Serotonin-Specific Reuptake Inhibitor (SSRIs) as antiinflammatory agents?

We know that Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor (SSRIs) are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. They are also typically effective and used in treating premature ejaculation problems as well as some cases of insomnia.  Now researchers from Brighton and Sussex Medical School (BSMS) in the UK, lead by Dr. Sandra Sacre have come up with an interesting findings, i.e., two SSRIs fluoxetine &  citalopram significantly inhibited disease progression of collagen-induced arthritis (CIA) in mice. As per the claim by the researchers both SSRIs exhibited antiinflammatory effects and may provide drug development opportunities for arthritic conditions such as rheumatoid arthritis (RA).

Prior studies (of SSRIs)  have shown that patients with depression,  who respond to treatment with SSRIs display a reduction in cytokine levels (signals that can induce inflammation), suggesting a connection between SSRIs and the immune system. 

In the current study, researchers used a CIA mouse model due to the similarities to human RA, including synovitis, bone erosion and pannus formation. At the onset of arthritis, mice were treated daily for 7 days with a dose of 10 or 25 mg/kg of fluoxetine and 25 mg/kg of citalopram. At the lower dose of fluoxetine the mice showed a small reduction in the clinical score (a combined measure of redness, swelling and joint mobility/deformity) and a slower increase in paw swelling. At a dose of 25 mg/kg, fluoxetine halted disease progression and no further elevation was noted in the clinical score or paw swelling.

Researchers observed reduced inflammation, reduced cartilage and bone erosion, and a preservation of the joint structure in the mice treated with a higher dose of fluoxetine.  Citalopram was not as effective as fluoxetine at inhibiting disease progression in this model. 

They  also observed a decrease in cytokine production from cultures of human RA synovial joint tissues that were treated with SSRIs.  Toll-like receptors (TLRs) are strong activators of immune cells leading to the production of cytokines that can induce inflammation. Fluoxetine was found to inhibit the activation of TLRs more effectively than citalopram. 

Researchers conclude that SSRIs effectively target TLRs contributing to inflammation and could provide therapeutic benefit in RA, they are not ideal candidates to progress into clinical trials (from the data, the  effective inhibition of RA requires levels of the drugs higher than the safe therapeutic dosages.) The authors suggest further study of the role of TLRs in chronic inflammation may uncover drugs that offer an effective treatment of RA in the future..... 

Ref : http://www3.interscience.wiley.com/journal/123235497/abstract

Bitter melon (gourd) extract inhibits breast cancer cell proliferation.....

Momordica charantia (picture, source : wikipedia) is a tropical  and subtropical vine of the family Cucurbitaceae, widely grown for edible fruit, which is among the most bitter of all vegetables. English names for the plant and its fruit include bitter melon or bitter gourd.  Extract of this vegetable is being popularized as a dietary supplement in Western Countries, since it is known to contain additional glycosides such as mormordin, vitamin C, carotenoids, flavanoids and polyphenols.

Momordica charantia has a non-nitrogenous neutral principle charantin (see structure  an insulin-like chemical that can lower blood sugar and cholesterol), and on hydrolysis gives glucose and a sterol.

Now researchers from Saint Louis University, have come up with an in interesting finding, i.e., bitter melon extract, a common dietary supplement, exerts a significant effect against breast cancer cell growth and may eventually become a chemopreventive agent against this form of cancer.

Previous research has shown Momordica charantia, to have hypoglycemic and hypolipidemic effects. Because of these effects, the extract is commonly used in folk medicines as a remedy for diabetes in locales such as India, China and Central America, as per  the claim by  researchers.

Using human breast cancer cells and primary human mammary epithelial cells in vitro, Dr. Ratna  Ray (Professor in the Department of Pathology at Saint Louis University) and colleagues found the bitter melon extract significantly decreased proliferation, of cell growth and division, and induced death in breast cancer cells. These early results offer an encouraging path for research into breast cancer. Researchers claim that, "this study may provide us with one more agent as an extract that could be used against breast cancer if additional studies hold true". 

