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C26-(1,3-dioxolanyl)-12,13-Epo D 20 (Figure 1-3) exhibits enhanced in vitro anti-
proliferative activity over Epo D,
108
but it was found to be significantly less effica-
cious than Epo D in vivo. In contrast, C26-fluoro-Epo B 21 (Figure 1-3), which
exhibits comparable in vitro antiproliferative activity with Epo B,
107
was demon-
strated to possess significantly better antitumor activity than paclitaxel in a human
prostate xenograft model when both compounds were administered at equitoxic
doses.
109
No comparison with Epo B was included in this work, but data from
our laboratory indicate that the in vivo profile of C26-fluoro-Epo B is similar to
that of Epo B.
110
1.3.5
Side-Chain Modifications
Not too surprisingly the second part of the epothilone structure that has been tar-
geted for SAR studies most extensively, apart from the epoxide moiety, is the unsa-
turated heterocycle-bearing side chain. Structural changes in this area, in particular
involving the pendant heterocycle, hold the potential to modulate the physico-
chemical, and perhaps the pharmacokinetic, properties of the natural products.
The corresponding SAR studies include modifications of the thiazole moiety at
the 2- and 4-positions,
99,106,111-113
the replacement of the thiazole ring by other
heterocyclic structures
62,99,114
or a simple phenyl group,
62,106,115
and the synthesis
of C16-desmethyl-Epo B.
115,116
For example, these studies have shown that the
allylic methyl group attached to C16 can be removed with only a minor change
in biological activity (see Ref. 45). Likewise, the substitution of oxygen for sulphur
in the heterocycle (to produce oxazole-derived epothilone analogs) does not affect
biological potency.
62,99
Replacement of the 2-methyl group on the thiazole ring by
relatively small substituents such as CH
2
OH, CH
2
F, SCH
3
,orCH
2
CH
3
is well tol-
erated, whereas more bulky substituents result in a substantial loss in potency.
37,105
O
S
S
21
21
HO
HO
N
OH
N
NH
2
O
O
O
OH
O
O
HO
23
22
Out of this latter family of analogs, in vivo data have been reported by the Sloan-
Kettering group for deoxyEpo F [C21-hydroxy-Epo D (22)]. The compound was
found to exhibit comparable in vivo efficacy as Epo D,
74,117
but by virtue of its
enhanced water-solubility, it may be a more attractive drug development candidate.
Employing a 6-h continuous intravenous infusion regimen for both compounds, 22
was found to have significantly superior antitumor effects over BMS-247550 (1)in
a CCRF-CEM as well as a MX-1 tumor model.
72,74
It should be emphasized, how-
ever, that although the 6-h continuous infusion schedule may be optimal for Epo D
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