Berberines inhibitors

Protoberberines Berberine (umbellatine) (MD—Phe C5N C5N Phe) (DNA-binding cytotoxic, adrenergic receptor antagonist and AChE inhibitor from Berberis vulgaris (Berberidaceae) and other plants). 

DNA/RNA polymerases repair enzymes topoisomerase I/II Intercalators berberine, indoles, isoquinolines Alkylants PAs, aristolochic acids, cycasin Protein inhibitors camptothecin... 

Structures are solved for DNA-binding to the alkaloid berberine, " the telomerase inhibitor a DNA binding cyclic polyamideand a... 

Recently, it has been demonstrated that medicinal plants contain MDR pump inhibitors that actually enhance the activity of their own natural antimicrobial compounds. Plant amphipathic cations, such as berberine, have been shown to be good MDR substrates. Recent research has shown that in addition to berberine, Berberis species produce 5 -methoxyhydnocarpin-D, Fig. 10, an MDR inhibitor that enhances the action of this compound. In addition, isoflavones isolated Ifom Lupinus argenteus were found to enhance the antibacterial activity of a-linolenic acid, also found in the same plant [99]. 

Figure 10. The structure of 5 -methoxyhydnocarpin-D, an MDR inhibitor isolated from Berberis species that enhances the antibacterial activity of berberine.

A new method of bioactivity-directed fractionation, based on multidrug resistant pump (MDR) inhibition in Staphylococcus aureus, was reported for medicinal plants. This work resulted in the isolation, from berberine-containing Berberis species, two compounds that are themselves devoid of antibacterial activity, but that form potent synergistic couples with a sub-inhibitory concentration of berberine. The bacterial MDR pump inhibitors were identified as the flavonolignan 2 and the porphyrin 3 [98]. The isoflavones not only enhanced the antibacterial activity of the natural product, berberine. Fig. 4, but also the activity of synthetic... 

Bioassay-guided fractionation of an extract of Artemisia annua was conducted in order to assess the possible presence in the plant material of inhibitors of bacterial multidrug resistance pumps [218]. Fractions were tested for Staphylococcus aureus growth inhibition in the presence of a subinhibitory dose of weak antibacterial alkaloid berberine. Active fractions yielded the flavones chrysoplenol D and chrysoplenetin,... 

Fluorescence data for the interaction with acetylcholinesterase (EC 3.1.1.7, ACHE) from the electric eel Electrophorus electricus with some quaternary protoberberine and benzophenanthridine alkaloids was obtained. Berberine and other related compounds were bound to the gamma y-anionic site of ACHE via a comparison with known inhibitors of acetylcholinesterase, including tetramethylammonium and tacrine. Furthermore, during the interaction, two molecules of the ligand were bound to one molecule of the enzyme [226]. 

Berberine chloride was evaluated for antimalarial activity against Plasmodium falciparum in vitro (two clones of human malaria Plasmodium falciparum D-6 [Sierra Leone clone] and W-2 (Indochina clone) and Plasmodium berghei in vivo (mice). The alkaloid exhibited an antimalarial potency equivalent to that of quinine in vitro, but was inactive in vivo. The results were consistent with those of others who have found berberine to be a potent inhibitor in vitro of both nucleic acid and protein biosynthesis in P. falciparum, and have demonstrated a strong interaction of berberine with DNA. In addition, the lack of in vivo antimalarial activity in mice observed with berberine and other protoberberine alkaloids agrees with clinical reports that have claimed berberine to be inactive as an antimalarial drug [228]. 

Four protoberberine alkaloids and one aporphine alkaloid were evaluated for lipoxygenase inhibition. Oxyberberine and columbamine were the most potent lipoxygenase inhibitors tested, with jatrorrhizine being intermediate, whereas berberine and magnoflorine exhibited only low potencies. A strong linear correlation between lipoxygenase inhibition and lipid antioxidant properties of these alkaloids was observed. These data suggest that the mechanism of... 

Stermitz, RR., P. Lorenz, J.N. Tawara, L.A. Zenewicz, and K. Lewis. 2000. Synergy in a medicinal plant Antimicrobial action of berberine potentiated by 5 -methoxyhydnocar-pin, a multidrug pump inhibitor. Proc. Natl. Acad. Sci. U.S.A. 97(4) 1433-1437. 

The P. a. are readily soluble in ethanol, chloroform, and ether. Berberine is a toxic yellow pigment occurring in Berberis and Mahonia species. Silk, cotton, and leather can be dyed with berberine. It has also been the subject of intensive pharmaceutical research and exhibits many interesting properties including stimulation of respiration, hypotensive and convulsive activities. It is an inhibitor of choline esterase, tyrosine... 

Figure 4. Indirect mechanism of AMPK activation by ETC inhibitors. Metformin and berberine are inhibitors of ETC, producing decrease of mitochondrial ATP synthesis. Berberine increases AMP/ATP ratio and ROS production, activating AMPK in cancer cells. This event produces anti-cancer effects.

Shan WJ, Huang L, Zhou Q, Meng FC, Li XS (2011) Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant, inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid- aggregation. Eur J Med Chem 46 5885... 

Benson A (2005) Alzheimer s disease a tangled issue. Drag Discov Today 10 749-751 Huang L, Shi A, He F, Li X (2010) Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors. Bioorg Med Chem 18 1244-1251... 

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