Chunmei Chen

Bioactive Acylphloroglucinols with Adamantyl Skeleton from Hypericum sampsonii

Hyperisampsins A-D (1-4), with tetracyclo[6.3.1.1(3,10).0(3,7)]tridecane skeletons and seven biogenetically related congeners (5-11), were isolated from Hypericum sampsonii. Their structures were elucidated by comprehensive spectroscopic techniques. The absolute configuration of 1 was established by ECD calculations, and those of 5 and 9 were confirmed by single X-ray crystallographic analyses. Hyperisampsins A and D showed potent anti-HIV activities with EC50 of 2.97 and 0.97 μM and selectivity index of 4.80 and 7.70, respectively.

Asperchalasine A, a Cytochalasan Dimer with an Unprecedented Decacyclic Ring System, from Aspergillus flavipes

Asperchalasine A (1), the first cytochalasan dimer featuring a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of 20 chiral centers, was isolated from the culture broth of Aspergillus flavipes. Three biogenetically related intermediates, asperchalasines B-D (2-4), were also isolated. Their structures, including their absolute configurations, were elucidated using a combination of HRESIMS, NMR, ECD, molecular modeling, and single-crystal X-ray diffraction techniques. Compound 1, which possesses an unprecedented 13-oxatetracyclo[7.2.1.1(2,5).0(1,6)]tridec-8,12-dione core structure, is the first example of a dimeric cytochalasan alkaloid. The biogenetic pathways of 1-4 were described starting from the co-isolated compounds 5 and 6. More importantly, 1 induced significant G1-phase cell cycle arrest by selectively inhibiting cyclin A, CDK2 and CDK6 in cancerous, but not normal, cells, highlighting it as a potentially selective cell cycle regulator against cancer cells.

Epicochalasines A and B: Two Bioactive Merocytochalasans Bearing Caged Epicoccine Dimer Units from Aspergillus flavipes

Two bioactive merocytochalasans, epicochalasines A (1) and B (2), a new class of cytochalasans bearing unexpected scaffolds consisting of fused aspochalasin and epicoccine dimer moieties, were isolated from the liquid culture broth of Aspergillus flavipes. Both 1 and 2 possess a hendecacyclic 5/6/11/5/6/5/6/5/6/6/5 ring system containing an adamantyl cage and as many as 19 stereogenic centers; however, the fusion patterns of 1 and 2 differ greatly, thus resulting in different carbon skeletons. The absolute configurations of 1 and 2 were determined by X-ray diffraction and calculated ECD, respectively. The biogenetic pathways of 1 and 2 are proposed to involve Diels-Alder and nucleophilic addition reactions. Both 1 and 2 induced significant G2/M-phase cell-cycle arrest. Furthermore, we found that merocytochalasans induce apoptosis in leukemia cells through the activation of caspase-3 and the degradation of PARP.

Armochaeglobines A and B, Two New Indole-Based Alkaloids from the Arthropod-Derived Fungus Chaetomium globosum

Armochaeglobines A (1) and B (2), two indole-based cytochalasan alkaloids with new carbon skeletons, were obtained from the fungus Chaetomium globosum TW1-1, which was first isolated from the arthropod Armadillidium vulgare. Their structures were elucidated by extensive spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction analysis. Interestingly, compound 1 featured a unique tetracyclic 5/6/7/5 fused ring system and 2 possessed a rare 12-membered carbon scaffold.

Hyperascyrones A-H, polyprenylated spirocyclic acylphloroglucinol derivatives from Hypericum ascyron Linn.

Eight polyprenylated spirocyclic acylphloroglucinol derivatives (PSAPs), hyperascyrones A-H, were isolated from the aerial parts of Hypericum ascyron Linn., together with six known analogs. Their structures were established by spectroscopic analyses including HRESIMS, 1D and 2D NMR, and their absolute configurations were determined by electronic circular dichroism calculations (ECD, Gaussian 09). Structures of previously reported tomoeones C, D, G, and H were revised. Hyperascyrones A-H were evaluated for their cytotoxic and anti-HIV-1 activities, with hyperascyrones C and G exhibiting significant cytotoxicities against HL-60 cell lines with IC50 values of 4.22 and 8.36 μM, respectively. In addition, the chemotaxonomic significance of these compounds was also discussed.

