Synthesis of cytochalasan analogues with aryl substituents at position 10.

Cytochalasans are fungal metabolites that are known to inhibit actin polymerization. Despite their remarkable bioactivity, there are few studies on the structure-activity relationship (SAR) of the cytochalasan scaffold. The full potential of structural modifications remains largely unexplored. The substituent at position 10 of the cytochalasan scaffold is derived from an amino acid incorporated into the cytochalasan core, thus limiting the structural variability at this position in natural products. Additionally, modifications at this position have only been achieved through semisynthetic or mutasynthetic approaches using modified amino acids. This paper introduces a modular approach for late-stage modifications at position 10 of the cytochalasan scaffold. Iron-mediated cross-coupling reactions with corresponding Grignard reagents were used to introduce aryl or benzyl groups in position 10, resulting in the synthesis of six new cytochalasan analogues bearing non-natural aromatic residues. This methodology enables further exploration of modifications at this position and SAR studies among cytochalasan analogues.

Diversely Functionalised Cytochalasins through Mutasynthesis and Semi-Synthesis.

Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4'-substituted cytochalasin analogues in titres as high as the wild-type system (≈60 mg L-1 ). Halogenated, O-alkyl, O-allyl and O-propargyl examples were formed, as well as a 4'-azido analogue. 4'-O-Propargyl and 4'-azido analogues reacted smoothly in Huisgen cycloaddition reactions, whereas p-Br and p-I compounds reacted in Pd-catalysed cross-coupling reactions. A series of examples of biotin-linked, dye-linked and dimeric cytochalasins was rapidly created. In vitro and in vivo bioassays of these compounds showed that the 4'-halogenated and azido derivatives retained their cytotoxicity and antifungal activities; but a unique 4'-amino analogue was inactive. Attachment of larger substituents attenuated the bioactivities. In vivo actin-binding studies with adherent mammalian cells showed that actin remains the likely intracellular target. Dye-linked compounds revealed visualisation of intracellular actin structures even in the absence of phalloidin, thus constituting a potential new class of actin-visualisation tools with filament-barbed end-binding specificity.

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.

Total Syntheses of Asperchalasines†A-E.

The first total syntheses of asperchalasines A-E, a collection of unprecedented merocytochalasans, are reported. Aspochalasin B, a key tricyclic cytochalasan monomer, was first synthesized through a unified approach that hinges on a Diels-Alder reaction and a ring-closing metathesis reaction. The bioinspired Diels-Alder reactions of aspochalasin B with different epicoccine precursors were then explored, which enabled the divergent access of the heterodimers asperchalasines B-E as well as related congeners. Furthermore, the heterotrimer asperchalasine A was obtained from one epicoccine unit and two aspochalasin B units through a biomimetic Diels-Alder reaction followed by an oxidative [5+2]-cycloaddition.

Total Synthesis of Asperchalasines†A, D, E, and H.

The first total syntheses of the cytochalasan dimers asperchalasines A, D, E, and H have been accomplished. The key steps of the synthesis include a highly stereoselective intermolecular Diels-Alder reaction and a Horner-Wadsworth-Emmons macrocyclization to establish the key monomer aspochalasin B, and an intermolecular Diels-Alder reaction followed by a biomimetic oxidative heterodimerization by 5+2 cycloaddition to furnish asperchalasine A. The synthetic efforts provide insight into the biosynthetic pathway of cytochalasan dimers and enables the further study of their biological properties.

Cytochalasins from an Australian Marine Sediment-Derived Phomopsis sp. (CMB-M0042F): Acid-Mediated Intramolecular Cycloadditions Enhance Chemical Diversity.

Chemical analysis of an Australian coastal marine sediment-derived fungus, Phomopsis sp. (CMB-M0042F), yielded the known cytochalasins J (1) and H (2), together with five new analogues, cytochalasins J1-J3 (3-5) and H1 and H2 (6 and 7). Structures of 1-7 were assigned on the basis of detailed spectroscopic analysis, chemical interconversion, and biosynthetic and mechanistic considerations. Of note, 1 and 2 proved to be highly sensitive to acid-mediated transformation, with 1 affording 3-5 and 2 affording 6 and 7. Whereas 1, 2, 4, and 5 were detected as natural products in crude culture extracts, 3, 6, and 7 were designated as acid-mediated handling artifacts. We propose novel stereo- and regiospecific intramolecular cycloadditions, under tight functional group control, that facilitate selective conversion of 1 and 2 to the rare 5/6/6/7/5- and 5/6/5/8-fused heterocycles 5 and 7, respectively. Knowledge of acid sensitivity within the cytochalasin family provides a valuable cautionary lesson that has the potential to inform our analysis of past and future investigations into this structure class and inspire novel biomimetic transformations leading to new chemical diversity.

Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products.

A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering a novel, unexplored and underrepresented chemical space in fragment based drug discovery (FBDD).

First Total Synthesis, Structure Revision, and Natural History of the Smallest Cytochalasin: (+)-Periconiasin G.

The total synthesis of the smallest cytochalasin isolated so far, periconiasin G, which bears a seven-membered ring in lieu of the usual macrocycle, has been performed from both enantiomers of citronellal, relying on an intramolecular Diels-Alder reaction in favor of the natural endo stereochemistry. We show that, among the four synthesized stereoisomers, including the exo isomers, the one matching the NMR data of the natural product was not that assigned in the original report, imposing structure revision. The natural product, previously isolated from a plant-mutualistic fungus, was biologically investigated taking into account its natural history, showing significant effects against the phytopathogenic fungus Botrytis cinerea and thus opening new opportunities in combating this pest.

Total synthesis of diaporthichalasin by using the intramolecular Diels-Alder reaction of an α,ß-unsaturated γ-hydroxylactam in aqueous media.

The first total synthesis of diaporthichalasin has been successfully achieved and complete structure elucidation, including the absolute configuration, was also accomplished. The intramolecular Diels-Alder (IMDA) reaction between the diene side chain on the decalin skeleton and α,ß-unsaturated γ-hydroxy-γ-lactam in aqueous media was effectively employed as the key step. From this synthetic study, we found that α,ß-unsaturated γ-hydroxy-γ-lactam is an essential precursor for the construction of the diaporthichalasin-type pentacyclic skeleton. This important finding strongly suggests that this route is involved in the biosynthetic pathway for diaporthichalasin.

An enantioselective, modular, and general route to the cytochalasins: synthesis of L-696,474 and cytochalasin B.

The cytochalasins are structurally complex natural products with a broad range of apparently unrelated effects in different biological systems. Different members of the family have variously demonstrated inhibitory activity toward the formation of actin filaments, toward the functioning of HIV protease, and toward the process of angiogenesis. The structural series is defined by a largely conserved, rigid bicyclic isoindolone core that is fused to a macrocyclic appendage. The latter structural component varies widely within the cytochalasins and seems to play an important role in the determination of biological activity. In this work, we describe the development of a convergent and enantioselective synthetic route to the cytochalasins that allows for the late-stage introduction of macrocyclic appendages of different sizes and constitutions. We illustrate the route with the synthesis of the 14-membered macrolactone cytochalasin B (1, an inhibitor of the formation of actin filaments) and the 11-membered macrocarbocyclic cytochalasin L-696,474 (2, an inhibitor of HIV protease) by using common precursors.

Antimalarial halorosellinic acid from the marine fungus Halorosellinia oceanica.

Three known compounds, 2-hexylidene-3-methylsuccinic acid (1), cytochalasin Q (2), and 5-carboxymellein (3), together with two new derivatives, 2-hexylidene-3-methylsuccinic acid 4-methyl ester (4) and an ophiobolane sesterterpene named halorosellinic acid (5), were isolated from culture broth of the marine fungus Halorosellinia oceanica BCC 5149. Compounds 1-3 exhibited moderate cytotoxicity against KB and BC-1 cell lines with IC(50) values of 1-13 microg/mL, while compounds 2, 3, 5, and 6 showed antimalarial activity with respective IC(50) values of 17, 4, 13, and 19 microg/mL. Halorosellinic acid (5) possessed only weak antimycobacterial activity with the minimum inhibitory concentration of 200 microg/mL.

Structure-activity correlations of cytochalasins. Novel halogenated and related cytochalasin C and D derivatives.

A series of halogenated and related analogues of cytochalasin C (CC) and D (CD) has been synthesized, and the biological activities of the analogues as inhibitors in a cell-free contractility model system obtained from Ehrlich ascites tumor cells were evaluated. The reaction sequence involved treatment of CD with phenyltrimethylammonium perbromide to give 6,12-dibromo-CD (2), dehydrohalogenation of 2 to 12-bromo-CC (3), and the subsequent conversions of 3 to 12-azido- (4), 12-iodo- (5), and 12-cyano-CC (6). The ID50 values for 5, 3, 4, 2, and 6 are 6.0, 7.4, 8.8, 45, and 77 X 10(-7) M, respectively, in comparison to ca. 2.8 X 10(-7) M for the parental compounds. The potential cell and molecular biological applications of these compounds are delineated.