13 research outputs found
Efficient Total Synthesis of Lissodendrin B, 2-Aminoimidazole Marine Alkaloids Isolated from Lissodendoryx (Acanthodoryx) fibrosa
Lissodendrin B is a 2-aminoimidazole alkaloid bearing a (p-hydroxyphenyl) glyoxal moiety that was isolated from the Indonesian sponge Lissodendoryx (Acanthodoryx) fibrosa. We reported the first efficient total synthesis of Lissodendrin B. The precursor 4,5-disubstituted imidazole was obtained through Suzuki coupling and Sonogashira coupling reactions from 4-iodoimidazole. C2-azidation and reduction of the azide then provided the core structures of Lissodendrin B. Subsequent triple-bond oxidation, demethylation, and deacetylation gave the final product. The synthesis approach consists of ten steps with an overall yield of 1.1% under mild reaction conditions, and it can be applied for future analog synthesis and biological studies
Total Synthesis and Biological Activity of Marine Alkaloid Eudistomins Y1âY7 and Their Analogues
Eudistomin Y class compounds are a series of ÎČ-carbolines which was originally isolated from a marine turnicate or ascidian near the South Korea Sea. These compounds contain bromo-substituted groups, which is one of the typical characters of marine natural products. We report herein the chemical synthesis and biological evaluation of seven new ÎČ-carboline-based metabolites, Eudistomins Y1âY7, and their hydroxyl-methylated phenyl derivatives. Using bromo-substituted tryptamines and bromo-substituted phenylglyoxals as the key intermediates, Eudistomins Y1âY7 and their derivatives were synthesized via the acid-catalyzed Pictet-Spengler reaction and fully characterized by 1H- and 13C-NMR and mass spectroscopy. Biological studies revealed that all of the compounds showed moderate growth inhibitory activity against breast carcinoma cell line MDA-231 with IC50 of 15â63 ÎŒM and the inhibitory activities of hydroxyl-methylated phenyl products were higher than that of the corresponding natural products Eudistomins Y1âY7
1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,ÎČ-D-glucopyranose (PGG) analogs: design, synthesis, anti-tumor and anti-oxidant activities
International audience1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,ÎČ-D-glucopyranose (PGG) 12 has been reported for its antioxidant activities, where the free OH groups in PGG seem to be critical for activities. To explore PGG-based compounds as chemotherapeutic agents and to analyze the contribution of specific OH groups in PGG for anti-cancer activities, we designed and synthesized a series of 27 benzoic and cinnamic acid analogs of PGG. These analogs were tested for cytotoxicities against two human lung (A549 and H1299) and two human colon (HCT116 and HT29) cancer cell lines. Compound 12 (PGG) had highest cytotoxicities against HCT116 and A549 cells with IC50 of 1.61â”M and 3.02â”M, respectively. In contrast, the compound 16 (1,2,3,4,6-pentakis[-O-(4-hydroxy-3-methoxybenzoyl)]-α,ÎČ-D-glucopyranose, PVG) was most effective at killing HT29 and H1299 cells with IC50 of 1.76â”M and 3.65â”M, respectively, indicating the mutual contribution of m-methoxy and p-hydroxy groups to the observed cytotoxicities. Moreover, cinnamic acid analogs were less active than the benzoic acid analogs evidenced by higher IC50 values. Furthermore, in cinnamic acid analogs the hydrogenation of double bond to saturated 2-C side chain enhance the cytotoxicities in all four cell lines. Compounds also possess good anti-oxidant and reducing activities. Compound 12 and 26 show the highest antioxidant and reducing activities
Antitumor Activity of FL118, a Survivin, Mcl-1, XIAP, and cIAP2 Selective Inhibitor, Is Highly Dependent on Its Primary Structure and Steric Configuration
We
recently reported the identification and characterization of
a novel small chemical molecule designated FL118. FL118 selectively
inhibits multiple cancer survival and proliferation-associated antiapoptotic
proteins (survivin, Mcl-1, XIAP, cIAP2) and eliminates small and large
human tumor xenografts in animal models (Ling et al., <i>PLoS
One</i> <b>2012</b>, <i>7</i>, e45571). Here,
we report a follow-up study on the structureâactivity relationship
(SAR) of the hydroxyl group in the lactone ring of FL118. We found
that the superior antitumor efficacy of FL118 heavily depends on its
steric configuration through comparing the antitumor activity of FL118
with FL113 (the racemic mixture of FL118). Consistently, FL118 proved
much more effective in inhibiting the expression of survivin, Mcl-1,
and cIAP2, both <i>in vitro</i> and <i>in vivo</i>, compared to FL113. Additionally, Tet-on controlled induction of
survivin or forced expression of Mcl-1 protects cancer cells from
FL118-mediated growth inhibition and cell death. To further explore
the SAR, we synthesized seven position 20-esterifiable FL118 and FL113
derivatives. Studies on these seven new compounds revealed that keeping
a free hydroxyl group of FL118 is also important for high antitumor
efficacy. Together, these studies confirm the superior anticancer
activity of FL118 and narrow the window for further SAR studies to
generate novel analogues based on FL118 core structure on its other
potential chemical positions