Ray and colleagues are currently conducting follow-up studies using a number of cancer cell lines to examine the anti proliferative effect of the extract. They are also planning a preclinical trial to evaluate its chemopreventive efficacy by oral administration. Hope they come up with positive results.......

Ref : Dr. Ratna Ray et.al., Cancer Research, 10.1158/0008-5472, February 23, 2010.

Closantel for treating river blindness ?

Closantel (see structure) is a broad-spectrum salicylanilide  anthelmintic used as antitrematode, antinematodes and antiarthropods in combination with benzimidazole anthelmintic such as mebendazole.  Closantel is used also as an acaricide.

Now  scientists  at the  Scripps  Research  Institute,  lead   by  Dr. Christian Gloeckner have discovered a potential new use for the drug closantel, i.e., the drug may be useful in combating river blindness, a tropical disease that is the world's second leading infectious cause of blindness for humans. 

River blindness is caused by thread-like filarial nematode worms, Onchocerca volvulus, which are transmitted among humans through the bite of a black fly. The nematodes then multiply and spread throughout the body. When they die, they cause a strong immune system response that can destroy surrounding tissue, including that of the eye. Currently, the only drug available for mass treatment of river blindness is ivermectin  and it now appears that resistance to that drug is emerging.

Chitin is the protective outer covering that forms part of O. volvulus's outer cuticle. While knowledge of chitin biosynthesis in nematodes is limited, scientists do know that two classes of enzymes are critical for maintenance of the pathway chitin synthases and chitinases, digestive enzymes that break down glycosidic bonds in chitin. The dynamic synthesis and degradation of chitin by these enzymes is a prerequisite for the organism's development and therefore a potential drug target. Therefore, researchers focused on these enzymes. 

In this method,  chitinase's enzymatic activity was monitored by a fluorescent signal  (when a huge decrease in the signal was observed the enzyme was essentially  knocked-out). Researchers  tried in vivo method (Closantel,  completely prevented molting from the L3 to L4 stage) also. As per the claim by the researchers, out of levfloxacin, lomefloxacin, dexketoprofen, and closantel (tried), only closantel was found to exhibit potent enough inhibition to warrant further investigation. 

Researchers conclude that based on its specificity, potency, and ease of synthesis, closantel or one its analogues might represent a promising alternative or adjunct therapy in combination with ivermectin for the treatment of onchocerciasis....

Ref : Christian Gloeckner et. al., Proceedings of the National Academy of Sciences (PNAS)

New evidence that green tea may help fight glaucoma and other eye diseases

In continuation of my update on green tea and its usefulness, I am sharing herewith this interesting article, where in the researchers claim that there is a possibility that green tea may protect against glaucoma and other common eye diseases.....

New evidence that green tea may help fight glaucoma and other eye diseases

New insight for design of novel antibiotic derivatives for drug resistant microorganisms...

Viomycin and Capreomycin (a group of nonribosomal peptide antibiotics) belong to the tuberactinomycin (an essential component in the drug cocktail currently used to fight infections of Mycobacterium tuberculosis) Are among the most effective antibiotics against multidrug-resistant tuberculosis. Viomycin was the first member of the tuberactinomycins to be isolated and identified and was used to treat TB until it was replaced by the less toxic, but structurally related compound, Capreomycin. The tuberactinomycins target bacterial ribosomes, binding RNA and disrupting bacterial protein biosynthesis.

Now Dr. Steitz and his colleagues at Yale's Department of Molecular Biophysics and Biochemistry, have identified two structures of tuberactinomycins bound to the ribosome. The researchers claims that,   the identification of these structures provides an insight for the design of novel antibiotic derivatives that could be effective against a variety of drug resistant microorganisms.

