Chemistry Reference
In-Depth Information
O
O
O
S
O
O
O
H
H
N
H
N
NH
N
NH
N
OMe
N
N
HN
O
O
O
O
Me
O
O
N
O
O
Apicidin (
123
)
Trapoxin B (
124
)
125
OH
OH
O
O
O
H
3
CO
HO
2
C
HO2C
H
N
H
OH
OH
O
CH
3
Platensimycin (
126
)
Platencin (
127
)
modification as a mode of action. Apicidin does not contain the epoxy-ketone
but showed potent antitumor activity (161). The mode of action of apicidin was
shown to be the inhibition of histone deacetylase (HDAC) (157). The amino-
oxo
-
decanoic acid (L-Aoda) mimics the acetylated lysine residue and positions itself
at the zinc-binding site of HDAC (162). Chemical modification of apicidin with
retention of the ethyl or methyl ketone led to the synthesis of small dipeptides
(e.g.,
125
) that retained the HDAC and tumor cell line inhibitory activities with
significant reduction of inhibition of normal cells (161).
In summary, nature has provided a great set of molecules with enormous
chemical diversity that has contributed to the treatment of many human diseases.
Nature continues to amaze us with novel chemical diversity with unimaginable
biological activity and target specificity, as illustrated by the recent discovery
of the fatty acid synthesis inhibitor antibiotic platensimycin (
126
) (163, 164)
and platencin (
127
) (165, 166). The former shows exquisite selectivity for FabF,
whereas the latter compound is a balanced inhibitor of both condensing enzymes,
FabF and FabH.
REFERENCES
1. Butler M. The role of natural product chemistry in drug discovery. J. Nat. Prod.
2004;67:2141-2153.
2. Clardy J, Walsh CT. Lessons from natural molecules. Nature 2004;432:829-836.
3. Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs
over the period 1981-2002. J. Nat. Prod. 2003;66:1022-1037.
4. Newman DJ, Cragg GM, Snader KM. The influence of natural products upon drug
discovery. Nat. Prod. Rep. 2000;17:215-234.
5. Singh SB, Barrett JF. Empirical antibacterial drug discovery-foundation in natural
products. Biochem. Pharmacol. 2006;71:1006-1015.
