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Anti-Cancer Efficacy of Silybin Derivatives - A Structure-Activity Relationship

<div><p>Silybin or silibinin, a flavonolignan isolated from Milk thistle seeds, is one of the popular dietary supplements and has been extensively studied for its antioxidant, hepatoprotective and anti-cancer properties. We have envisioned that potency of silybin could be further enhanced through suitable modification/s in its chemical structure. Accordingly, here, we synthesized and characterized a series of silybin derivatives namely 2,3-dehydrosilybin (DHS), 7-<i>O</i>-methylsilybin (7OM), 7-O-galloylsilybin (7OG), 7,23-disulphatesilybin (DSS), 7-<i>O</i>-palmitoylsilybin (7OP), and 23-<i>O</i>-palmitoylsilybin (23OP); and compared their anti-cancer efficacy using human bladder cancer HTB9, colon cancer HCT116 and prostate carcinoma PC3 cells. In all the 3 cell lines, DHS, 7OM and 7OG demonstrated better growth inhibitory effects and compared to silybin, while other silybin derivatives showed lesser or no efficacy. Next, we prepared the optical isomers (A and B) of silybin, DHS, 7OM and 7OG, and compared their anti-cancer efficacy. Isomers of these three silybin derivatives also showed better efficacy compared with respective silybin isomers, but in each, there was no clear cut silybin A versus B isomer activity preference. Further studies in HTB cells found that DHS, 7OM and 7OG exert better apoptotic activity than silibinin. Clonogenic assays in HTB9 cells further confirmed that both the racemic mixtures as well as pure optical isomers of DHS, 7OM and 7OG were more effective than silybin. Overall, these results clearly suggest that the anti-cancer efficacy of silybin could be significantly enhanced through structural modifications, and identify strong anti-cancer efficacy of silybin derivatives, namely DHS, 7OM, and 7OG, signifying that their efficacy and toxicity should be evaluated in relevant pre-clinical cancer models in rodents.</p> </div

Mutasynthesis of Lincomycin Derivatives with Activity against Drug-Resistant Staphylococci▿ †

The lincomycin biosynthetic gene lmbX was deleted in Streptomyces lincolnensis ATCC 25466, and deletion of this gene led to abolition of lincomycin production. The results of complementation experiments proved the blockage in the biosynthesis of lincomycin precursor 4-propyl-l-proline. Feeding this mutant strain with precursor derivatives resulted in production of 4′-butyl-4′-depropyllincomycin and 4′-pentyl-4′-depropyllincomycin in high titers and without lincomycin contamination. Moreover, 4′-pentyl-4′-depropyllincomycin was found to be more active than lincomycin against clinical Staphylococcus isolates with genes determining low-level lincosamide resistance

¹H NMR (400.13 MHz for ¹H, 100.61 MHz for ¹³C, DMSO-<i>d₆</i>, 30°C).

<p>¹H NMR (400.13 MHz for ¹H, 100.61 MHz for ¹³C, DMSO-<i>d₆</i>, 30°C).</p

¹³C NMR (400.13 MHz for ¹H, 100.61 MHz for ¹³C, DMSO-<i>d₆</i>, 30°C).

<p>¹³C NMR (400.13 MHz for ¹H, 100.61 MHz for ¹³C, DMSO-<i>d₆</i>, 30°C).</p

Effect of silybin and its derivatives on HTB9, HCT116, and PC3 cancer cell growth.

*<p>p≤0.001;</p>#<p>p≤0.01;</p>$<p>p≤0.05.</p

Effect of low doses of pure optical isomers of silybin and its derivatives on HTB9 cell growth.

<p>HTB9 cells were treated with 5 and 10 µM doses of silybin A, 2,3-dehydrosilybin A, 7-<i>O</i>-methylsilybin A, 7-<i>O</i>-galloylsilybin A or silybin B, 2,3-dehydrosilybin B, 7-<i>O</i>-methylsilybin B, 7-<i>O</i>-galloylsilybin B. After 24 or 48 h of each treatment, total cell number was determined as detailed in the ‘<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060074#s2" target="_blank">Materials and Methods</a>’. In the bar diagrams, each data-point is representative of mean ± SD of 3 samples. *p≤0.001; #p≤0.01; $p≤0.05.</p

Effect of pure optical isomers of silybin, 2,3-dehydrosilybin, 7-<i>O</i>-methylsilybin, and 7-<i>O</i>-galloylsilybin on HTB9, HCT116, and PC3 cancer cell growth.

*<p>p≤0.001;</p>#<p>p≤0.01;</p>$<p>p≤0.05.</p

Chemical structure of silybin and its derivatives.

<p>(<b>a–h</b>) Chemical structures of silybin, silybin A, silybin B, 2,3-dehydrosilybin, 7-<i>O</i>-methylsilybin, 7-<i>O</i>-galloylsilybin, 7,23-disulphate silybin, 7-<i>O</i>-palmitoylsilybin, and 23-<i>O</i>-palmitoylsilybin.</p