As per the claim by Dr.Steitz, both antibiotics (Viomycin and Capreomycin) bind to the same site on the ribosome, which lies at the interface between helix 44 of the small ribosomal subunit and helix 69 of the large ribosomal subunit. The structures of these complexes suggest that the tuberactinomycins inhibit translocation by stabilizing the tRNA in the A site in the pretranslocation state. In addition, these structures show that the tuberactinomycins bind adjacent to the binding sites for the paromomycin and hygromycin B antibiotics, which may enable the development of new derivatives of tuberactinomycins that are effective against drug-resistant strains. The authors have presented two crystal structures of the 70S ribosome in complex with three tRNAs and bound to either viomycin or capreomycin at 3.3-and 3.5-Å resolution, respectively in "Nature Structural & Molecular Biology 14 February 2010 ".

Interestingly, Dr. Steitz was awarded the 2009 Nobel Prize in Chemistry   for his groundbreaking work determining a high resolution crystal structure of the 50S subunit of the ribosome which has proved to be a major target for antibiotic development.

Hope this discovery will lead to a new insight for design of novel antibiotic derivatives that could be effective against a variety of drug-resistant microorganisms ....

Ref: http://www.rib-x.com/news_and_events/release_2010_02_16

New class of antibiotics with a novel mode of action (against drug resistant bacterii)

Many Gram-negative bacteria have become multi-drug resistant in recent years, as they have developed mechanisms to escape the therapeutic effects of current antibiotic drugs. New antibiotics against drug resistant bacteria are thus urgently needed as the current arsenal of drugs becomes ineffective against such resistant pathogens. Many research groups are trying different approaches, but now Polyphor Ltd., has come up with an interesting finding, they have discovered  a new class of antibiotics with a novel mode of action (Science 19 February 2010: Vol. 327. no. 5968, pp. 1010 - 1013). As per the claim by the lead researcher, Prof. John Robinson at the University of Zürich (in collaboration with Polyphor Ltd.,) the  new class of antibiotics is effective against multi-drug resistant Gram-negative bacteria, opening up new treatment options for serious and often life-threatening infections. The most advanced drug candidate in this new class,  POL7080, selectively kills the dangerous bacteria Pseudomonas aeruginosa. 

Polyphor applied its proprietary Protein Epitope Mimetics Technology (PEM Technology) to identify new antibiotics that either act against a broad-spectrum of bacteria or selectively target one particular bacterial strain. This joint research effort resulted in the discovery of a new drug target and mechanism of action by which Gram-negative bacterii are killed effectively. 

About Protein Epitope Mimetics (PEM Technology) :

Using a biologically relevant peptide or protein structure as a starting point for lead identification represents one of the most powerful approaches in modern drug discovery. In  protein epitope mimetic (PEM) approach, where folded 3D structures of peptides and proteins are taken as starting points for the design of synthetic molecules that mimic key epitopes involved in protein–protein and protein–nucleic acid interactions. By transferring the epitope from a recombinant to a synthetic scaffold that can be produced by parallel combinatorial methods, it is possible to optimize target affinity and specificity as well as other drug-like ADMET properties (Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties by Quantitative Structure-Activity Relationships, QSAR). The PEM technology is a powerful tool for target validation, and for the development of novel PEM-based drugs.

As per the claim by the lead researcher Prof. J. A. Robinson, one major target recently has been the development of PEMs with antibiotic activity against Gram negative bacteria, in particular, Pseudomonas aeruginosa. Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. 

Researchers, synthesized a family of peptidomimetic antibiotics (fully synthetic, medium-size cyclo peptide-like molecules), based on the antimicrobial peptide protein I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against gram-negative Pseudomonas sp.,  

Researchers conclude that, the leading antibiotic PEMdrug candidate POL7080 represents an important new weapon to combat life threatening infections with Pseudomonas aeruginosa which frequently occur in the hospital setting or in chronic lung infections.

Polyphor is currently preparing the start of Phase I clinical trials with POL7080 to rapidly advance the clinical development and has initiated out-licensing negotiations with Pharma partners.  The company is optimistic  about  the  positive clinical results and there by making way for this new class of antibiotics...

