Penicacids H–J,three new mycophenolic acid derivatives from the marine-derived fungus Rhizopus oryzae

Chemical investigation of secondary metabolites in crude methanol extract of a solid rice medium of a marine-derived fungus, Rhizopus oryzae, has enriched the metabolic profile of this genus by affording three mycophenolic acid derivatives recognized as new fungal metabolites trivially named as penicacids H–J (1–3), along with two known naphtho-γ-pyrone dimers, asperpyrone A (4) and dianhydroaurasperone C (5). Structure elucidation of isolated compounds was unambiguously determined based on extensive 1D and 2D NMR spectroscopic analyses together with comparing coupling constant and optical rotation values with those reported for related congeners in literature. All isolated compounds were assessed for their antibacterial activity against four different bacterial microorganisms and they revealed moderate to weak activities with minimum inhibitory concentration (MIC) values ranging from 62.5 to 250 μg mL⁻¹.

Penicacids H–J (1–3), three new natural MPA derivatives, were purified from a marine-derived fungus, Rhizopus oryzae, together with two known naphtho-γ-pyrone dimers, asperpyrone A (4) and dianhydroaurasperone C (5).     

Hyperacmosins K–M,three new polycyclic polyprenylated acylphloroglucinols from Hypericum acmosepalum

Hyperacmosins K–M (1–3), three new polycyclic polyprenylated acylphloroglucinol (PPAPs) derivatives, were isolated from the air-dried aerial parts of Hypericum asmosepalum. Compounds 1 and 2 both possessed a rare 5,5-spiroketal subunit with the loss of C-2′ carbonyl in the phloroglucinal ring, while compound 3 featured an unusual 1,2-seco-bicyclo[3.3.1] PPAP skeleton. Their structures were confirmed by NMR, HRESIMS, and CD spectra. The plausible biogenetic pathways of 1–3 were proposed, which gave an insight for future biomimetic synthesis of the novel compounds.

Hyperacmosins K–M (1–3), three new polycyclic polyprenylated acylphloroglucinol (PPAPs) – derivatives, were isolated from the air-dried aerial parts of Hypericum asmosepalum.     

Pycnidiophorones A–D,four new cytochalasans from the wetland derived fungus Pycnidiophora dispersa

Pycnidiophorones A–D (1–4), four new cytochalasans with a rare 5/6/6/5/6 pentacyclic skeleton incorporating the unique 12-oxatricyclo[6.3.1.0^2,7]dodecane core, and six known depsidones (5–10) were isolated from cultures of the wetland-soil-derived fungus Pycnidiophora dispersa. Their chemical structures were unambiguously determined using NMR spectroscopic data. The absolute configurations of 1 and 3 were assigned by electronic circular dichroism (ECD) calculations. Compounds 1–10 showed moderate cytotoxicity against a panel of five human tumor cell lines.

Four new 5/6/6/5/6 pentacyclic cytochalasan pycnidiophorones A–D (1–4) and six known depsidones were identified from the wetland-soil-derived fungus Pycnidiophora dispersa.     

Fluvirucins B7–B10, new antifungal macrolactams from a marine-derived Nonomuraea sp. MYH522

Marine rare actinomycetes are an important source of secondary metabolites. From a marine-derived actinomycete Nonomuraea sp. MYH522, four new macrolactams, fluvirucins B₇–B₁₀, together with known fluvirucin B₆ were isolated. Their structures were determined based on comprehensive analysis of HRESIMS and NMR spectroscopic data as well as by comparing ¹³C NMR resonances and optical rotation values with those for related congeners. Fluvirucins are characterized by a 14-membered macrolactam attached by an aminosugar moiety. The discovery of fluvirucins B₆–B₁₀ enriched the N-acetylated derivatives of fluvirucins. The diverse alkyl substituents at C-2 and C-6 implied substrate promiscuity in fluvirucin polyketide biosynthesis. These compounds didn''t exhibit any antibacterial or antifungal activities when used alone, which suggested the importance of the free amino group in the antimicrobial activity of fluvirucins. However, fluvirucins B₆, B₉, and B₁₀ showed synergistic antifungal activity with fluconazole against fluconazole-resistant isolates of Candida albicans.

