RECENT PROGRESS ON THE CHEMICAL SYNTHESIS OF ANNONACEOUS ACETOGENINS AND THEIR STRUCTURALLY MODIFIED MIMICS - Medicinal Chemistry of Bioactive Natural Products - page 432

OH O

1

C 8 H 17 O

10

24

O OMe

15

OH

238a (15 R , 24 R , 36 S )
238c (15 S , 24 S , 36 S )

238b (15 S , 24 R , 36 S )
238d (15 R , 24 S , 36 S )

OH O

R 1

1

R 2

O

C 10 H 21

24

O

O ( ) 9 O

( ) n

15

HO

R 1 , R 2 = H, OH

O

ent- 232a

R

n = 10, 12, 14

239

OH

O

O

O ( ) 9 O

O

240

Scheme 10-41. Compounds 238, 239, ent-232, and steroid hybrid 240.

segment seemed to have no effect on activities; ent-232a exhibited similar activities
as 232a. We also prepared a steroid hybrid 240 (Scheme 10-41) to examine the
influence of lipophilic property on activities. Unfortunately, hybrid 240 showed
little activities against the cancer cells screened, such as HCT-8. 98
Inspection of the structures of acetogenins revealed that C4 and C10 were the
two carbons where the hydroxy group was frequently located. We thus introduced,
respectively, a hydroxy group to C4 and C10 of mimic 232c to give two new
mimics 243 and 246 (Scheme 10-42). Mimic 243 possessed one more free hydroxy
group at C10 than did 232c and had activities comparable with that of 232c.In
contrast, C4 hydroxy containing mimic 246 was 15 times as active as 232c toward
HT-29; furthermore, it had no cytotoxity toward the normal human cell HELF
(Table 10-5). 97,99
From these results, we can see that it is possible to tune the activities and cyto-
toxic selectivities of acetogenin mimics by appropriate modification of their struc-
tures. To accelerate the space of searching for more potent acetogenin mimics with
different cytotoxic selectivities, a systematic synthesis involving parallel fragment
assembly strategy was developed. By using this strategy, a small library of ten
mimics was established (Scheme 10-43). 100 Six of these ten mimics, 247a-f, could
be assembled from building blocks mesylate A, tartaric acid derivatives B, epoxide
C, trimethylsilyacetylene D, and epoxide F, whereas the other four 247g-j could be
from A, B, C, 1,7-octadiyne E, and epoxide G. An example for the synthesis of
247d is illustrated in Scheme 10-44. Two successive O-alkylations of 249 with
mesylate 248 and R-epichlorohydrin afforded epoxide 251, which was then con-
verted to alkyne 252 via a three-step procedure: (1) epoxide opening reaction
with lithium trimetylsilyacetylide, (2) hydroxy protection as a MOM ether, and
(3) desilylation by TBAF. Finally, the coupling reaction of epoxide 253 and alkyne