Ref : http://www.polyphor.com/PolyphorInhalt/Infogate/PressReleases/PressRelease20100219_en.pdf

Researchers able to predict and reverse resistance to Sunitinib treatment....

Van Andel Research Institute (VARI) researchers have found a way to  reverse resistance to Sunitinib (see structure), a treatment that is currently the first line of defense against clear cell renal cell carcinoma (ccRCC), a deadly form of kidney cancer. Most patients who show a positive response to Sunitinib develop a resistance to the drug after one year of treatment.

Researchers lead by Dr. Teh, Bin Tean found that ccRCC tumor cells that had developed a resistance to Sunitinib had increased secretion of the protein interleukin-8 (IL-8). Administering Sunitinib and IL-8 neutralizing antibodies re-sensitized tumors to sunitinib treatment. Researchers also found that IL-8 may serve as a useful biomarker to predict patients' response to sunitinib treatment.

Interestingly,  another  study from same  group  of  Teh’s laboratory, looked into exactly how sunitinib works.  The study found that the treatment does not target tumor cells, but rather the tumor’s blood supply.

Researchers conclude that “it is now of critical importance to validate these findings in the clinical setting" and they hope that these insights will help to build upon recent advances to extend clinical benefits to more patients with metastatic kidney cancer....

Ref : 1.  Cancer Research 70, 1053, February 1, 2010. 

        2.  Cancer Research 70, 1063, February 1, 2010

New strategy to overcome drug resistance (tamoxifen) in breast cancer ?

A solution to tamoxifen resistance is sorely needed, and if a strategy like this can work, it would make a difference in our clinical care of breast cancer,” says the study’s lead investigator. Yes, the researchers lead by Dr. Robert Clarke of Georgetown Lombardi Comprehensive Cancer Center have come with an interesting finding i.e., combining tamoxifen, the world’s most prescribed breast cancer agent  with a compound (Parthenolide,  see left structure source : ChemSpider) found in the flowering plant feverfew (right picture) may prevent initial or future resistance to the drug. 

 

As per the claim by the researchers tamoxifen resistance is regulated by the protein complex NF- κB (nuclear factor kappa B), which is often found to be over-expressed in ER+ breast cancer. NF- κB is known to help cells survive when damaged. Earlier the same researchers have also found that, the resistance to another tamoxifen-like drug, fulvestrant, was controlled by a protein (Bcl2) which is also regulated by NF- κB. These findings  encouraged  them to think that,  blocking NF- κB might affect tamoxifen resistance. 

Researchers conducted a variety of tests using parthenolide, which has been shown to act on NF- κB. They found that in resistant breast cancer cells, the chemical blocked the activity of NF- κB, making the cells sensitive once again to tamoxifen. Researchers then silenced NF- κB in tamoxifen resistant cells, and found that this had the same effect as using parthenolide. 

They further found that increased activation of NF- κB can alter sensitivity of tamoxifen by modulating the protein CASP8 (which is involved in programmed cell death), which affects Bcl2  and there by  helping  to  push a damaged cell to die.  
 

About Feverfew : 

Feverfew (Tanacetum parthenium) is edible and medicinal plant and   has a good reputation as alternative medicine and extensive research has proved it to be of special benefit in the treatment of certain types of migraine headaches and rheumatism or arthritis. The plant is rich in sesquiterpene lactones, the principal one being parthenolide. Parthenolide helps prevent excessive clumping of platelets and inhibits the release of certain chemicals, including serotonin and some inflammatory mediators. (other constituents are: pinene, pinene derivatives, bornylacetate, angelate, b-farnesine, spiroketalenol ethers, flavonoid glycosides and costic acid) .

Though the leaves and flowering heads are reported to possess antiinflammatory, antispasmodic, aperient,  sedative, stimulant, stomachic, vasodilator and vermifuge. activities, this type of activity has been reported  for the first time. 

