Chemistry Reference
In-Depth Information
Our work in the area of C12/C13-modified epothilone analogs was initially
guided by the potent biological activity associated with the deoxyepothilone struc-
tural framework; this approach will be discussed in Section 1.3.6. In addition, we
have investigated a series of semisynthetic derivatives of Epo A, which were
obtained through nucleophilic ring opening of the epoxide moiety.
45
Acid-catalyzed
hydrolytic epoxide opening in Epo A leads to an inseparable mixture of trans-diols,
which were elaborated into the corresponding acetonides 16a and 16b.
27-36,67
The
corresponding cis-analogs 17a and 17b were obtained via Epo C and standard cis-
dihydroxylationn of the double bond.
45
Very similar chemistry has been indepen-
dently reported by Sefkow et al.
67
O
O
O
O
S
S
HO
HO
N
N
O
O
O
OH
O
O
OH
O
16a
16b
O
O
O
O
S
S
HO
HO
N
N
O
O
O
OH
O
O
OH
O
17a
17b
None of the various diols or a related amino alcohol (structure not shown)
showed any appreciable biological activity, with IC
50
's for cancer cell growth inhi-
bition being above 1 mM in all cases. In contrast, azido alcohol 18 (obtained through
epoxide ring opening with NaN
3
) is significantly more potent (e.g., IC
50
'sof18
against the human epidermoid cancer cell lines KB-31 and KB-8511 are 61 nM
and 64 nM, respectively).
45
N
3
OH
S
HO
N
O
O
O
OH
18
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