Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides..

When I  was working with one of the leading agrochemicals company, I was using 4-chlorobenzotriflouride as starting material for my two projects (trifluralin and a pyrazole derivative with diflouromethyl substituted phnyl).  I know how difficult is to introduce the triflouromethyl group (use of anhydrous HF to convert CCl3 to CF3) and that is why we got the starting material imported. 

Now, MIT chemists have designed a new way to attach a trifluoromethyl group to certain compounds, which they believe could allow pharmaceutical companies to create and test new drugs much faster and potentially reduce the cost of drug discovery. 

MIT Chemistry Professor Stephen Buchwald, who led the research team, says achieving the synthesis has been a long-standing challenge for chemists. "Some people said it couldn't be done, so that's a good reason to try," says Buchwald, the Camille Dreyfus Professor of Chemistry at MIT.

With the new reaction, the CF₃ group can be added at a much later stage of the overall drug synthesis. The reaction can also be used with a broad range of starting materials, giving drug developers much more flexibility in designing new compounds.  Though many groups are trying, the major challenge has been finding a suitable catalyst  to transfer the CF₃ entity from another source to the carbon ring. 

CF₃^- (trifluoromethyl negative ion) tends to be unstable when detached from other molecules, so the catalyst must act quickly to transfer the CF₃ group before it decomposes. The MIT team chose to use a catalyst built from palladium i.e., BrettPhos (see structure). MIT team is not the first to try palladium catalysis for this reaction, but the key to their success was the use of a ligand (a molecule that binds to the metal to stabilize it and hasten the reaction) called BrettPhos 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl,  which they had previously developed for other purposes. 

During the reaction, a CF₃ group is transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl-CF₃ unit is released and the catalytic cycle begins anew. The researchers tried the synthesis with a variety of aryl compounds and achieved yields ranging from 70 to 94 percent of the trifluoromethylated products. 

Researchers conclude that, in its current state the process is too expensive for manufacturing use. For drug discovery, however, it may lower overall costs because it streamlines the entire synthesis process.

"For discovery chemistry, the price of the metal is much less important," says Kinzel....

Ref :  http://www.sciencemag.org/cgi/content/abstract/328/5986/1679

Blueberry consumption is beneficial for hepatic diseases....

We know that blueberry has many chemicals such as anthocyanins, proanthocyanidins, resveratrol, flavonols and tannins and how blueberry inhibit mechanisms of cancer cell development and inflammation in vitro. Similar to red grape, some blueberry species contain in their skins significant levels of resveratrol a phytochemical. 

Now research team led by Ming-Liang Cheng, MD, from Department of Infectious Diseases, Guiyang Medical College, Guiyang,  have found that blueberries could reduce liver indices, serum levels of hyaluronic acid and alanine aminotransferase, and increase levels of superoxide dismutase and decrease levels of malondialdehyde in liver homogenates compared with the model group.  Meanwhile, the stage of hepatic fibrosis was significantly weakened. Blueberries increased the activity of glutathione-S-transferase in liver homogenates and the expression of Nrf2 and Nqo1 compared with the normal group, but there was no significant difference compared with the model group. 

The authors suggest that blueberry consumption is beneficial for hepatic diseases (including fibrosis)....

I read an article in the same lines, where in the  researchers from Miyazaki prefecture of southern Japan and University of Miyazaki, screened nearly 300 different agricultural products for potential compounds that suppress HCV replication and uncovered a strong candidate in the leaves of rabbit-eye blueberry (native to the southeastern US). They purified the compound and identified it as proanthocyandin (a polyphenol similar to the beneficial chemicals found in grapes and wine). While proanthocyandin can be harmful, Kataoka and colleagues noted its effective concentration against HCV was 100 times less than the toxic threshold. The researchers are  hoping to explore the detailed mechanisms of how this chemical stops HCV replication....

Ref :  http://www.biologynews.net/archives/2009/08/07/the_hepatitis_healing_power_of_blueberry_leaves.html

Liquid Crystals - A New Way to Better Data Storage ?

In continuation of my update on liquid crystals (after a long gap)....

As cell phones and computers continue to shrink, many companies are seeking better ways to store hundreds of gigabytes of data in small, low-power devices. A special type of liquid crystal (similar to those used in computer displays and televisions) offers a solution  and lasers can encode data throughout a liquid crystal known as holographic storage, the technique makes it possible to pack much more information in a tiny space.   