 

Researchers conclude that the chemical, clearly has the potential to be able to figure out fairly  and it can help solve tamoxifen’s resistance problem with a caution that the science is much too early to make any recommendations. Let us wait for some more time.......

Ref :  Robert Clarke et. al., Feb. 12 in FASEB

Positive phase II clinical results of abiraterone (for advanced prostate cancer)....

We know that,  Abiraterone (discovered and developed at the Institute of Cancer Research in London, see structure) is a drug under investigation for use in hormone-refractory prostate cancer (prostate cancer not responding to treatment with antiandrogens). Abiraterone acts  by blocking the formation of testosterone by inhibiting CYP17A1 (CYP450c17), an enzyme also known as 17α-hydroxylase/17,20 lyase.  This enzyme is involved in the formation of DHEA and androstenedione, which may ultimately be metabolized into testosterone.

 

The latest trial, which was led by the ICR and the Royal Marsden  NHS Foundation Trust, is the first to investigate the drug in men with such advanced prostate cancer.

A total of 47 men were recruited for the trial, all of whom had late-stage castration-resistant prostate cancer, which means that their disease was advanced and their tumors were no longer responsive to androgen deprivation therapy. In almost all cases, the men's cancer had spread to their bones. All of the participants had already received hormone therapy and the chemotherapy drug docetaxel, but were no longer responding to those treatments. By the end of the study period, researchers found that around three-quarters of men had experienced a drop in levels of prostate specific antigen (PSA), which is often raised in men with prostate cancer and can be used to measure disease activity.

 In around half of the men,  PSA levels fell by at least 50 per cent, while three-quarters of participants also had a drop in the number of tumor cells circulating in their blood. Three years after the start of the trial, five of the patients were still taking abiraterone and benefitting from the treatment. Lead researcher Dr Alison Reid, also from the ICR and the Royal Marsden, noted that "abiraterone shrank or stabilised men's cancers for an average of almost six months, which is a very impressive result with only mild side-effects". 

Though the initial results are exciting, the researchers conclude that there's a lot more work needed to establish what abiraterone's place will be in treating men with prostate cancer....

Ref :http://info.cancerresearchuk.org/news/archive/cancernews/2010-02-16-New-drug-shows-promise-for-advanced-prostate-cancer-patients

TB disease mechanism and the molecule to block It - discovered ......

We know about the drug resistant tuberculosis and the havoc its causing, so there is an urgent need to  develop new drugs that can be useful. (have covered some articles on  drug development  for drug resistant TB in my earlier blogs). Many groups have tried to explain the resistance,  but now  researchers from Indiana University School of Medicine have identified a mechanism used by the tuberculosis bacterium to evade the body's immune system and have identified a compound that blocks the bacterium's ability to survive in the host, which could lead to new drugs to treat tuberculosis. 

The focus of the research was TB actions inside macrophages (infection fighting cells in the body's immune system). Macrophage cells' tools include the production of special proteins called cytokines to attack foreign invaders. Infected macrophages can also initiate a self-destruction mechanism called apoptosis, which signals other immune system cells to mount a defense against the infection. 

TB bacteria are able to disable the macrophage defenses by secreting virulent factors into the host. The IU team found that the actions of a particular virulent factor a protein phosphatase enzyme called mPTPB  blocked both the production of the infection-fighting cytokines, and the macrophage's self-destruct system. 

As for as my knowledge goes,  phosphatases  (VE-PTP, Cdc25A, PTP1b, VHR, Shp-2, MptpA und MptpB) the  key regulators of various life processes are being studied for the diverse activities. The following is the brief summary ;

a). VE-TPT inhibition is very promising in the development of antiangiogenesis inhibitors in cancer therapy.
b). Cdc25A influences cell cycle regulation and may also be a target of interest in cancer therapy.
c). The phosphatase MptpB, from Mycobacterium tuberculosis, influences the host's immune 
     reaction in a tuberculosis infection.
d) VHR dephosphorylates MAP kinases in the activation loop THX, which plays an important role in signal
    transduction processes.
e) Inhibiting MptpB and Shp-2 opens up new directions in the search for antibiotics and
f) The Ptp1B enzyme plays an important role in developing a medicine against type 2 diabetes and the
   metabolic syndrome.

