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Epothilone
s are ma
crocyclic bacterial natural product
s with potent mi
crotubule-
stabilizing and antiproliferative activity. They have
served a
s succe
ssful lead
structure
s for the development of
several clinical candidate
s for anticancer therapy. However, the
structural diver
sity of thi
s group of clinical compound
s i
s rather limited, a
s their
structure
s show little divergence from the original natural product lead
s. Our own re
search ha
s explored the que
stion of whether epothilone
s can
serve a
s a ba
si
s for the development of new
structural
scaffold
s, or chemotype
s, for mi
crotubule
stabilization that might
serve a
s a ba
si
s for the di
scovery of new generation
s of anticancer drug
s. We have elaborated a
serie
s of epothilone-derived ma
crolactone
s who
se overall
structural feature
s significantly deviate from tho
se of the natural epothilone
scaffold and thu
s define new
structural familie
s of mi
crotubule-
stabilizing agent
s. Key element
s of our hypermodification
strategy are the change of the natural epoxide geometry from
cis to
trans, the incorporation of a conformationally con
strained
side chain, the removal of the C3-hydroxyl group, and the replacement of C12 with nitrogen. So far, thi
s approach ha
s yielded analog
s 30 and
40 that are the mo
st advanced, the mo
st rigorou
sly modified,
structure
s, both of which are potent antiproliferative agent
s with low nanomolar activity again
st
several human cancer cell line
s in vitro. The
synthe
si
s wa
s achieved through a ma
crolactone-ba
sed
strategy or a high-yielding RCM reaction. The 12-aza-epothilone (“azathilone”
40) may be con
sidered a “non-natural” natural product that
still retain
s mo
st of the overall
structural characteri
stic
s of a true natural product but i
s structurally unique, becau
se it lie
s out
side of the general
scope of Nature’
s bio
synthetic machinery for polyketide
synthe
si
s. Like natural epothilone
s, both
30 and
40 promote tubulin polymerization
in vitro and at the cellular level induce cell cycle arre
st in mito
si
s. The
se fact
s indicate that cancer cell growth inhibition by the
se compound
s i
s ba
sed on the
same mechani
stic underpinning
s a
s tho
se for natural epothilone
s. Intere
stingly, the 9,10-dehydro analog of
40 i
s significantly le
ss active than the
saturated parent compound, which i
s contrary to ob
servation
s for natural epothilone
s B or D. Thi
s may point to difference
s in the bioactive conformation
s of
N-acyl-12-aza-epothilone
s like
40 and natural epothilone
s. In light of their di
stinct
structural feature
s, combined with an epothilone-like (and taxol-like)
in vitro biological profile,
30 and
40 can be con
sidered a
s repre
sentative example
s of new chemotype
s for mi
crotubule
stabilization. A
s such, they may offer the
same potential for pharmacological differentiation from the original epothilone lead
s a
s variou
s newly di
scovered mi
crotubule-
stabilizing natural product
s with ma
crolactone
structure
s,
such a
s laulimalide, peloru
side, or dictyo
statin.