Weiming Zhu

New quinazolinone alkaloids within rare amino acid residue from coral-associated fungus, Aspergillus versicolor LCJ-5-4.

Cottoquinazoline D (3), a new alkaloid with a 1-aminocyclopropane-1-carboxylic acid residue rarely discovered in nature, was isolated and identified together with two new quinazolinone alkaloids, cottoquinazolines B (1) and C (2), from coral-associated fungus Aspergillus versicolor LCJ-5-4. Their structures including absolute configurations were elucidated based on spectroscopic methods, X-ray single crystal diffraction analysis, and chemical methods. A possible biogenetic pathway for them was proposed.

Novel cyclic hexapeptides from marine-derived fungus, Aspergillus sclerotiorum PT06-1.

Two novel cyclic hexapeptides containing both anthranilic acid and dehydroamino acid units, sclerotides A (1) and B (2), were isolated from the marine-derived halotolerant Aspergillus sclerotiorum PT06-1 in a nutrient-limited hypersaline medium. Both 1 and 2 are photointerconvertible and could be interconverted via a radical reaction initiated by direct photoisomerization. Both compounds showed moderate antifungal activity. Compound 2 also showed weak cytotoxicity and antibacterial activity.

Streptocarbazoles A and B, Two Novel Indolocarbazoles from the Marine-Derived Actinomycete Strain Streptomyces sp. FMA

Streptocarbazoles A (1) and B (2), two novel indolocarbazoles featuring unprecedented cyclic N-glycosidic linkages between 1,3-carbon atoms of the glycosyl moiety and two indole nitrogen atoms of the indolocarbazole core, were isolated from the marine-derived actinomycetes strain Streptomyces sp. FMA. Their structures were established by spectroscopic methods, CD spectra, and ECD quantum mechanical calculations. Compound 1 was cytotoxic on HL-60 and A-549 cell lines and could arrest the cell cycle of Hela cells at the G(2)/M phase.

Cyclic bipyridine glycosides from the marine-derived actinomycete Actinoalloteichus cyanogriseus WH1-2216-6.

Cyanogrisides A-D (1-4), four new glycosidic derivatives of bipyridine featuring a novel cyclic glycoside generated by vicinal hydroxyl groups of an aglycone with both the anomeric center and the adjacent carbonyl of a keto sugar, were isolated from the marine-derived actinomycete Actinoalloteichus cyanogriseus WH1-2216-6. The structures of 1-4 were elucidated by spectroscopic analysis, X-ray single crystal diffraction, CD spectra, and chemical methods.

Identification of caerulomycin A gene cluster implicates a tailoring amidohydrolase.

The biosynthetic gene cluster for caerulomycin A (1) was cloned and characterized from the marine actinomycete Actinoalloteichus cyanogriseus WH1-2216-6, which revealed an unusual hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) system. The crmL disruption mutant accumulated caerulomycin L (2) with an extended L-leucine at C-7, implicating an amidohydrolase activity for CrmL. The leucine-removing activity was confirmed for crude CrmL enzymes. Heterologous expression of the 1 gene cluster led to 1 production in Streptomyces coelicolor.

New indolocarbazoles from a mutant strain of the marine-derived actinomycete Streptomyces fradiae 007M135.

Fradcarbazoles A-C (1-3), three new indolocarbazoles, were isolated from a mutant strain of the marine-derived actinomycete Streptomyces fradiae 007M135. Their structures were established by spectroscopic analysis, quantum chemical calculation, CD spectra, and chemical transformation. Fradcarbazole A (1) possessed a unique skeleton consisting of a staurosporine core, a thiazole ring, and an indole fragment. Compounds 1-3 displayed significant cytotoxicity against HL-60, K562, A-549, and BEL-7402 cell lines and inhibitory effects on the kinase PKC-α with IC(50) values of 0.001-4.58 μM.

