Unified Strategy Enables the Collective Syntheses of Structurally Diverse Indole Alkaloids.

Natural products and their analogues are significant sources of therapeutic lead compounds. However, synthetic strategies for generating large collections of these molecules remain a significant challenge. The most difficult step in their synthesis is the design of a common intermediate that can be easily transformed into natural products belonging to different families. This study demonstrates the evolution of synthetic tactics designed to assemble the functionalized piperidines present in indole alkaloids from a common intermediate. More importantly, we also report a previously unknown Ir- and Er-catalyzed dehydrogenative spirocyclization reaction that enables direct access to spirocyclic oxindole alkaloids. As a practical application, the asymmetric total syntheses of 29 natural alkaloids belonging to different families were accomplished by following a uniform synthetic route. The proposed methodology extends the capability of the iridium-catalyzed dehydrogenative coupling reaction to the realm of indole-alkaloid synthesis and provides new opportunities for the efficient preparation of natural product-like molecules.

Undobolins A-L, Ophiobolin-Type Sesterterpenoids from Aspergillus undulatus.

Twelve previously undescribed ophiobolin-type sesterterpenoids, undobolins A-L (1-12), were isolated from Aspergillus undulatus, and their structures were elucidated by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction experiments. Compound 1 was the second example of 20-nor-ophiobolin reported, while compounds 2-6 were notable for oxygenation of C-2, and compound 6 showed significant inhibitory activity against ConA-induced T lymphocyte proliferation with an IC50 value of 2.3 µM, which suggests a promising new direction in the quest for immunosuppressive agents.

Discovery of Natural Potent HMG-CoA Reductase Degraders for Lowering Cholesterol.

Exploitation of key protected wild plant resources makes great sense, but their limited populations become the major barrier. A particular strategy for breaking this barrier was inspired by the exploration of a resource-saving fungal endophyte Penicillium sp. DG23, which inhabits the key protected wild plant Schisandra macrocarpa. Chemical studies on the cultures of this strain afforded eight novel indole diterpenoids, schipenindolenes A-H (1-8), belonging to six diverse skeleton types. Importantly, semisyntheses suggested some key nonenzymatic reactions constructing these molecules and provided targeted compounds, in particular schipenindolene A (Spid A, 1) with low natural abundance. Remarkably, Spid A was the most potent HMG-CoA reductase (HMGCR) degrader among the indole diterpenoid family. It degraded statin-induced accumulation of HMGCR protein, decreased cholesterol levels and acted synergistically with statin to further lower cholesterol. Mechanistically, transcriptomic and proteomic profiling suggested that Spid A potentially activated the endoplasmic reticulum-associated degradation (ERAD) pathway to enhance the degradation of HMGCR, while simultaneously inhibiting the statin-activated expression of many key enzymes in the cholesterol and fatty acid synthesis pathways, thereby strengthening the efficacy of statins and potentially reducing the side effects of statins. Collectively, this study suggests the potential of Spid A for treating cardiovascular disease.

Cytotoxic C-20 non-oxygenated ent-kaurane diterpenoids from Isodon wardii.

Twenty new ent-kaurane diterpenoids, wardiisins A-T (1-20), along with two previously undescribed artefactual compounds (21 and 22) and twelve known analogues (23-34), were isolated from the aerial part of Isodon wardii. Their structures were elucidated by comprehensive analysis of spectroscopic data and single-crystal X-ray diffraction, and most of them were found to bear unusual C-12 oxygenation. Compounds 4, 7, 8, 19, 20, 21 exhibited remarkable cytotoxicity against the cancer cell lines HL-60, SMMC-7721, A-549, MDA-MB-231, and SW480, with IC50 values ranging from 0.3 to 5.2 µM. Moreover, 7 was found to induce G2/M cell cycle arrest and promote apoptosis in SW480 cell lines.

Pegriseofamines A-E: Five cyclopiazonic acid related indole alkaloids from the fungus Penicillium griseofulvum.

Five new cyclopiazonic acid related indole alkaloids, pegriseofamines A-E (1-5), were isolated from the fungus Penicillium griseofulvum. Their structures and absolute configurations were determined by NMR, HRESIMS, quantum-chemical calculation, and X-ray diffraction experiments. Among them, pegriseofamine A (1) possesses an undescribed 6/5/6/7 tetracyclic ring system generated by the fusion of an azepine and an indole unit via a cyclohexane, and the postulated biosynthetic origin of 1 was discussed. Compound 4 could relieve liver injury and prevent hepatocyte apoptosis in ConA-induced autoimmune liver disease.

Asymmetric Total Synthesis of Antibiotic Elansolid A.

