Synthesis of Annonaceous Acetogenins from Muricatacin

Synthetic studies of annonaceous acetogenins starting from (?)-muricatacin (1a) or (+)-muricatacin are described, involving (?)-muricatacin (1a), mono-THF acetogenin, solamin (2), reticulatacin (3), (15R, 16R, 19S, 20S)-cis-solamin (4a) and (15S, 16S, 19R, 20R)-cis-solamin (4b), non-adjacent bis-THF acetogenin, 4-deoxygigantecin (5), and epoxide-bearing acetogenin, (15S, 16R, 19S, 20R)-diepomuricanin (6a).     

Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I

Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation/ubiquinone reduction to create the proton motive force used to drive ATP synthesis in oxidative phosphorylation. High-resolution single-particle electron cryo-EM analyses have provided detailed structural knowledge of the catalytic machinery of complex I, but not of the molecular principles of its energy transduction mechanism. Although ubiquinone is considered to bind in a long channel at the interface of the membrane-embedded and hydrophilic domains, with channel residues likely involved in coupling substrate reduction to proton translocation, no structures with the channel fully occupied have yet been described. Here, we report the structure (determined by cryo-EM) of mouse complex I with a tight-binding natural product acetogenin inhibitor, which resembles the native substrate, bound along the full length of the expected ubiquinone-binding channel. Our structure reveals the mode of acetogenin binding and the molecular basis for structure–activity relationships within the acetogenin family. It also shows that acetogenins are such potent inhibitors because they are highly hydrophobic molecules that contain two specific hydrophilic moieties spaced to lock into two hydrophilic regions of the otherwise hydrophobic channel. The central hydrophilic section of the channel does not favor binding of the isoprenoid chain when the native substrate is fully bound but stabilizes the ubiquinone/ubiquinol headgroup as it transits to/from the active site. Therefore, the amphipathic nature of the channel supports both tight binding of the amphipathic inhibitor and rapid exchange of the ubiquinone/ubiquinol substrate and product.     

Probing the Ubiquinone Reduction Site in Bovine Mitochondrial Complex I Using a Series of Synthetic Ubiquinones and Inhibitors

Studies of the structure–activity relationships of ubiquinones and specific inhibitors are helpful to probe the structural and functional features of the ubiquinone reduction site of bovine heart mitochondrial complex I. Bulky exogenous short-chain ubiquinones serve as sufficient electron acceptors from the physiological ubiquinone reduction site of bovine complex I. This feature is in marked contrast to other respiratory enzymes such as mitochondrial complexes II and III. For various complex I inhibitors, including the most potent inhibitors, acetogenins, the essential structural factors that markedly affect the inhibitory potency are not necessarily obvious. Thus, the loose recognition by the enzyme of substrate and inhibitor structures may reflect the large cavitylike structure of the ubiquinone (or inhibitor) binding domain in the enzyme. On the other hand, several phenomena are difficult to explain by a simple one-catalytic site model for ubiquinone.     

Annonsilin A -- A Novel Seco-Tris-Tetrahydrofuranyl Annonaceous Acetogenin

Compound A4 isolated from the seeds of Annona squamosa L. was a new compound with structural characteristics of adjacent bis-tetrahydrofuran and seco-bis-tetrafuranyl annonaceous acetogenins. A4 was found as the first example of this new type of seco-tris-tetrahy- drofuranyl annonaceous acetogenins and was named annonsilin A.     

Squamosinin A: a Novel Para-Tris-Tetrahydrofuranyl Annonaceous Acetogenins

Compound A has been isolated from the seeds of Annona squarnosa L. It was a new compound containing C36 with para-tris-tetrahydrofuran rings. Compound A was found as the first example of the new type of para-tris-tetrahydrofuranyl annonaceous acetogenins and was named squamosinin A.     

The Chemical Constituents of Goniothalamus howii (Ⅱ)

Crystal V, VI and VII were isolated from the seeds of Goniothalamus howii Merr. Et Chun. Based on the analysis of IR, 1H-NMR, 13C-NMR, MS and spectral analysis of their derivatives, they were identified as a new type of annonaceous acetogenins—seco-biste-trahydrofuran annonaceous acetogenins. V and VI were named as howiicin D and howiicin E, respectively. VII is a mixture of two compounds, named howiicins F and C, which have the same plane structure.     

Halogenated metabolites from Japanese Laurencia spp

Further investigation of Laurencia species from Japanese waters, which were collected at three locations, yielded brominated metabolites, a labdane- type diterpene and a C15 acetogenin possessing a terminal bromoallene group. Their structures were deduced from analysis of spectroscopic data.     

Design and synthesis of C35-fluorinated solamins and their growth inhibitory activities against human cancer cell lines

The convergent synthesis of C35-fluorinated analogues of solamin, a mono-THF Annonaceous acetogenin, has been achieved by the Sonogashira coupling of the THF ring fragment and the fluorinated γ-lactone fragment. It was revealed that the number of fluorine atoms on the γ-lactone moiety affects the growth inhibitory activities against human cancer cell lines.     

海南哥纳香化学成分研究（Ⅱ）

从海南哥纳香（Ｇｏｎｉｏｔｈａｌａｍ ｕｓｈｏｗ ｉｉＭｅｒｒ． ｅｔＣｈｕｎ）的种子分离到结晶Ｖ、ＶＩ和ＶＩＩ。根据它们的ＩＲ、１Ｈ－ＮＭＲ、１３Ｃ－ＮＭＲ、ＭＳ分析及衍生物光谱分析,它们均属番荔枝内酯的新类型——裂双四氢呋喃型番荔枝内酯。晶Ｖ和晶ＶＩ分别命名为海南哥纳香丁素（ｈｏｗ ｉｉｃｉｎ Ｄ）和戊素（ｈｏｗ ｉｉｃｉｎ Ｅ）。晶ＶＩＩ系两个平面结构相同的化合物海南哥纳香己素和庚素（ｈｏｗ ｉｉｃｉｎｓ Ｆ,Ｇ）的混晶