Though many researchers  tried to study the mechanism of action by which the  tuberculosis bacterium is getting resistance,  this group has come up with a drug and this is of great significance in my opinion.

Using combinatorial chemical synthesis and high-throughput screening, (HTS) the researchers developed the I-A09 compound, which successfully blocked the action of mPTPB. Tests involving live TB bacteria were conducted at the Institute of Tuberculosis Research, University of Illinois at Chicago. 

As per the claim by the lead researcher, Dr. Zhong-Yin Zhang, compound I-A09 is being evaluated in a TB animal model at the Johns Hopkins University School of Public Health. More potent forms of the I-A09 compound are being pursued by the IU team for possible future clinical testing. Hope the team  will come up with a solution to this problem in the days to come...

Ref : http://www.medicine.indiana.edu/news_releases/viewRelease.php4?art=1232

Latrepirdine (dimbon) may ease cognitive effects of Huntington's disease....

We know that Dimebon (latrepirdine), an investigational drug currently in  Phase 3 development, that halt the onset of advanced Alzheimer’s (AD) and dramatically improve the quality of life for patients. Dimebon has a unique mechanism of action, distinct from currently available treatments. In preclinical studies, dimebon has been shown to protect brain cells from damage and enhance brain survival, potentially stabilising and improving mitochondrial function.

Now researchers from School of Medicine and Dentistry at the University of Rochester in New York lead by Dr. Karl Kieburtz, have found that  Dimebon may improve thinking, learning and memory skills in people with Huntington's disease  an inherited neurodegenerative disorder. 

Mitochondria are critical to brain cell functioning as they are the primary source of energy for cells. Drugs that protect mitochondria or restore their function could potentially be a valuable treatment approach in AD and Huntington's disease.

As per the claim by the researchers, the drug stabilizes and improves the function of mitochondria, parts of cells that help convert food into energy. Researchers found that, Dimebon (Latrepirdine)  at a dosage of 20 mg three times daily, is well-tolerated for 90 days in patients with Huntington's disease and may have a beneficial effect on cognition. Though further studies are essential to substantiate the claim, its good to see at l(e)ast a drug for Huntington's disease (the only approved therapy for Huntington's is tetrabenazine, which treats movement problems but does not prevent cognitive decline or change the course of the disease).....more...

FDA approves Olmesartan (Benicar, Olmetec) for children....

Olmesartan (Benicar, Olmetec-by Ranbaxy) is an angiotensin II  receptor antagonist used to treat high blood pressure. 

Mode of action : Olmesartan works by blocking the binding of angiotensin II to the AT₁ receptors in vascular muscle; it is therefore independent of angiotensin II synthesis pathways, unlike ACE inhibitors. By blocking binding rather than synthesis of angiotensin II, olmesartan inhibits the negative regulatory feedback on renin secretion. As a result of this blockage, olmesartan reduces vasoconstriction and the secretion of aldosterone. This lowers blood pressure by producing vasodilation, and decreasing peripheral resistance.

Now FDA has approved the hypertension treatment Benicar (olmesartan medoxomil) for use in children and adolescents 6 to 16 years of age.  Benicar was originally approved in 2002 for the treatment of hypertension in adults (Daiichi Sankyo, Inc.).

The approval of this expanded indication was based on a phase III study examining the antihypertensive effects of Benicar in pediatric patients. The study found Benicar to be safe and efficacious in children ages 6-16 with hypertension, resulting in blood pressure reductions that were statistically different in comparison to placebo. Benicar was generally well tolerated in pediatric patients, and the adverse event profile was similar to that for adults.