Elansolid A is a structurally complex polyketide macrolactone natural product that exhibits promising antibacterial properties. Its challenging asymmetric total synthesis was achieved by a convergent strategy, in which the tetrahydroindane core of the molecule and an eastern vinyl iodide moiety were combined as the main fragments. The central tetrahydroindane motif was constructed with high stereoselectivity by a bioinspired intramolecular Diels-Alder cycloaddition, generating four stereogenic centers in a single step. The stereocontrol of this key step could be achieved by virtue of a 1,3-allylic strain generated by the temporary introduction of a steric-directing iodine substituent on the substrate. The formation of the macrolactone motif that completes the synthesis was achieved via two different retrosynthetic disconnections, namely, a Suzuki-Miyaura cross-coupling or an alternative Mukaiyama esterification reaction.

Scopariusicides D-M, ent-clerodane-based isomeric meroditerpenoids with a cyclobutane-fused γ/δ-lactone core from Isodon scoparius.

Scopariusicides D-M (1-10), ten new ent-clerodane-based meroditerpenoids with a cyclobutane-fused γ/δ-lactone core, were isolated from Isodon scoparius. Their structures were determined by comprehensive analysis of spectroscopic data, single-crystal X-ray diffraction, chemical transformation, and TDDFT ECD calculation. A plausible biosynthetic pathway of 1-10 was proposed in which the asymmetrical cyclobutane ring was formed via a crossed "head-to-tail" intermolecular [2 + 2] cycloaddition in anti/syn facial approaches between an ent-clerodane lactone and a cis-4-hydroxycinnamic acid. Bioactivity evaluation manifested that 5 exhibited significant neuroprotective effect against corticosterone-induced injury in PC12 cells, while 6 and 7 exhibited moderate immunosuppressive activity against human T cell proliferation stimulated by anti-CD3/anti-CD28 mAb.

Spiroligustolides A and B: Two pairs of enantiomeric spiro-orthoester-containing phthalide dimers as Cav3.1 calcium channel inhibitors from Ligusticum Chuanxiong Hort.

Two pairs of unprecedented enantiomeric phthalide dimers, spiroligustolides A (1a/1b) and B (2a/2b), featuring a unique spiroorthoster linkage between two monomeric units to form a 5/6/5/6/6-fused ring system, were isolated from the roots of Ligusticum chuanxiong. The structures and relative configurations of 1 and 2 were determined by HR-ESI-MS, IR, and NMR spectroscopic data, coupled with single-crystal X-ray diffraction analysis, and the absolute configurations of 1a, 1b, 2a, and 2b were established by comparing the experimental and calculated electronic circular dichroism (ECD) data. Plausible biosynthetic pathway for 1 and 2 was proposed. Moreover, compounds 1, 1b, and 2b showed remarkable inhibitory activities on Cav3.1 calcium channel with IC50 values of 8.34, 7.08, and 8.60 µM, respectively.

Structurally diverse diterpenoids from Isodon oresbius and their bioactivity.

Twelve new diterpenoids, isoresbins A-L (1-12), together with twenty-eight known ones, were isolated from the aerial parts of Isodon oresbius. Their diverse structures included 6,7-seco-ent-kaurane, 7,20-epoxy-ent-kaurane, 6,7:8,15-diseco-ent-kaurane, and abietanes skeletons, which were elucidated by spectroscopic data interpretation, single-crystal X-ray diffraction, and quantum chemical calculation. Isoresbins A (1) and B (2) possessed a new rearranged 15(8 â†’ 11)-abeo-6,7-seco-ent-kaurane skeleton. 1 and 5 promoted lysosomal function, which was evaluated by LysoTracker Red staining and DQ-ovalbumin dequenching assay. 1 showed cytotoxicity against six human tumor cell lines with IC50 values in 2.07-4.04 µM range. Moreover, 1 induced damage of mitochondrial membrane potential, G2/M cell cycle arrest and apoptosis in SW480 cells.

Anti-Neuroinflammatory Activity of New Naturally Occurring Benzylated Hydroxyacetophenone Analogs from the Endophytic Fungus Alternaria sp. J030.

Chemical studies on the culture broth of the endophytic fungus Alternaria sp. J030 led to the identification of three benzylated hydroxyacetophenone derivatives, bauvaroalterins A-C (1-3), and 34 structurally diverse metabolites (4-37). The new structures were elucidated by extensive spectroscopic analyses including UV, IR, 1D and 2D NMR, HR-ESI-MS, and further confirmed using single crystal X-ray diffraction. The in vitro anti-neuroinflammatory effects of the co-isolated metabolites were evaluated in lipopolysaccharide (LPS)-stimulated microglial cells. Compounds 1-3 were shown to significantly reduce LPS-induced NO production by inhibiting the expression of iNOS, as well as inhibiting LPS-induced production of the inflammatory factors TNF-α, IL-1ß and IL-6. Further studies revealed that 1-3 were capable of down-regulating the expression of NF-κB subunits p50 and p65, thereby suppressing the activation of NF-κB by inhibiting the LPS-induced phosphorylation of IκB-α. Together these findings demonstrate that bauvaroalterins A-C (1-3) exert anti-neuroinflammatory effects via inhibition of the NF-κB/iNOS signalling pathway in LPS induced BV-2 cells.