But attempts to use liquid crystals for data storage have had limited success. In order to reliably record and rewrite data, researchers must figure out a way to uniformly control the orientation of liquid crystal molecules as the most liquid crystal technologies currently rely on physical or chemical manipulation, such as rubbing in one direction, to align molecules in a preferred direction. 

In an important advance, scientists at the Tokyo Institute of Technology have created a stable, rewritable memory device that exploits a liquid crystal property called the "anchoring transition". Researchers  demonstrated memory and rewritable bistable devices based on an anchoring transition of a nematic liquid crystal on a perfluoropolymer surface. Spontaneous orientation changes between planar and homeotropic occur on cooling and heating with a large temperature hysteresis. Orientation switching also occurs by applying an electric field with a response time of several milliseconds depending on the field strength claims the researchers.

Using either a laser beam or an electric field, the researchers can align rod-like liquid crystal molecules in a polymer. Their tests show that the liquid crystal created by the team can store data, be erased and used again...

"This is the first rewritable memory device utilizing anchoring transition," said Hideo Takezoe, who led the research. And because the device is bi-stable -- the liquid crystals retain their orientation in one of two directions -- it needs no power to keep images, adds Takezoe.

 Ref : http://jap.aip.org/japiau/v107/i12/p123108_s1?isAuthorized=no

Resveratrol in Red Wine Neutralizes Toxicity of Proteins Related to Alzheimer's

We know that, Resveratrol (found in the skin of red grapes and is a constituent of red wine, see structure)  (trans-resveratrol) is a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi.  And also it has been reported to possess diverse activities such as, anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects in mouse and rat models of testings. In the only positive human trial, extremely high doses (3–5 g) of resveratrol in a proprietary formulation have been necessary to significantly lower blood sugar.Claims of anti-aging effects of the same compounds is to be still established.

Now researchers led by Rensselaer Professor Peter M. Tessier, have come up with an interesting finding i.e., resveratrol - has the ability to neutralize the toxic effects of proteins linked to Alzheimer's disease. 

As per the claims by the researchers, resveratrol picks out the clumps of peptides that are bad and leaves alone the ones that are benign, it helps us to think about the structural differences between the peptide isoforms (different packing arrangements of a particular peptide) Deformations of a particular peptide  the Aβ1-42 peptide,   have been linked to Alzheimer's disease. 

Improperly folded peptides have been shown to collect in accumulations called "plaques (often found near areas of cell death in diseased brain)" within the brain.

Researchers conclude that, though it is not clear that resveratrol is able to cross the blood-brain barrier. However, the molecule has garnered interest in recent years for its potential impact on cancer and aging...

Ref : http://www.jbc.org/content/early/2010/05/28/jbc.M110.133108....

New use of old drugs (Metformin & AICAR ) in treating hepatitis C...

In continuation of my update on Metformin...

Researchers from  University of Leeds have found drugs such as antidiabetic  drug  Metformin  (right  structure)  and                AICAR, (5-Amino-4-imidazole carboxamide ribonucleotide) below right structure) used to combat obesity, can prevent the hepatitis C virus from replicating in the body.

Drugs such as Metformin and AICAR work by stimulating an enzyme called AMP kinase (AMPK) which regulates energy within our cells,  the very enzyme that hepatitis C virus represses to enable it to replicate. As per the claim by the researchers, the hepatitis C virus switches off AMPK so that the cell continues production of lipids and membranes, both of which are vital to its survival. 

AMPK's usual function is to conserve the energy balance in cells (it does by temporarily shutting down the production of lipids (fats) and membranes) when it senses an increase in energy requirements. Researchers  claim that, when a cell becomes infected by a virus,  AMPK gets activated and  shuts down certain functions of the cell temporarily until the cell's energy is rebalanced. 

Building on this finding, the research team were able to examine how cells would react when treated with common drugs that stimulate AMPK. They found that in infected cells, the drugs were able to halt virus replication, enabling cells to clear the infection...

"We're very excited about these findings," says Professor Mark Harris from the University's Faculty of Biological Sciences. "These drugs are already on the market, and whilst substantial clinical trials still need to take place before they can be used to treat hepatitis C infection, we think it could be an enormous step forward in the battle against the virus."  ....

Ref : http://www.leeds.ac.uk/news/article/825/new_use_for_old_drugs_in_treating_hepatitis_c?research

Crizotinib Shows Dramatic Results for Shrinking Tumors (lung cancer)....