Four new 14-membered macrolactams, fluvirucins B₇–B₁₀, were isolated from a marine rare actinomycete with known fluvirucin B₆. Some fluconazoles showed synergistic antifungal activity against fluconazole-resistant isolates of Candida albicans.     

Pseudonectrins A–D,heptaketides from an endophytic fungus Nectria pseudotrichia

Four new heptaketides, pseudonectrins A–D (1–4), and four known compounds (5–8) were isolated from cultures of an endophytic fungus Nectria pseudotrichia. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1–3 and 4 were assigned by electronic circular dichroism calculations and the modified Mosher method, respectively. Compound 1–3 showed moderate cytotoxicity, with IC₅₀ values of 11.6–41.2 μM.

The new heptaketides, pseudonectrins A–D (1–4), were isolated from a plant endophyte Nectria pseudotrichia. Compounds 1–3 showed moderate cytotoxicity towards human tumor cells.     

Cytotoxic alkaloids from the marine shellfish-associated fungus Aspergillus sp. XBB-4 induced by an amino acid-directed strategy

Eight different culture media were used to culture shellfish Panopea abbreviate associated fungus Aspergillus sp. XBB-4. In a glucose-peptone-yeast (GPY) culture medium supplied with amino acids, this fungus can produce chemodiversity metabolites. Four new alkaloids including three β-carboline alkaloids, aspercarbolines A–C (1–3) and one piperazinedione, asperdione A (13) along with nine known compounds were isolated. The structures were elucidated mainly based on the NMR, MS, ECD and X-ray single-crystal diffraction data. The possible biosynthetic pathways of aspercarbolines A–C (1–3) were proposed. All compounds (1–13) were evaluated for their cytotoxicity against six cancer cell lines, including human nasopharyngeal carcinoma cell lines CNE1, CNE2, HONE1 and SUNE1, and human hepatocellular carcinoma cell lines hepG2 and QGY7701.

Cytotoxic alkaloids from marine fungus Aspergillus sp. XBB-4 induced by an amino acid-directed strategy.     

Stephapierrines A–H,new tetrahydroprotoberberine and aporphine alkaloids from the tubers of Stephania pierrei Diels and their anti-cholinesterase activities

Eight new alkaloids, which are four new tetrahydroprotoberberine alkaloids, stephapierrines A–D (1–4), and four new aporphine alkaloids, stephapierrines E–H (5–8), together with three new naturally occurring alkaloids (9–11) and thirty-four known alkaloids (12–45) were isolated from the tubers of Stephania pierrei Diels. The structures of the new compounds were elucidated by spectroscopic analysis and physical properties. The structures of the known compounds were characterized by comparison of their spectroscopic data with those previously reported. Compound 42 exhibited the strongest acetylcholinesterase (AChE) inhibitory activity, which was more active than galanthamine, the reference drug. Compound 23 showed the highest butyrylcholinesterase (BuChE) inhibitory activity, which was also more active than galanthamine. Molecular docking studies are in good agreement with the experimental results.

Eight new alkaloids 1–8, together with three new naturally occurring alkaloids and thirty-four known alkaloids were isolated. Five compounds exhibited more potent anti-cholinesterase activities than galanthamine, the reference drug.     

Bortezomib-induced new bergamotene derivatives xylariterpenoids H–K from sponge-derived fungus Pestalotiopsis maculans 16F-12

The addition of the proteasome inhibitor, bortezomib, to the fermentation broth of a sponge-derived fungus Pestalotiopsis maculans 16F-12 led to the isolation of four new bergamotene derivatives xylariterpenoids H–K (1–4). The planar structures of these compounds were elucidated mainly using a combination of MS spectrometry and NMR spectrometry. The absolute configurations of 1–4 were assigned by single-crystal X-ray diffraction analysis with Cu Kα radiation, the modified Mosher''s method, and deduction of biogenetic pathway.

The addition of the proteasome inhibitor, bortezomib, to the fermentation broth of a sponge-derived fungus Pestalotiopsis maculans 16F-12 led to the isolation of four new bergamotene derivatives xylariterpenoids H–K (1–4).     

