Simplified discodermolide analogues: synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents.
Several novel analogues of (+)-discodermolide were synthesized via a convergent strategy that used Wittig reactions to append left and right side chains to a central scaffold and then tested for biological activity. Three of the analogues in the 4-epi-7-dehydroxy-14,16-didemethyl series, 6a-c, had interesting actions. The C3-methoxymethyl ether analogue 6b was more active in antiproliferative cell-based assays as well as in hypernucleation and paclitaxel site competition assays with isolated tubulin than the other analogues, including 6a, which contained a free hydroxyl group at the C3 position. The biological results validated the initial hypothesis that the C7 hydroxy group and the C14 and C16 methyl groups of (+)-discodermolide could be deleted without undermining activity. Although less potent than (+)-discodermolide and paclitaxel, compounds 6b and 6c both showed properties unique to (+)-discodermolide. These properties, particularly the capacity to cause hypernucleation of isolated tubulin at lower temperature than paclitaxel, as well as stabilizing preformed microtubules to cold disassembly, are considered mechanistically superior to those of paclitaxel. Other variations in the right and left sides of the discodermolide scaffold revealed additional structure/activity information.
Choy
Nakyen
N
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Shin
Youseung
Y
Nguyen
Phu Qui
PQ
Curran
Dennis P
DP
Balachandran
Raghavan
R
Madiraju
Charitha
C
Day
Billy W
BW
D000473:Alkanes; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002219:Carbamates; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
D000473:Alkanes; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; D014404:Tubulin; C071229:discodermolide; D017239:Paclitaxel