Armochaetoglobins A–J: Cytochalasan Alkaloids from Chaetomium globosum TW1-1, a Fungus Derived from the Terrestrial Arthropod Armadillidium vulgare

Ten new cytochalasan alkaloids, termed armochaetoglobins A-J (1-10), and four known chaetoglobosins (11-14) were isolated from a methanol extract of Chaetomium globosum TW1-1, a fungus isolated from the medicinal terrestrial arthropod Armadillidium vulgare. Their structures were elucidated by a combination of spectroscopy, single-crystal X-ray crystallography, and ECD calculations. Armochaetoglobins A-E (1-5) represented the first examples of seco-chaetoglobosins arising from an oxidative cleavage of C-19 and C-20. Among these compounds, armochaetoglobin A (1) features an unusual pyrrole ring. The cytotoxic activities of 2-10 were evaluated, and armochaetoglobin H (8) showed moderate inhibitory activities against five human cancer cell lines, with IC50 values ranging from 3.31 to 9.83 μM.

(±)-Japonicols A–D, Acylphloroglucinol-Based Meroterpenoid Enantiomers with Anti-KSHV Activities from Hypericum japonicum

(±)-Japonicols A-D (1a/1b-4a/4b), four pairs of new phloroglucinol-based terpenoid enantiomers, were isolated from Hypericum japonicum. Their absolute configurations were confirmed through comparison of their experimental and calculated electronic circular dichroism spectra and single-crystal X-ray diffraction analyses. Compounds 1a/1b, 2a/2b, and 3a/3b possess 2-oxabicyclo[3.3.1]nonane, pyrano[3,2-b]pyran, and benzo[b]cyclopenta[e]oxepine ring systems, respectively. The effects of the phloroglucinols on anti-Kaposis sarcoma-associated herpesvirus were assessed, and 2a exhibited a moderate inhibitory effect, with an EC50 value of 8.75 μM and a selectivity index of 16.06.

Asperflavipine A: A Cytochalasan Heterotetramer Uniquely Defined by a Highly Complex Tetradecacyclic Ring System from Aspergillus flavipes QCS12

Asperflavipines A (1) and B (2), two structurally complex merocytochalasans, were isolated from Aspergillus flavipes. Asperflavipine A (1), which contains two cytochalasan moieties and two epicoccine moieties, is the first cytochalasan heterotetramer to be discovered. It is uniquely defined by 5/6/11/5/6/5/6/5/6/5/5/11/6/5 fused tetradecacyclic rings with three continuous bridged ring systems. Asperflavipine B (2) is a cytochalasan heterotrimer containing a cytochalasan and two epicoccine moieties with a 5/6/11/5/5/6/5/6/5 nonacyclic ring system. The hypothetical biosynthesis of 1 and 2 is proposed to involve Diels-Alder and [3+2] cycloaddition reactions as key steps and reveals unparalleled plasticity in the biosynthesis of merocytochalasans. The existence of 1 adds a new dimension to the diversity of the cytochalasan family. Compound 1 showed moderate cytotoxicity and induced apoptosis in Jurkat, NB4, and HL60 cells through the activation of caspase-3 and degradation of poly(ADP-ribose) polymerase (PARP).

Hyperisampsins H–M, Cytotoxic Polycyclic Polyprenylated Acylphloroglucinols from Hypericum sampsonii

Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), named hyperisampsins H–M (1–6), were isolated from the aerial parts of Hypericum sampsonii, together with five known analogs (7–11). The structures of 1–6 were established by extensive spectroscopic analyses, including HRESIMS and NMR. In addition, the absolute configurations of these new compounds were determined by electronic circular dichroism (ECD) calculations. Compounds 1 and 2 represent the first examples of PPAPs possessing a unique γ-lactone ring at C-23, while 3–6 differed from normal PPAPs with an unprecedented 1,2-dioxane ring. Compounds 1–7 were evaluated for their cytotoxic activities against a panel of human cancer cell lines in vitro, of which 3, 4, and 6 exhibited significant cytotoxic activities with IC50 values ranging from 0.56 to 3.00 μM. Moreover, compound 3 induces leukemia cell apoptotic death, evidenced by activation of caspase-3, degradation of PARP, up-regulation of Bax, and down-regulation of Bcl-2 and Bcl-xl.

Aspergilasines A–D: Four Merocytochalasans with New Carbon Skeletons from Aspergillus flavipes QCS12

Aspergilasines A-D (1-4), four merocytochalasans with new skeletons, were isolated from the liquid culture broth of Aspergillus flavipes QCS12. Aspergilasine A (1) possesses a uniquely caged pentacyclo[7.2.0.14,11.02,7.05,10]dodecane skeleton with an unexpected cyclobutane ring that formed by the fusion of two epicoccine moieties via two [3 + 2] cycloadditions. Aspergilasines B-D (2-4) are key biosynthetic intermediates of epicochalasine B that fit well with our previous biosynthetic proposal.