Ipomoeassin F is a potent natural
cytotoxin that inhibits growth
of many tumor cell lines with single-digit nanomolar potency. However,
its biological and pharmacological properties have remained largely
unexplored. Building upon our earlier achievements in total synthesis
and medicinal chemistry, we used chemical proteomics to identify Sec61α
(protein transport protein Sec61 subunit alpha isoform 1), the pore-forming
subunit of the Sec61 protein translocon, as a direct binding partner
of ipomoeassin F in living cells. The interaction is specific and
strong enough to survive lysis conditions, enabling a biotin analogue
of ipomoeassin F to pull down Sec61α from live cells, yet it
is also reversible, as judged by several experiments including fluorescent
streptavidin staining, delayed competition in affinity pulldown, and
inhibition of TNF biogenesis after washout. Sec61α forms the
central subunit of the ER protein translocation complex, and the binding
of ipomoeassin F results in a substantial, yet selective, inhibition
of protein translocation in vitro and a broad ranging
inhibition of protein secretion in live cells. Lastly, the unique
resistance profile demonstrated by specific amino acid single-point
mutations in Sec61α provides compelling evidence that Sec61α
is the primary molecular target of ipomoeassin F and strongly suggests
that the binding of this natural product to Sec61α is distinctive.
Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based
member of a novel structural class that offers new opportunities to
explore Sec61α function and to further investigate its potential
as a therapeutic target for drug discovery.
Convergent total synthesis of bryostatin 8 has been accomplished by an organosilane-based strategy. The C ring is constructed stereoselectively through a geminal bis(silane)-based [1,5]-Brook rearrangement, and the B ring through geminal bis(silane)-based Prins cyclization, thus efficiently joining the northern and southern parts of the molecule.
Ipomoeassin F, a plant-derived macrolide, exhibited single-digit nanomolar growth inhibition activity against many cancer cell lines. In this report, a series of 5-oxa/aza analogues was prepared and screened for cytotoxicity. Replacement of 5-CH with O/NH simplified the synthesis and led to only a small activity loss. N-methylation almost completely restored the potency. Further studies with additional 5-oxa analogues suggested, for the first time, that size and flexibility of the ring also significantly influence the bioactivity of ipomoeassin F.
Geminal bis(silyl) enal 2a is shown to be a useful scaffold for anion relay chemistry (ARC) aimed at the stereoselective synthesis of C(3),O(1)-disilylated allylic alcohols. The ARC reaction is initiated by the addition of an alkyllithium to the aldehyde and features a CuCN-promoted C(sp2)-to-O 1,4-silyl migration to generate a vinylcuprate that reacts with activated electrophiles.
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