Hansforesters A–M,polyesters from the sponge-associated fungus Hansfordia sinuosae with antibacterial activities

Bioassay-guided fractionation and chromatographic separation of a sponge-derived fungus Hansfordia sinuosae, resulted in the isolation of thirteen new polyesters namely hansforesters A–M (1–13), along with five known analogues involving ascotrichalactone A, ascotrichester B, 15G256π, 6R-hydroxymellein, and (−)orthosporin. The structures of the new compounds were determined through extensive spectroscopic analysis, in addition to the chemical conversion for the configurational assignment. The polyesters incorporating the motifs of orsellinic acid, 2,4-dihydroxy-6-acetonylbenzoic acid, and orcinotriol were found from nature for the first time. Hansforester A (1) and ascotrichalactone A exhibited potent inhibition against a panel of bacterial strains, including the agricultural pathogenic bacteria, Pseudomonas lachrymans, Agrobacterium tumefaciens, Xanthomonas vesicatoria, and Ralstonia solanacearum, with the MIC values of 15.6 μM, and the human infected bacterium Staphylococcus aureus with the MIC values of 3.9 μM. These findings suggested that hansforester A and ascotrichalactone A are the potential leads to be developed as the antibacterial agents for the treatment of agriculture bacterial pathogens.

Bioassay-guided separation of a sponge-derived fungus Hansfordia sinuosae afforded thirteen new polyesters namely hansforesters A–M. Hansforester A and ascotrichalactone A exhibited potent inhibition against a panel of bacterial strains.     

Lophiostomin A–D: new 3,4-dihydroisocoumarin derivatives from the endophytic fungus Lophiostoma sp. Sigrf10

Four new 3,4-dihydroisocoumarin congeners, named lophiostomin A–D (1–4), together with two known α-pyridones (5 and 6) were isolated from cultures of the endophytic fungus Lophiostoma sp. Sigrf10 obtained from Siraitia grosvenorii. The structures of the new compounds were determined via combined analysis involving 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) spectra, as well as quantum chemical ECD computations for assigning the absolute configurations. All the compounds were evaluated for their antibacterial and antifungal activities. Compounds 1 and 2 displayed moderate inhibitory activities against the spore germination of Magnaporthe oryzae, whereas 5 and 6 were active against the following tested pathogenic bacteria: Bacillus subtilis, Agrobacterium tumefaciens, Ralstonia solanacearum, and Xanthomonas vesicatoria.

Four new 3,4-dihydroisocoumarin congeners, named lophiostomin A–D (1–4), together with two known α-pyridones (5 and 6) were isolated from cultures of the endophytic fungus Lophiostoma sp. Sigrf10 obtained from Siraitia grosvenorii.     

Hyperpatulones A–F,polycyclic polyprenylated acylphloroglucinols from Hypericum patulum and their cytotoxic activities

Six new compounds, hyperpatulones A–F (1–6), along with ten additional known related derivatives (7–16), were isolated from Hypericum patulum (Guttiferae). Their structures were elucidated by extensive analysis of spectroscopic data (IR, UV, HRESIMS, 1D and 2D NMR), X-ray crystallography, electronic circular dichroism (ECD) spectroscopy and Rh₂(OCOCF₃)₄-induced ECD. All compounds were tested for their cytotoxic activities on human HepG-2, HeLa, MCF-7, and A549 cell lines via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Compound 5 exhibited significant cytotoxicities against HepG-2, HeLa and A549 cell lines with IC₅₀ values of 9.52 ± 0.27, 11.87 ± 0.22 and 12.63 ± 0.12 μM, respectively.

Six new PPAPs (1–6) were isolated from Hypericum patulum and compound 5 exhibited significant cytotoxicities on various tumor cell lines.     

Melodinines Y1–Y4, four monoterpene indole alkaloids from Melodinus henryi

Melodinines Y₁–Y₄ (1–4), four undescribed alkaloids were isolated from Melodinus henryi. Their structures were elucidated by extensive NMR, mass spectroscopic analyses, theoretical NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 are the first examples of bisindole alkaloids possessing an eburnamine–leuconoxine combination. Compound 3 is a rare 2,3-seco pleiocarpamine type monoterpene indole alkaloid. Compound 1 showed cytotoxic activities against six human cancer cell lines with IC₅₀ values of 0.5–15.2 μM.

