Chemistry Reference
In-Depth Information
grouped into two distinct functional classes, namely compounds that inhibit the
assembly of tubulin heterodimers into microtubule polymers (''tubulin polymeriza-
tion inhibitors'') and those that stabilize microtubules under normally destabilizing
conditions (''microtubule stabilizers'').
4
The latter will also promote the assembly
of tubulin heterodimers into microtubule polymers. While the use of tubulin poly-
merization inhibitors such as vincristine and vinblastine in cancer therapy dates
back around 40 years (vincristine and vinblastine received U.S. Food and Drug
Administration (FDA) approval in 1963 and 1965, respectively), the introduction
of microtubule stabilizers into clinical practice constitutes a relatively recent devel-
opment, which took place only in 1993. The first agent of this type to obtain FDA
approval was paclitaxel (Taxol) in 1992, which was followed by its closely related
analog docetaxel (Taxotere) in 1996 and the emergence of microtubule-stabilizing
anticancer drugs clearly marks a significant advance in cancer chemotherapy.
5
While several small synthetic molecules are known, which act as efficient tubulin
polymerization inhibitors,
6
it is intriguing to note that all potent microtubule-
stabilizing agents identified to date are natural products or natural product-derived
(for a recent review, see Altmann
7
). Historically, more than a decade passed after
the elucidation of paclitaxel's mode of action in 1979
8
before alternative microtubule-
stabilizing agents were discovered, bearing no structural resemblance to pacli-
taxel or other taxanes. Most prominent among these new microtubule stabilizers
is a group of bacteria-derived macrolides, which were discovered in 1993
by Reichenbach and H ¨fle and have been termed ''epothilones'' by their disco-
verers
9,10
. Although not immediately recognized, these compounds were subse-
quently demonstrated by a group at Merck Research Laboratories to possess a
paclitaxel-like mechanism of action.
11
O
O
OH
26
O
R
O
S
9
12
13
O
NH
O
11
21
HO
O
N
2
O
3'
15
17
O
HO
O
6
1
O
OH
O
O
O
OH
O
R = H:
Epothilone A
R = CH
3
:
Epothilone B
Paclitaxel
The major products originally isolated from the myxobacterium Sorangium cel-
lulosum Sc 90 are epothilone A and epothilone B (Epo A and B), but numerous
related members of this natural products family have subsequently been isolated
as minor components from fermentations of myxobacteria.
12
The relative and abso-
lute stereochemistry of Epo B was determined by H ¨fle et al. in 1996 based on a
combination of x-ray crystallography and chemical degradation studies,
13
and the
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