Proposal for the classification of sinomenine alkaloids.

The chemical structure of sinoacutine is formed by a phenanthrene nucleus and an ethylamine bridge. Because it has a similar parent structure to morphine, it is subdivided into morphinane. At present, all reports have pointed out that the basic skeleton of morphine alkaloids is salutaridine (the isomer of sinoacutine), which is generated by the phenol coupling reaction of (R)-reticuline. This study shows that the biosynthetic precursors of sinoacutine and salutaridine are different. In this paper, the sinoacutine synthetase (SinSyn) gene was cloned from Sinomenium acutum and expressed SinSyn protein. Sinoacutine was produced by SinSyn catalyzed (S)-reticuline, according to the results of enzyme-catalyzed experiments. The optical activity, nuclear magnetic resonance, and mass spectrum of sinoacutine and salutaridine were analyzed. The classification and pharmacological action of isoquinoline alkaloids were discussed. It was suggested that sinoacutine should be separated from morphinane and classified as sinomenine alkaloids.

Structural requirement of spirostanol glycosides for rat uterine contractility and mode of their synergism.

OBJECTIVES: Total steroidal saponins extracted from the rhizome of Paris polyphylla (TSSP) have been used in China for the treatment of abnormal uterine bleeding. The aim of this study was to analyse the structure-activity relationship of steroidal saponins purified from P. polyphylla Sm. var. yunnanensis on rat myometrial contractions, and investigate the synergism among themselves as well as with known inherent agonists, such as Prostaglandin F(2alpha) (PGF-2alpha). METHODS: In this study, 22 steroidal saponins purified from TSSP were screened for their contractile activity in isolated uterine strips from estrogen-primed rats. KEY FINDINGS: It was shown that spirostanol glycosides exhibited inducible or inhibitory activity in rat uterine contraction based on the difference of their structures, which was not only attributed in part to the number, the length and the position of sugar side chains attached by a glycoside, but also related to the structure of the aglycone. Furthermore, synergistic actions were observed among pennogenin or diosgenin glycosides as well as with the known inherent agonist PGF-2alpha, indicating they may share, at least in part, similar pathways with PGF-2alpha in stimulating myometrial contractions. Finally, the contractile response of rat myometrium to spirostanol glycosides was significantly enhanced with advancing pregnancy. CONCLUSIONS: Together, these data support the possibility that some spirostanol glycosides may represent a new type of contractile agonist for the uterus and their synergism may be responsible for the therapeutic effect of TSSP on abnormal uterine bleeding.

Melissoidesin G, a diterpenoid purified from Isodon melissoides, induces leukemic-cell apoptosis through induction of redox imbalance and exhibits synergy with other anticancer agents.

Melissoidesin G (MOG) is a new diterpenoid purified from Isodon melissoides, a plant used in Chinese traditional medicine as antitumor and anti-inflammatory agents. In our study, MOG was shown to specifically inhibit the growth of human leukemia cell lines and primary acute myeloid leukemia (AML) blasts via induction of apoptosis, with the evidence of mitochondrial DeltaPsim loss, reactive oxygen species production, caspases activation and nuclear fragmentation. Furthermore, it was shown that thiol-containing antioxidants completely blocked MOG-induced mitochondrial DeltaPsim loss and subsequent cell apoptosis, while the inhibition of apoptosis by benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone only partially attenuated mitochondrial DeltaPsim loss, indicating that MOG-induced redox imbalance is an early event upstream to mitochondrial DeltaPsim loss and caspase-3 activation. Consistently, it was found that MOG rapidly decreased the intracellular glutathione (GSH) content in a dose-dependent manner and the significance of GSH depletion in MOG-induced apoptosis was further supported by the protective effects of tert-butylhydroquinone (tBHQ) and the facilitative effects of DL-buthionine (S,R)-sulfoximine (BSO). Furthermore, it was showed that GSH depletion induced by MOG rendered some leukemia cell lines more sensitive to arsenic trioxide (As2O3), doxorubicin or cisplatin. Additionally, the synergistic apoptotic effects of MOG with As2O3 were detected in HL-60 and primary AML cells, but not in normal cells, suggesting the selective toxicity of their combination to the malignant cells. Together, we proposed that MOG alone or administered with other anticancer agents may provide a novel therapeutic strategy for leukemia.