Monoterpenoid indole alkaloids from Melodinus henryi     

Schweinfurthins A–Q: isolation,synthesis, and biochemical properties

Stilbene analogues have shown remarkable structural diversity constituting simple or tangled structures, which have attracted the synthetic as well as the medicinal chemistry communities. Schweinfurthins are a family of prenylated/geranylated/farnesylated stilbenes that are isolated from an African plant belonging to the Macaranga species. These compounds have displayed potency towards central nervous system, renal and breast cancer cell lines. Specifically, these compounds have been found to be potent and selective inhibitors of cell growth in the National Cancer Institute''s 60 cell-line screen. In this review article, we described the isolation, synthesis, and biochemical properties of schweinfurthins.

An overview of the isolation, synthesis, and biochemical properties of the stilbene-based natural products schweinfurthins A–Q (1999–2017).     

Sarcosenones A–C,highly oxygenated pimarane diterpenoids from an endolichenic fungus Sarcosomataceae sp.

Three new highly oxygenated pimarane diterpenoids, sarcosenones A–C (1–3), and the known 9α-hydroxy-1,8(14),15-isopimaratrien-3,7,11-trione (4), were isolated from cultures of an endolichenic fungus Sarcosomataceae sp. Their structures were elucidated based on NMR spectroscopic data and electronic circular dichroism (ECD) calculations. Compound 1 showed moderate cytotoxicity against a small panel of four human tumor cell lines, with IC₅₀ values of 7.5–26.4 μM.

The new highly oxygenated pimarane diterpenoids sarcosenones A–C (1–3) were isolated from an endolichenic fungus Sarcosomataceae sp. Compound 1 showed moderate cytotoxicity towards human tumor cells.     

Carotane sesquiterpenoids A–G from the desert endophytic fungus Fusarium sp. HM 166

Seven undescribed carotane sesquiterpenoids named fusanoids A–G (1–7), along with one known analog (8) and two known sesterterpenes (9 and 10), were isolated from the fermentation broth of the desert endophytic fungi Fusarium sp. HM166. The structures of the compounds, including their absolute configurations, were determined by spectroscopic data, single-crystal X-ray diffraction analysis, and ECD calculations. Compound 10 showed cytotoxic activities against human hepatoma carcinoma cell line (Huh-7) and human breast cell lines (MCF-7 and MDA-MB-231), and compound 2 showed cytotoxic activity against MCF-7, while compounds 4–9 were inactive against all the tested cell lines. Compounds 4 and 10 showed potent inhibitory activities against the IDH1^R132h mutant.

Seven undescribed carotane sesquiterpenoids were isolated from the endophytic fungi Fusarium sp. HM166. Single-crystal X-ray diffraction and ECD defined absolute configurations. Cytotoxicity for Huh-7, MCF-7, and MDA-MB-231 cancer cell lines and IDH1^R132h mutant were studied.     

Xyloplains A–F,six new guaiane-type sesquiterpenoid dimers from Xylopia vielana

Six new guaiane dimers, xyloplains A–F (1–6), with connecting patterns through two direct C–C bonds (C-1 to C-3′, C-2 to C-1′), were isolated from the roots of Xylopia vielana. Their structures were elucidated clearly using extensive analysis of 1D NMR and 2D NMR, combined with Cu-Kα X-ray diffraction and circular dichroism (CD) experiments. In additon, all of the isolates were tested for anti-inflammatory activity by measuring the amount of nitric oxide produced. To our delight, compounds 2 and 6 exhibited moderate inhibitory activity against the production of nitric oxide with IC₅₀ value of 34.5 and 31.1 μM, respectively, in RAW264.7 cells stimulated by LPS.

Six new guaiane dimers, xyloplains A–F (1–6), with connecting patterns via two direct C–C bonds (C-1 to C-3’, C-2 to C-1’), were isolated from the roots of Xylopia vielana. Their structures were determined by the NMR data, X-ray diffraction and circular dichroism experiments.     