Patients with a specific kind of lung cancer may benefit from a Phase III clinical trial offered by the Moores UCSD Cancer Center. The new drug, crizotinib (structure), under development by Pfizer, showed dramatic results in reducing lung cancer tumors in some patients during Phase I and II clinical trials.

"The results of the first two trials have been very encouraging," said Lyudmila Bazhenova, MD, assistant clinical professor at UC San Diego School of Medicine and a member of the Moores UCSD Cancer Center...

According to a preliminary study,  57% of patients had their tumors reduced and at eight weeks of the treatment, 87% showed disease stabilization.

The Phase III clinical trial will compare crizotinib with standard-of-care chemotherapy in the treatment of ALK-positive recurrent NSCLC. Through a randomized selection process, patients will either be treated with chemotherapy or crizotinib. If the patients who are given the chemotherapy do not respond to treatment, they will be given crizotinib at the end of the trial....

Ref : http://ucsdnews.ucsd.edu/newsrel/health/06-22ShrinkingTumors.asp

FDA approves Jevtana to treat men with prostate cancer

In continuation of my update on Cabazitaxel......

FDA approves Jevtana to treat men with prostate cancer

Synergistic activity of Sorafenib and Sulforaphane abolishes pancreatic cancer...

In continuation of my update on "Sorafenib", I find this info interesting to share with...

A team led by Professor Dr. Ingrid Herr, Head of the Department of Molecular Oncosurgery, a group of the Department of Surgery at Heidelberg University Hospital, have come up with an interesting finding, i.e.,  Sorafenib  (used for advanced liver and kidney cancer) also appears to be effective against cancer stem cells in pancreatic cancer. It inhibits resistant tumor stem cells and is also especially effective in combination with sulforaphane, an organic compound found in broccoli. 

In their tests on cancer cells and mice, the researchers showed that sorafenib inhibited typical properties of cancer stem cells from pancreas tumors and greatly reduced tumor growth. However, this effect lasted only for a short time and after four weeks, new colonies of cancer stem cells formed that no longer reacted to further treatment with sorafenib. The resistance is probably related to a certain metabolic pathway, the NF-kB pathway, that is activated by sorafenib, claims the researchers. 

Naturally occurring substance(s) e.g., sulforaphane (vegetables from the cruciferous family such as broccoli and cauliflower possess a high content of sulforaphane, an anti-cancer compound)  that block precisely this undesired NF-KB pathway and thus make the dangerous cells vulnerable.  The experiments show that sulforaphane prevents the activation of the NF-kB pathway by sorafenib and hence the combination treatment reinforces the effect of sorafenib without causing additional side effects. Researchers conclude that the invasive potential of cancer cells was prevented  and  metastasis was completely blocked in cell culture experiments. 

"We assume that nutrition may be a suited approach to break therapy resistance of cancer stem cells and thus make tumor treatment more effective," Professor Herr suggested....

Ref : http://cancerres.aacrjournals.org/content/70/12/5004

New evidence that chili pepper ingredient fights fat

In continuation of effect of chilli pepper on obesity.......

New evidence that chili pepper ingredient fights fat

New world Helicobacter pylori genome sequenced, dynamics of inflammation-related genes revealed

In continuation of my update on Helicobacter pylori.......
New world Helicobacter pylori genome sequenced, dynamics of inflammation-related genes revealed

Sulindac inhibits tumor growth !...

We know that, Sulindac(structure), is useful in the treatment of acute or  chronic inflammatory conditions. Sulindac is a prodrug, derived from sulfinylindene, that is converted in the body to the active NSAID. More specifically, the agent is converted by liver enzymes to a sulfide that is excreted in the bile and then reabsorbed from the intestine. This is thought to help maintain constant blood levels with reduced gastrointestinal side effects. Some studies have shown sulindac to be relatively less irritating to the stomach than other NSAID's except for drugs of the COX-2 inhibitor class. The exact mechanism of its NSAID properties is unknown, but it is thought to act on enzymes COX-1 and COX-2, inhibiting prostaglandin synthesis.

Now researchers from Sanford-Burnham Medical Research Institute (Sanford-Burnham) and their colleagues have figured out how  Sulindac, inhibits tumor growth. The study reveals that Sulindac shuts down cancer cell growth and initiates cell death by binding to nuclear receptor RXRα, a protein that receives a signal and carries it into the nucleus to turn genes on or off. 

