英语翻译A series of other analogues were prepared to furthereval

英语翻译
A series of other analogues were prepared to further
evaluate the SAR (Table 3) of the C-2 and C-3 positions.
Ethyl 29a showed good potency,whereas difluoromethyl
analogue 33b,cyclopropylmethyl 29c,and isopropyl indazolone
29b displayed reduced activity.The activity of the
2,3-dimethyl indolone 35 was comparable but not superior
to 34 or 22c.In general,larger or functional groups introduced
at available C-2 or C-3 or both positions of the indolone or
indazolone led to loss of potencies.
Concurrently,we explored optimization of 2-amino substitutions
in conjunction with the favored bottom moieties
bearing small C-3 groups and data for representative
compounds are summarized (Table 4).The overall SAR
trends were consistent with our earlier findings.The favored
side chains were aminocyclic structures that contained
oxygen (36) or a weak hydrogen bond acceptor such as
the less stable alkene (37) or sulfur (38).The less favored
side chains were either rings without such H-bond acceptors
(39) or rings having an extra linear spacer (40,41,42).
Open chain structures designed to improve flexibility and
solubility,were also less active (43,44,45,46,47).Particularly
disfavored side chains were those containing strongly
basic amines (48,49).The comparator compound,epimeric4-cis-hydroxycyclohexylamino (50),was 25- to 30-fold less
potent compared to the trans analogue 9.Compound 10,the
glycine ester prodrug of compound 9 that was made for
further evaluation for reasons described below,still maintained
nanomolar level of potencies.
Overall,compounds 34 and 9 remained among the most
potent compounds.Their detailed cellular activity profiles,
along with those of prodrug 10 and 17-AAG (2),are presented
in Tables 5 and 6.All compounds summarized
showed potent antiproliferative activity against a broad range
of cancer cell types (Table 5).Additionally,17-AAG treatment
resulted in calculated IC50 values spanning a much
greater range (0.1-1487 nM) than 9 (3 nM to 53 nM).One
explanation for this observation is that the different cell
lines tested have differing abilities to reduce 17-AAG to its
more potent dihydroquinone form via DT-diaphorase
(NQO1).39 Compounds 9,10,and 34 all exhibited potent
effects on Her2 stability and caused expected up-regulation
of Hsp70 (Table 6).Additionally,treatment with the inhibitors
down regulated both the MAPK and AKT signaling
pathways as measured by the loss of p-S6 and p-ERK in
treated cells.These pathways are implicated in uncontrolled
cellular division and antiapoptotic signaling and have
been targeted for drug development.The results shown here
highlight the advantage of Hsp90 inhibition as a single
mechanism that is capable ofmodulating a number of known
pathways involved in cancer progression.