Ref : http://www.dsi.com/news/pdfs/FINAL_Benicar_Pediatric_Approval_Press_Release.pdf

Triapine with cisplatin a new standard of care for cervical cancer?

In continuation of my update on cancer drug development,   I found this  info interesting to share with. Researchers  lead by Dr. Charles Kunos at the Ireland Cancer Center of University Hospitals (UH)  have found that,  Triapine, (3-aminopyridine-2-carbox -aldehyde   thiosemicarbazone, see structure), which suppresses tumor growth shows a great deal of promise for cervical cancer patients who are at high risk for relapse and cancer-related death. 

The phase I study found that the chemotherapy medicine  Triapine, was well tolerated in combination with standard-of-care cisplatin chemotherapy and radiation treatment in women with cervical cancer. This regimen provided both significant reduction in cancer disease and cancer control.

In the study   (ten-patient study) patients,  were treated three times weekly with Triapine (a potent Ribonucleotide Reductase Inhibitor) in combination with weekly cisplatin treatment and daily pelvic radiation therapy over five weeks.  The researchers claims that  "a 100% complete response rate was observed and no disease progression was documented through 18 months of median follow-up."A phase two follow-up study is ongoing at the Ireland Cancer Center. UH Case Medical Center  Hope this new found combintaton will be  a promising new treatment to help women fight this aggressive disease in the days to come...

Ref : http://clincancerres.aacrjournals.org/content/16/4/1298.abstract?sid=f3df7c2d-9e46-4baf-b47b-83d310b87641

Enantioselective synthesis of Kinamycin F - a new hope for anticancer drug development ?

The kinamycins are a series of naturally occurring compounds endowed with intriguing molecular architectures and potent biological properties such as  antibiotic and antitumor activities. These novel diazofluorene-containing compounds defied chemical synthesis since their initial disclosure by Omura et al. in 1970 until the first total synthesis of kinamycin C by Porco et al. in late 2006.

Now, researchers from Yale University,  have  developed a new method to recreate this structure that allows them to synthesize the kinamycins with much greater efficiency than previously possible.

As per the claim by the researchers,  key to the success of the route was  the development of a three-step sequence for construction of the diazonapthoquinone (diazofluorene, blue in structure source : JACS) function of the natural product.

While scientists have produced kinamycins in the laboratory in the past, the Yale team was able to halve the number of steps required to go from simple, easily obtainable precursors to the complete molecule from 24 down to 12. 

This sequence comprises fluoride-mediated coupling of a β-(trimethylsilylmethyl)-cyclohexenone and halonapthoquinone, palladium-mediated cyclization to construct the tetracyclic scaffold of the natural product, and mild diazo-transfer to a complex cyclopentadiene to introduce the diazo function. Ortho-quinone methide intermediates, formed by reduction and loss of dinitrogen from (structure), have been postulated to form in vivo, and this approach provides a straightforward synthetic pathway to such compounds.

This research is of great importance because by shortening the synthesis one can now prepare these molecules in the quantities required for further studies, including animal studies and even clinical trials.

Working with researchers at the Yale School of Medicine and the Yale Chemical Genomics Screening Facility, the team has begun testing several of the compounds against cancer cells, with promising preliminary results. Next, they will work to understand the exact mechanism that makes the compounds,  which are benign on their own  highly toxic once they penetrate cells. Lead researcher Dr. Seth Herzon, says "the key to success will be whether they can develop selectivity - whether they can kill cancer cells in the presence of non-cancerous tissue". Dr.Herzon  is also optimistic about lomaiviticin A (which also has the reactive core kinamycin,  and is even more toxic and could prove even more effective in destroying cancer cells)...let us hope positive results from this study....

Ref : http://pubs.acs.org/doi/abs/10.1021/ja910769j 

Denosumab exhibits superiority over Zometa in treatment of prostate cancer men with bone metastases

Denosumab exhibits superiority over Zometa in treatment of prostate cancer men with bone metastases