As per the claim by the researchers, RXRα normally suppresses tumors, but many types of cancer cells produce a truncated form of this nuclear receptor that does just the opposite. This study showed that shortened RXRα enhances tumor growth by stimulating other proteins that help cancer cells survive. Luckily, the researchers also found that Sulindac can be used to combat this deviant RXRα by switching off its pro-survival function and turning on apoptosis, a process that tells cells to self-destruct.  The interesting part of their research lies in the fact that, they were able to overcome the limitation (cardiovascular side effects associated with Sulindac and other NSAIDs), the researchers tweaked Sulindac, creating a new version of the drug now called K-80003 that both decreases negative consequences and increases binding to truncated RXRα..

"Depending on the conditions, the same protein, such as RXRα, can either kill cancer cells or promote their growth," Dr. Zhang said. "The addition of K-80003 shifts that balance by blocking survival pathways and sensitizing cancer cells to triggers of apoptosis."

Ref :  http://www.cell.com/cancer-cell/retrieve/pii/S1535610810001595

The Revolutionary alkaline diet

I am really happy to share an interesting and important article on Alkaline Diet, by Emma Deangela, who has written exclusively for the readers/followers of my blog. I thank Emma for this info, on behalf of  all my blog readers. Its good to see many  authors /writers coming forward to share the knowledge through the social media like facebook/blog/twitter and hope this awareness will help those needy people....

Boost Your Healthy Simply by Alkalizing your Diet!

You've probably heard of alkalizing your body by now and how it will boost your health. But in order to fully appreciate how an alkaline body helps in our daily living, it is imperative to know the components of an alkaline diet and the importance of maintaining the pH of our body.

pH refers to the measure of acidity or basicity of a solution. More accurately, it pertains to the extent of dissociation of hydrogen ions of our body. If we consume the right types and amounts of nutrients and minerals conducive to our body's development, our body is able to maintain the right pH balance. But you may wonder for a moment what exactly are the 'right' nutrients and minerals? This is where alkaline diet comes into the picture.

The concept of alkaline diet is ultimately about foods that leaves an alkaline residue in our body after digestion. Our body's pH balance fluctuates with each intake of food, and in order to maintain it at the optimum pH, our body must have enough alkaline reserves which can only be obtained if we include at the minimum 80% of alkaline foods in our diet.

How do we classify foods into acidic or alkaline foods?

Chlorine, phosphorus and sulfur in food will probably give acidic residue after the food has been digested. Conversely, minerals such as calcium, sodium, magnesium and potassium found in food will leave an alkaline residue.

We should always bear in mind that all foods leave residue in our body after digestion. If you recall the food pyramid taught in Health education classes, meat and seafood, dairy products, alcoholic drinks, chemical sweeteners, sweets and chocolates, and even grains forms acidic residue! However, green leafy vegetables and fruits low in sugar contain organic aids and are full of alkaline goodness after digestion. So do remember to include a larger proportion of greens and fruits in your diet to maintain an alkaline pH in your body.

Why is it Important to Alkalize the Body?

People living in the modern society are plagued with many diseases and the growing number of sufferers far outstripped our ancestors? Why is such a scenario happening? It can be attributed to our diet which is heavily acidic. Foods that leaves a high content of acidic residues revolves in our circulatory system and are not rid of by our kidneys, lungs and bowels.

According to Dr Theodore Baroody, author of the critically acclaimed book "Alkalize or Diet", the reason for these diseases was due to excessive acidic residue in our body. Acidic mediums are conducive for the breeding of diet-related diseases, which will lead to death. When our body is deprived of the essential alkaline reserves, nutrients and minerals, excessive acids in our bloodstream may lead to slow poisoning of our body due to our diet which comprises of a high percentage of acidic foods. Excess acids will also weaken and in severe cases, damage our bodily functions and cellular actives such as respiration, digestion, hormone production and blood circulation.

Start with an Alkaline Diet Today!

If you are guilty of consuming acid-rich food, fret not. You can definitely reverse the situation through alkalizing your body today. We will be able to enjoy a new lease of energy if we maintain the pH balance in our body. On top of that, another benefit of the alkaline diet is to remove the acidic environment that serves as the breeding ground of acidic toxins which will over time result in an onslaught of diseases. Nutritionists and medical doctors recommends a daily consumption of at least five servings of vegetables and green foods which are highly alkaline.

