtOH, concentration. Partition between aqueous phase and chloroform- Drying and concentration of organic phase. Still not pure compound
Three steam distillations
Crystallization from benzene
Dereplication
: no cytotoxic compounds with such MW, novel
Structural determination
: blind chemistry. X-rays.
1
. taxol
2
. taxotere
3
. taxanes
EPIBATIDINE
NPs from
amphibians
Epipedobates tricolor
Production
Skinning/killing, drying and trituration, extraction with MeOH (3 times).
Concentration to 500 ml, 1:1 dilution with water to make it hydrophilic
Extraction
with chloroform (partitioning the two extracts in organic and inorganic phase) -> biological activity found in the organic phase
Neutralization of aqueous phase with base and extraction with chloroform. Drying and concentration
MS of crude extracts: main fraction (MW 251), 3 minor fractions (MW 217, 323, 341), traces of other metabolites
Separation
by chromatography: identification of known pumiliotoxins
Other chromatography -> unknown substance called
epibatidine
MS 208-210
Contain an NH function
Chloropyridine fragment
NP-derived Libraries
Decorative libraries
Ex-novo libraries
Hybrid libraries