Oxoglaucine

TCM active ingredient oxoglaucine metal complexes: crystal structure, cytotoxicity, and interaction with DNA.[Pubmed: 22309171]

Inorg Chem. 2012 Feb 20;51(4):1998-2009.

The alkaloid Oxoglaucine (OG), which is a bioactive component from traditional Chinese medicine (TCM), was synthesized by a two-step reaction and used as the ligand to react with transition metal salts to give four complexes: [OGH][AuCl(4)]·DMSO (1), [Zn(OG)(2)(H(2)O)(2)](NO(3))(2) (2), [Co(OG)(2)(H(2)O)(2)](ClO(4))(2) (3), and [Mn(OG)(2)(H(2)O)(2)](ClO(4))(2) (4).
METHODS AND RESULTS:
The crystal structures of the metal complexes were confirmed by single crystal X-ray diffraction. Complex 1 is an ionic compound consisting of a charged ligand [OGH](+) and a gold complex [AuCl(4)](-). Complexes 2-4 all have similar structures (inner-spheres), that is, octahedral geometry with two OG coordinating to one metal center and two aqua ligands occupying the two apical positions of the octahedron, and two NO(3)(-) or ClO(4)(-) as counteranions in the outer-sphere. The complexation of OG to metal ion was confirmed by ESI-MS, capillary electrophoresis and fluorescence polarization. The in vitro cytotoxicity of these complexes toward a various tumor cell lines was assayed by the MTT method. The results showed that most of these metal-Oxoglaucine complexes exhibited enhanced cytotoxicity compared with Oxoglaucine and the corresponding metal salts, with IC(50) values ranging from 1.4 to 32.7 μM for sensitive cancer cells, which clearly implied a positive synergistic effect. Moreover, these complexes appeared to be selectively active against certain cell lines.
CONCLUSIONS:
The interactions of Oxoglaucine and its metal complexes with DNA and topoisomerase I were investigated by UV-vis, fluorescence, CD spectroscopy, viscosity, and agarose gel electrophoresis, and the results indicated that these OG-metal complexes interact with DNA mainly via intercalation. Complexes 2-4 are metallointercalators, but complex 1 is not. These metal complexes could effectively inhibit topoisomerase I even at low concentration. Cell cycle analysis revealed that 1-3 caused S-phase cell arrest.

Antiplatelet aggregation constituents from Annona purpurea[Pubmed: 9868142 ]

J Nat Prod. 1998 Dec;61(12):1457-61.

METHODS AND RESULTS:
Bioactivity-directed fractionation led to the isolation of 19 compounds, including three oxoaporphines, oxopurpureine (5), oxonuciferine (6), and Oxoglaucine (7); three aporphines, (+)-predicentrine (8), (-)-glaucine (9), and thalbaicalidine (10); one aporphine sensu stricto, N-formyl-purpureine (11); one proaporphine, glaziovine; one phenanthrene, thalicpureine (12); two 6a,7-dehydroaporphines, dehydrolirinidine (13) and 7-hydroxy-dehydroglaucine (14); four flavonoids, quercetin-3-O-rhamnoside, kaempferol-3-O-rhamnoside, isorhamnetin-3-O-rhamnoside, and tanarixetin-3-O-rhamnoside; one purine, adenine; one lactam amide, squamolone; and two steroids, beta-sitosterol and beta-sitosterol-beta-D-glucoside from the MeOH extract of the leaves of Formosan Annona purpurea.
CONCLUSIONS:
Among them, 11-14 were characterized as new compounds and alkaloids, 5-8, 10, and 12-14 exhibited significant antiplatelet aggregation activity.

Immunopharmacological activity of aporphinoid alkaloid oxoglaucine.[Pubmed: 9264041]

Pharmacol Res. 1997 Apr;35(4):267-72.