Immunosuppresive Sesterterpenoids and Norsesterterpenoids from Colquhounia coccinea var. mollis.

A pair of new C-14 epimeric sesterterpenoids, colquhounoid D (1) and 14-epi-colquhounoid D (2), and five degradation products featuring new C20 and C21 frameworks, norcolquhounoids A-E (3-7), were isolated from Colquhounia coccinea var. mollis. Their structures were elucidated by comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Degradation of the C25 skeleton to the C21 skeleton was also achieved using aqueous NaIO4 and RuCl3. Compounds 1 and 2 showed significant immunosuppressive activity on the cytokine IFN-γ secretion of mouse splenocytes induced by anti-CD3/CD4 monoclonal antibodies, with IC50 of 8.38 and 5.79 µM, respectively, and compounds 5 and 6 were moderately active.

Bisabolane, cadinane, and cyclonerane sesquiterpenes from an algicolous strain of Trichoderma asperelloides.

Ten new bisabolane derivatives, trichobisabolins Q-Z (1-10), one new cadinane derivative, cadin-4-en-11-ol (11), and three new cyclonerane derivatives, cycloner-3-en-7,11-diol (12), isoepicyclonerodiol oxide (13), and norepicyclonerodiol oxide (14), were isolated from the endophytic fungal strain RR-dl-6-11 of Trichoderma asperelloides that was obtained from a marine alga. Their structures along with relative configurations were established mainly by NMR and IR as well as MS techniques, and the absolute configurations of 10 and 11 were assigned by ECD and X-ray diffraction data, respectively. Sesquiterpenes from the fungus T. asperelloides are reported for the first time. It is interesting that half of the bisabolane derivatives are demethylated. Compound 12 represents the first the occurrence of cyclopentenyl-bearing cycloneranes, and 14 seems a cyclopentyl-degrading cyclonerane derivative. Several isolates feature potent inhibition of marine phytoplankton species.

Neuroprotective schinortriterpenoids from Schisandra neglecta collected in Medog County, Tibet, China.

Schisdilactones K-U (1-11), a series of previously unreported 16,17-secopreschisanartane-type schinortriterpenoids (SNTs), were isolated from the leaves and stems of Schisandra neglecta A. C. Smith. Their structures were mainly established through analysis of their spectroscopic data. Besides, schisdilactones K (1), O (5) and R (8) were confirmed by single-crystal X-ray crystallographic analysis, and the configurations of schisdilactones T and U (10 and 11) were elucidated via quantum chemical calculation of their NMR chemical shifts and electronic circular dichroism (ECD) spectra. Schisdilactones L-S (2-8) and U (11) were found to exhibit moderate protective activities against corticosterone-induced apoptosis of PC12 cells at 20 µM, with cell viability in the range of 62.95-66.97%.

Pesimquinolones I-S, eleven new quinolone alkaloids produced by Penicillium simplicissimum and their inhibitory activity on NO production.

Eleven undescribed quinolone alkaloids, pesimquinolones I-S (1-4 and 6-12), as well as eleven known congeners (5 and 13-22), were isolated from the solid culture broth of the fungus Penicillium simplicissimum. Their chemical structures with absolute configurations were established by a combination of NMR spectroscopy, single-crystal X-ray crystallography, and modified Mosher's methods. Pesimquinolones I-K (1-3) represent the first examples of natural occurring quinolone alkaloids that possess a 6/6/6/6 tetracyclic ring system. The anti-inflammatory activities of selected compounds on LPS-induced nitric oxide (NO) production in adherent cells were evaluated. Compounds 1 and 2 showed suppressive effects on the production of NO, with IC50 values of 10.13 and 8.10 µM, respectively.

(-)-Isoscopariusin†A, a Naturally Occurring Immunosuppressive Meroditerpenoid: Structure Elucidation and Scalable Chemical Synthesis.

(-)-Isoscopariusin A was isolated from the aerial parts of Isodon scoparius. Chemical synthesis and spectroscopic analysis established its structure as an unsymmetrical meroditerpenoid bearing a sterically congested 6/6/4 tricyclic carbon skeleton with seven continuous stereocenters. A gram-scale synthesis was achieved in 12 steps from commercially available (+)-sclareolide. A cobalt catalyzed, hydrogen atom transfer-based olefin isomerization was used to prepare a trisubstituted alkene, which underwent stereoselective [2+2] cycloaddition with a substituted keteniminium ion generated in situ from the corresponding amide. The cyclobutanone product was further elaborated into the fully substituted cyclobutane core through face-selective homologation, and the two side chains were installed by using nickel-catalyzed cross-electrophile coupling and carbodiimide-mediated esterification, respectively. (-)-Isoscopariusin A displayed selective inhibition of T-cell proliferation.

