Chemosynthesis pathway and bioactivities comparison of saponins in radix and flower of Panax notoginseng (Burk.) F.H. Chen.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk.) F.H. Chen is a well known medicinal plant. Its radix is used in the history while its flower is recently used for health care. In this study we compared chemical ingredients and bioactivities in cell culture for radix and flower of Panax notoginseng (Burk.) F.H. Chen. MATERIALS AND METHODS: The liquid chromatography-mass spectrometry system was applied to determine the contents of saponins in flower and radix of Panax notoginseng (Burk.) F.H. Chen. Transcription specific luciferase reporter assay and qPCR method for selected RNA were carried out to assess the impacts of flower and radix extract on the transcription signal pathways. RESULTS: The results of chemical analysis showed that the contents of saponins in flower and radix are very different: the contents of Rg1, Rb1, Re, R1, Rg3-20R, Rh1 and Rf in radix are abundant; in contrast, the contents of Rb3, Fc, Ft1, Rb2 and Rh2-20s in flowers are plentiful. There are substantial variations of those saponin contents from one batch vs another. Based on relative content of saponins, the chemosynthesis pathway of ingredients in radix and flower are proposed: for radix, both PPT (Protopanaxatriol) and PPD (Protopanaxadiol) type triterpenoids are involved, the main pathway is PPT→Rb1→Rg1→R1 or PPD→Rh2 20s→Rg3(20s)→Rd→Rb1; for flowers, only PPD is main passage with PPD→Rh2 (20s)→Rg3(20s)→Rd→Rb2→Fc. The results of signal transcription assays demonstrated that herb water extract of radix and flower had no significant influences on most of transcription activities. However, total saponins of radix and flower which have highly content of saponins were able to inhibit the inflammatory related transcriptional activities and their related mRNA expression of IFNα, TNFα, il-6 and TGFß as well as induce anti-oxygen NrF2 activities. In summary, although chemical ingredients and chemosynthesis pathway of flower and radix for Panax notoginseng (Burk.) F.H. Chen were different, these differences might not result in their differences of pharmacological activities.

Antitumor agents 294. Novel E-ring-modified camptothecin-4ß-anilino-4'-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase I inhibitors and cytotoxic agents.

Two conjugates (1 and 2) of camptothecin (CPT) and 4ß-anilino-4'-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT-derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties.

Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice.

Tumor vasculature is hyperpermeable to macromolecules compared to normal vasculature; however, the relationship between tumor hyperpermeability and tumor progression is poorly understood. Here we show that a cell-permeable peptide derived from caveolin-1, termed cavtratin, reduces microvascular hyperpermeability and delays tumor progression in mice. These antipermeability and antitumor actions of cavtratin occur in the absence of direct cytostatic or antiangiogenic effects. Cavtratin blocks microvascular permeability by inhibiting endothelial nitric oxide synthase (eNOS), as the antipermeability and antitumor actions of cavtratin are markedly diminished in eNOS knockout mice. Our results support the concepts that hyperpermeability of tumor blood vessels contributes to tumor progression and that blockade of eNOS may be exploited as a novel target for antitumor therapy.