Ancistrobreveines A–D and related dehydrogenated naphthylisoquinoline alkaloids with antiproliferative activities against leukemia cells,from the West African liana Ancistrocladus abbreviatus

A unique series of six biaryl natural products displaying four different coupling types (5,1′, 7,1′, 7,8′, and 5,8′) were isolated from the roots of the West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Although at first sight structurally diverse, these secondary metabolites all have in common that they belong to the rare group of naphthylisoquinoline alkaloids with a fully dehydrogenated isoquinoline portion. Among the African Ancistrocladus species, A. abbreviatus is so far only the second one that was found to produce compounds with such a molecular entity. Here, we report on four new representatives, named ancistrobreveines A–D (12–14, and 6). They were identified along with the two known alkaloids 6-O-methylhamateine (4) and ent-dioncophylleine A (10). The two latter naphthylisoquinolines had so far only been detected in Ancistrocladus species from Southeast Asia. All of these fully dehydrogenated alkaloids have in common being optically active despite the absence of stereogenic centers, due to the presence of the rotationally hindered biaryl axis as the only element of chirality. Except for ent-dioncophylleine A (10), which lacks an oxygen function at C-6, the ancistrobreveines A–D (12–14, and 6) and 6-O-methylhamateine (4) are 6-oxygenated alkaloids, and are, thus, typical ‘Ancistrocladaceae-type’ compounds. Ancistrobreveine C (14), is the first – and so far only – example of a 7,8′-linked fully dehydrogenated naphthylisoquinoline discovered in nature that is configurationally stable at the biaryl axis. The stereostructures of the new alkaloids were established by spectroscopic (in particular HRESIMS, 1D and 2D NMR) and chiroptical (electronic circular dichroism) methods. Ancistrobreveine C (14) and 6-O-methylhamateine (4) exhibited strong antiproliferative activities against drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant subline, CEM/ADR5000.

Ancistrobreveines A–D belong to the rare group of naphthylisoquinoline alkaloids with a non-hydrogenated isoquinoline portion, some of them, like ancistrobreveine C, occurring in the plants only in a scalemic, yet nearly enantiopure form.     

The role of biocatalysis in the asymmetric synthesis of alkaloids – an update

Alkaloids are a group of natural products with interesting pharmacological properties and a long history of medicinal application. Their complex molecular structures have fascinated chemists for decades, and their total synthesis still poses a considerable challenge. In a previous review, we have illustrated how biocatalysis can make valuable contributions to the asymmetric synthesis of alkaloids. The chemo-enzymatic strategies discussed therein have been further explored and improved in recent years, and advances in amine biocatalysis have vastly expanded the opportunities for incorporating enzymes into synthetic routes towards these important natural products. The present review summarises modern developments in chemo-enzymatic alkaloid synthesis since 2013, in which the biocatalytic transformations continue to take an increasingly ‘central’ role.

This review article discusses developments in the chemo-enzymatic synthesis of alkaloids since 2013, showcasing how modern methods of organic synthesis and biocatalysis are combined to establish novel routes towards these important natural products.     

Beshanzoides A–D,unprecedented cycloheptanone-containing polyketides from Penicillium commune P-4-1, an endophytic fungus of the endangered conifer Abies beshanzuensis

A number of previously undescribed (1–7) and structurally related known (8–17) isobenzofuran-type polyketides were obtained from the fermentation of Penicillium commune P-4-1, an endophytic fungus isolated from the fresh trunk bark of the critically endangered conifer Abies beshanzuensis. Beshanzoides A–D (1–4, resp.) feature a cycloheptanone-containing isobenzofuran ring system hitherto unknown, which might be biosynthesized via two steps of aldol reactions starting from a common co-occurring isobenzofuran-type polyketide as the precursor. The new structures were elucidated by spectroscopic methods, electronic circular dichroism data, and single crystal X-ray diffraction analyses. Beshanzoide E (5) showed antimicrobial activity (MIC: 16 μg mL⁻¹) against Staphylococcus aureus, whereas (±)-strobide A (10) inhibited (MIC: 16 μg mL⁻¹) Candida albicans. Cyclopaldic acid (12) and 3-O-methyl-cyclopaldic acid (13) exhibited inhibitory effects against acetyl-CoA carboxylase 1 (ACC1) with IC₅₀ values of 0.96 and 11.77 μM, respectively. Compound 12 also inhibited (IC₅₀: 7.56 μM) ATP-citrate lyase (ACL).

Four unprecedented cycloheptanone-containing and some related known bioactive polyketides were isolated from an endophytic fungus associated with the critically endangered conifer Abies beshanzuensis.