Affluence and technology have resulted in an epidemic of diet-related diseases. However, there is no need to remain pessimistic. Instead of blindness pursuit of wealth and fame, which will come to naught without good health, why not change your health for the better starting today? We should all grab this opportunity and start incorporating the alkaline diet into our everyday life. It may be difficult to give up your favorite acidic foods at the start, but be assured that your efforts will pay off when you see your overall health being restored. Instead of consuming supplements and medicine, start with the root of the problem - diet. And the solution is to begin alkalizing your body by providing an alkaline environment for every cells and bodily functions in your body to thrive.

About the Author –Emma Deangela is one of the key authors for Alkaline Diet.  She loves to share her experience with her readers on tips to stay healthy, disease free, and how to lose weight the alkaline way. Her alkaline diet newsletter is available at Alkaline Diet, so if you would like to find out more about juicy alkaline diet tips and recipes do visit her blog.....

Two-drug phase I trial shows promise in treating late-stage ovarian cancer

In continuation of my update on carboplatin .....

Researchers from Indiana University School of Medicine, have come up  with interesting finding from a two-Drug Phase I Trial Show, i.e.,  the combination of decitabine (see structure) and carboplatin appears to improve the outcome of women who have late-stage ovarian cancer. Researchers report four of 10 patients who participated in a phase I clinical trial had no disease progression after six months of treatment. One patient experienced complete resolution of tumor tissue for a period of time.

"Carboplatin is the most efficient drug therapy for ovarian cancer,"  unfortunately, patients with recurrent disease become resistant to the drug after one or two rounds claims the lead researcher.."

Decitabine was first used to treat the study patients intravenously daily for five days followed on the eighth day with carboplatin. After a month, the regimen begins again.

Encouraged by the results of the phase I trial, which determined the safety of two different dosing regimens, a phase II trial is now under way with 17 patients already enrolled. Phase II trials are primarily focused on assessing the effectiveness of a drug or treatment protocol.

As per the claim by the researcher, decitabine  (a known methylation inhibitor) can help return tumor suppression genes to an active state, and also improve cells' susceptibility to anti-cancer drugs like carboplatin. Researchers adds that decitabine isn't just targeting active ovarian cancer cells, but also cancer stem cells that seem to survive the first treatments. 

Researchers conclude that, by keeping tumor suppression genes from being methylated, carboplatin and other platinum-based treatments for ovarian cancer have a better chance of success in the late stages.

Ref : http://www3.interscience.wiley.com/journal/123500856/abstract?CRETRY=1&SRETRY=0

Eribulin mesylate drug may help extend lives of women with advanced breast cancer..

We know that, Eribulin (see structure E7389) is an investigational  anticancer drug. Eribulin was previously known as E7389.  Eribulin is currently being investigated by Eisai Co. for the third-line treatment of advanced breast cancer in patients who have been previously treated with anthracyclines, taxanes and capecitabine, as well as a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.

Structurally, eribulin is a fully synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B a potent mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges. Eribulin is a mechanistically-unique inhibitor of microtubule dynamics, exerting its anticancer effects by triggering apoptosis of cancer cells following prolonged mitotic blockage. A new synthetic route to E7389 was published in 2009.

Now   research team at the University of Leeds and St James's Institute of Oncology led an international trial of the new chemotherapy drug, eribulin mesylate. As per the claim by the researchers, average survival was typically 25 per cent longer for women who took eribulin mesylate.

In the EMBRACE trial, 762 patients with advanced breast cancer received either eribulin or standard cancer treatment. All of the patients had already been heavily treated with conventional therapies, but their disease had returned or spread to other parts of the body.  Researchers concluded that those who took the new drug lived for 13.1 months, on average, compared with 10.7 months for those on conventional chemotherapy. The drug was also well-tolerated by most patients. Researchers hope that these results may establish eribulin as a new, effective treatment for women with late-stage metastatic breast cancer (either single drug or in combination with other anticancer drug). The drug is not yet available for routine clinical treatment and is awaiting regulatory approval in the European Union, the US and Japan.

"Until now, there hasn't really been a standard treatment for women with such advanced breast cancer. For those women who have already received all of the recognised treatments, these are promising results, claims the lead investigator Professor Christopher Twelves...

Ref : http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50309

Polyphenols in red wine and green tea halt prostate cancer growth, study suggests

In continuation of my update on Green Tea and EGCG........

"The profound impact that the antioxidants in red wine and green tea have on our bodies is more than anyone would have dreamt just 25 years ago," Weissmann added. "As long as they are taken in moderation, all signs show that red wine and green tea may be ranked among the most potent 'health foods' we know." ....

Polyphenols in red wine and green tea halt prostate cancer growth, study suggests