Balb/c nu/nu mice) than nine known anticancer agents including
cisplatin, cytoxan and paclitaxel. Its efficacy was comparable to
that of mitomycin C.5 The efficacy of second generation
analogue acylfulvene 4 exceeded that of dehydroilludin M and
mitomycin C.6 Although these compounds prolonged lifespan
in the MV 522 model, they did not induce regression of the
primary tumour implants. However, a third generation analogue
hydroxymethylacylfulvene (HMAF) 5 caused complete tumour
regression in all animals at the maximum tolerated dose of 10
mg Kg21 (iv or ip) three times per week for three weeks. This
resulted in an increase in life span of more than 150%.7 HMAF
has also been found to exhibit outstanding activity against
breast, colon and skin cancer cell lines derived from human
tumours. This compound is now undergoing clinical trials.8
HMAF can be prepared readily from acylfulvene 4, with
paraformaldehyde in dilute H2SO4 solution in 73% yield, or
directly from illudin S. However, the total synthesis of
acylfulvenes remains a very desirable objective, because it will
make available a variety of analogues for structure–activity
investigations. The synthesis of (±)-hydroxymethylacylfulvene
has been accomplished as follows.
and methanol gave an unstable product and the hydroxy group
was eliminated on work up yielding the fulvene 18a (84%).
Reduction of the acetate 18a (LiAlH4, diethyl ether, room
temp., 10 min) followed by oxidation of the resulting alcohol
with Dess–Martin reagent14a,b yielded (±)-acylfulvene 19
(71%) as a yellow gum. Diacetate 17b could also be converted
similarly to 19 (40%). Finally, (±)-hydroxymethylacylfulvene
20 was obtained from 19 following the known procedure.2
The spectral properties of (±)-hydroxymethylacylfulvene 20
and (±)-acylfulvene 19 were identical to those of the hydroxy-
methylacylfulvene and acylfulvene derived from illudin S.
This investigation was supported by MGI Pharma Inc.,
Minnetonka, Minnesota, USA.
Footnote
† The new compounds 6–20 were fully characterised by spectroscopic data
including HRMS.
References
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A
mixture of mono- and di-acetate (17a 64%, 17b 19%) was
obtained. Reduction of 17a with NaBH4, CeCl3·7H2O in THF
Received, 17th October 1996; Com. 6/07077I
316
Chem. Commun., 1997