Cyanogramide with a New Spiro[indolinone-pyrroloimidazole] Skeleton from Actinoalloteichus cyanogriseus

Cyanogramide (1), an unprecedented alkaloid bearing a novel spirocyclic pyrrolo[1,2-c]imidazole skeleton, was identified from the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus WH1-2216-6. The structure was fully determined by spectroscopic analysis, an exciton chirality CD method, and quantum mechanical calculations. Cyanogramide (1) could efficiently reverse the adriamycin-induced resistance of K562/A02 and MCF-7/Adr cells, and the vincristine-induced resistance of KB/VCR cells at a concentration of 5 μM, with the reversal fold values of 15.5, 41.5, and 9.7, respectively.

Bisindolylmaleimide alkaloid BMA-155Cl induces autophagy and apoptosis in human hepatocarcinoma HepG-2 cells through the NF-κB p65 pathway

Bisindolylmaleimides, a series of derivatives of a PKC inhibitor staurosporine, exhibit potential as anti-cancer drugs and have received considerable attention in clinical trials. This study aims to investigate the effects of a bisindolylmaleimide alkaloid 155Cl (BMA-155Cl) with a novel structure on autophagy and apoptosis in human hepatocarcinoma HepG-2 cells in vitro and in vivo. The cell poliferation was assessed with a MTT assay. Autophagy was evaluated by MDC staining and TEM analysis. Apoptosis was investigated using Annexin V-FITC/PI and DAPI staining. The antitumor effects were further evaluated in nude mice bearing HepG-2 xenografts, which received BMA-155Cl (10, 20 mg/kg, ip) for 18 days. Autophagy- and apoptosis-associated proteins and their mRNA levels were examined with Western blotting, immunohistochemistry, and RT-PCR. BMA-155Cl (2.5–20 μmol/L) inhibited the growth of HepG-2 cells with IC50 values of 16.62±1.34, 12.21±0.83, and 8.44±1.82 μmol/L at 24, 48, and 72 h, respectively. Furthermore, BMA-155Cl (5–20 μmol/L) dose-dependently induced autophagy and apoptosis in HepG-2 cells. The formation of autophagic vacuoles was induced by BMA-155Cl (10 μmol/L) at approximately 6 h and peaked at approximately 15 h. Pretreatment with 3-MA potentiated BMA-155Cl-mediated apoptotic cell death. This compound dose-dependently increased the mRNA and protein levels of Beclin-1, NF-κB p65, p53, and Bax, but decreased the expression of IκB and Bcl-2. Pretreatment with BAY 11-7082, a specific inhibitor of NF-κB p65, blocked BMA-155Cl-induced expression of autophagy- and apoptosis-associated proteins. BMA-155Cl administration effectively suppressed the growth of HepG-2 xenografts in vivo, and increased the protein expression levels of LC3B, Beclin-1, NF-κB p65, and Bax in vivo. We conclude that the NF-κB p65 pathway is involved in BMA-155Cl-triggered autophagy, followed by apoptosis in HepG-2 cells in vitro and in vivo. Hence, BMA-155Cl could be a promising pro-apoptotic candidate for developing as a novel anti-cancer drug.

Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and plays important roles in multiple aspects of cancer aggressiveness. Thus, targeting STAT3 promises to be an attractive strategy for the treatment of advanced metastatic tumors. Bisindolylmaleimide alkaloid (BMA) has been shown to have anti-cancer activities and was thought to suppress tumor cell growth by inhibiting protein kinase C. In this study, we show that a newly synthesized BMA analog, BMA097, is effective in suppressing tumor cell and xenograft growth and in inducing spontaneous apoptosis. We also provide evidence that BMA097 binds directly to the SH2 domain of STAT3 and inhibits STAT3 phosphorylation and activation, leading to reduced expression of STAT3 downstream target genes. Structure activity relationship analysis revealed that the hydroxymethyl group in the 2,5-dihydropyrrole-2,5-dione prohibits STAT3 inhibitory activity of BMA analogs. Altogether, we conclude that the synthetic BMA analogs may be developed as anti-cancer drugs by targeting and binding to the SH2 domain of STAT3 and inhibiting the STAT3 signaling pathway.