Huperserratines A and B, Two Macrocyclic Lycopodium Alkaloids with an Unusual Skeleton from Huperzia serrata.

Huperserratines A (1) and B (2), two Lycopodium alkaloids with an unprecedented 5-aza-bicyclo[10.4.0]hexadecane skeleton and an oxime function, were isolated from Huperzia serrata. Their structures including absolute configurations were determined by extensive NMR spectroscopic and X-ray diffraction analysis. Compounds 1 and 2 were the first examples of macrocyclic Lycopodium alkaloids with an aza-12-membered ring. A plausible biogenetic pathway of these compounds was also proposed. Compound 1 exhibited moderate anti-HIV-1 activity with an EC50 of 52.91 µg/mL and a therapy index greater than 3.78.

Gentianelloids A and B: Immunosuppressive 10,11-seco-Gentianellane Sesterterpenoids from the Traditional Uighur Medicine Gentianella turkestanorum.

Two sesterterpenoids, possessing an unusual 10,11-seco-gentianellane skeleton, gentianelloids A and B, were isolated from a traditional Uighur medicine Gentianella turkestanorum. Through extensive spectroscopic analysis and single-crystal X-ray diffraction, their structures including absolute configurations were unambiguously determined. A plausible biosynthetic pathway for the two compounds was proposed. Both compounds showed remarkable immunosuppressive activity, including inhibition of the proliferation, activation, and cytokine IFN-γ production of T cells. The findings suggested that sesterterpenoids could contribute positively to the therapeutic effects of this popular traditional Uighur medicine.

ent-Kaurane-Based Diterpenoids, Dimers, and Meroditerpenoids from Isodon xerophilus.

Eight new diterpenoids (1-8) with varied structures were isolated from the aerial parts of Isodon xerophilus. Among them, xerophilsin A (1) was found to be an unusual meroditerpenoid representing a hybrid of an ent-kauranoid and a long-chain aliphatic ester, xerophilsins B-D (2-4) are dimeric ent-kauranoids, while xerophilsins E-H (5-8) are new ent-kauranoids. The structures of 1-8 were elucidated mainly through the analyses of their spectroscopic data. The absolute configurations of 2, 6, and 8 were confirmed by single-crystal X-ray diffraction, and the configuration of C-16 in 7 was established through quantum chemical calculation of NMR chemical shifts, as well as modeling of key interproton distances. Bioactivity evaluation of all isolated compounds revealed that 2, 3, and 5 inhibited NO production in LPS-stimulated RAW264.7 cells.

Callicarpins, Two Classes of Rearranged ent-Clerodane Diterpenoids from Callicarpa Plants Blocking NLRP3 Inflammasome-Induced Pyroptosis.

Callicarpins A-D (1-4), possessing an unprecedented A-homoent-clerodane scaffold with a bicyclo[5.4.0]undecane ring system, and callicarpins E-G (5-7), with 5/6-fused ent-clerodane diterpenoid skeletons, were isolated from Callicarpaarborea and C. integerrim. Their structures were elucidated by comprehensive spectroscopic data, X-ray crystal diffraction, chemical derivatization, and electronic circular dichroism (ECD) data. Putative biosynthetic pathways for these callicarpins are proposed. Compounds 2, 3b, and 6-8 showed potent inhibitory effects against the NLRP3 inflammasome with IC50 values from 1.4 to 5.3 µM, and 2 significantly blocked NLRP3 inflammasome-induced pyroptosis by inhibiting Casp-1 activation and IL-1ß secretion in J774A.1 cells.

Neuroprotective schinortriterpenoids with diverse scaffolds from Schisandra henryi.

Eleven undescribed schinortriterpenoids (SNTs) and one known analogue (12) were isolated from the stems and leaves of Schisandra henryi. Their diverse structures included preschisanartane (1), 18-norschiartane (2-5, 12), schiartane (6 and 7), and schisanartane (8-11) skeletons, which were elucidated by comprehensive NMR, MS, electronic circular dichroism analyses, single crystal X-ray diffraction and biogenetic considerations. 1 was the first case of preschisanartane-type SNT with six-membered lactone ring, and 2 was one of the most highly oxygenated 18-norschiartane SNTs. Three types of the highly oxygenated SNTs, 1, 4, 10 and 11, effectively prevent apoptosis induced by corticosterone in PC12 cells. In addition, 11 showed neurite outgrowth-promoting activity.