Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core

Abstract

Golgi-modifying properties of the spongian diterpene macfarlandin E (MacE) and a synthetic analog, t-Bu-MacE, containing its 2,7-dioxabicyclo[3.2.1]octan-3-one moiety are reported. Natural product screening efforts identified MacE as inducing a novel morphological change in Golgi structure defined by ribbon fragmentation with maintenance of the resulting Golgi fragments in the pericentriolar region. t-Bu-MacE, which possesses the substituted 2,7-dioxabicyclo[3.2.1]octan-3-one but contains a tert-butyl group in place of the hydroazulene subunit of MacE, was prepared by chemical synthesis. Examination of the Golgi-modifying properties of MacE, t-Bu-MacE, and several related structures revealed that the entire oxygen-rich bridged-bicyclic fragment is required for induction of this unique Golgi organization phenotype. Further characterization of MacE-induced Golgi modification showed that protein secretion is inhibited, with no effect on the actin or microtubule cytoskeleton being observed. The conversion of t-Bu-MacE and a structurally related des-acetoxy congener to substituted pyrroles in the presence of primary amines in protic solvent at ambient temperatures suggests that covalent modification might be involved in the Golgi-altering activity of MacE.organelle organization | chemical biology | natural product | reactivity

Divergent Synthesis and Chemical Reactivity of Bicyclic Lactone Fragments of Complex Rearranged Spongian Diterpenes

“…31 In our initial efforts, we cleaved the double bond of 25 by reaction with OsO 4 and NaIO 4 , followed by addition of trimethylsilyldiazomethane 32 to the crude product mixture to provide tricarbonyl product 24 in useful, albeit variable, yields (55–84%). 6 To improve the reproducibility of this conversion and avoid the undesirable use of TMSCHN 2 , an alternate sequence was developed. In this improved procedure, enoxysilane 25 was oxidized with OsO 4 (0.05 equiv) and N -methylmorpholine- N -oxide (NMO, 2.0 equiv), followed by cleavage of the resulting α-hydroxyketone with 1.3 equiv of methanolic Pb(OAc) 4 , a sequence that reproducibly delivered tricarbonyl intermediate 24 in 95% yield.…”

“…6 Additionally, we showed that t -Bu-MacE ( 13 ) and its deacetoxy congener 14 are converted to substituted pyrroles such as 15 and 16 in the presence of primary amines under mild conditions (eq 1). This latter finding suggests a functional role for the oxygenated ring system of MacE—formation of a protein-bound pyrrole species—which could be responsible for the unique biological properties of these compounds.…”

“…5 In addition, we reported in 2010 that macfarlandin E ( 4 , MacE) and a simplified analog 13 ( t -Bu-MacE, see eq 1) induce a novel Golgi organization phenotype that is characterized by small, pericentriolar Golgi fragments and blockage of protein transport from the Golgi to the plasma membrane. 6 …”

“…6,7 In addition, the structure-activity relationships reported to date for these two rearranged spongian natural products are quite distinct: the hydrophobic fragment is suggested to be essential for norrisolide's activity, 7 whereas the full 4,6-diacetoxy-2,7-dioxabicylo[3.2.1]octan-3-one subunit, and not the hydroazulene fragment, is believed to be essential for eliciting the MacE-Golgi phenotype. 6 …”

Covalent modification of biological targets with natural products through Paal–Knorr pyrrole formation

“…3) as well as the blockage of protein transport from the Golgi apparatus to plasma membranes. 35,36 This activity was retained by the structurally simplified analogue 30 , indicating that the dioxabicyclic lactone fragment is the key part of the pharmacophore.…”