The ability of aporphinoid alkaloid Oxoglaucine to influence T- and B-cell immune response was studied in mice models.
METHODS AND RESULTS:
The substance inhibited in vitro mitogen-induced lymphocyte proliferation and suppressed antibody response to sheep red blood cells (SRBC) and lipopolysaccharide (LPS) in vivo effectively. The action depended on the relative timing of antigen and Oxoglaucine administration. The substance manifested stimulatory effect in popliteal lymph node (PLN) reaction and LPS-induced B-cell activation. In the chronic inflammatory model of adjuvant arthritis Oxoglaucine exhibited stimulatory or suppressive action related to the kinetics of the process. At low doses (1 or 2 mg kg-1) Oxoglaucine improved the outcome of Klebsiella pneumoniae infection, while at higher doses (10 or 20 mg kg-1) the substance caused an impairment of host resistance to infectious agent. The comparison with cyclophosphamide in some tests showed that Oxoglaucine was effective in manifold lower doses.
CONCLUSIONS:
In conclusion, Oxoglaucine exerted immunomodulatory effects in vivo in a dose-dependent and protocol-dependent manner. Yet, its overall action might be attributed to the different sensitivity of the cells involved in the developing immune response.

Phosphatidylinositol 4-kinase III beta is the target of oxoglaucine and pachypodol (Ro 09-0179) for their anti-poliovirus activities, and is located at upstream of the target step of brefeldin A.[Pubmed: 25891300]

Microbiol Immunol. 2015 Jun;59(6):338-47.

In recent years, phosphatidylinositol 4-kinase III beta (PI4KB) has emerged as a conserved target of anti-picornavirus compounds.
METHODS AND RESULTS:
In the present study, PI4KB was identified as the direct target of the plant-derived anti-picornavirus compounds, Oxoglaucine and pachypodol (also known as Ro 09-0179). PI4KB was also identified as the target via which pachypodol interferes with brefeldin A (BFA)-induced Golgi disassembly in non-infected cells. Oxysterol-binding protein (OSBP) inhibitor also has interfering activity against BFA. It seems that this interference is not essential for the anti-poliovirus (PV) activities of BFA and PI4KB/OSBP inhibitors. BFA inhibited early to late phase PV replication (0 to 6 hr postinfection) as well as PI4KB inhibitor, but with some delay compared to guanidine hydrochloride treatment. In contrast with PI4KB/OSBP inhibitors, BFA inhibited viral nascent RNA synthesis, suggesting that BFA targets some step of viral RNA synthesis located downstream of the PI4KB/OSBP pathway in PV replication.
CONCLUSIONS:
Our results suggest that PI4KB is a major target of anti-picornavirus compounds identified in vitro for their anti-picornavirus activities and for some uncharacterized biological phenomena caused by these compounds, and that BFA and PI4KB/OSBP inhibitors synergistically repress PV replication by targeting distinct steps in viral RNA replication.

Immunosuppression and recovery of drug-impaired host resistance against Candida albicans infection by oxoglaucine.[Pubmed: 10600277 ]

Pharmacol Res. 2000 Jan;41(1):101-7.

The immunosuppressive action of aporphinoid alkaloid Oxoglaucine was studied in experimental Candida albicans (C. albicans) infection in mice.
METHODS AND RESULTS:
The alkaloid augmented host resistance to pathogen applied to mice (6-8 weeks of age) at a low dose of 2 mg kg(-1) in 3 days and impaired it at a high dose of 10 mg kg(-1). The suppressive activity observed under the latter schedule correlated with the inhibited proliferative response of splenic cells to mitogens and with decreased popliteal lymph node (PLN) reaction to C. albicans. Treatment of mice with Oxoglaucine (at the age of 5 days) at a dose of 5 mg kg(-1) in 3 consecutive days increased the susceptibility to Candida inoculation at the age of 6 weeks. Delayed type hypersensitivity (DTH) response to C. albicans was enhanced after pretreatment of adult mice and was suppressed after administration to newborn mice. Long-time treatment (10 days) with Oxoglaucine, cyclophoshamide or prednisolone at a dose of 10 mg kg(-1) increased the rate of mortality of Candida-infected mice.
CONCLUSIONS:
Combined pretreatment of mice with cyclophosphamide or prednisolone (5 days at a dose of 5 mg kg(-1)) followed by Oxoglaucine (5 days at a dose of 5 mg kg(-1)), prolonged the survival of infected mice.