MedchemBlog-medicinal chemistry and related sciences

Chem Coach Carnival

2012-10-28T02:32:00.000+09:00

It's a great pleasure to be a part of ChemCoachCarnival that has been started at Justlikecooking by See Arr Oh. He has asked people working in chemistry to answer few questions (as below) which can be helpful for those interested in chemistry.

Your current job

What you do in a standard "work day."

What kind of schooling/training/experience helped you get there?

How does chemistry inform your work?

Finally, a unique, interesting, or funny anecdote about your career.

It's such a great idea to celebrate National chemistry week, loved it. Here is my entry for the carnival.

Your current Job

Postdoctoral research scholar (synthetic medicinal chemist) working on anticancer drug discovery.

What you do in a standard "work day."

Work day starts with a refreshing cup of coffee. Daily work roughly divides into bench work and paper works.

Bench work includes putting reaction, purification (workup, column) and analysis (NMR, HPLC, LC/MS)
Paper work includes searching and reading articles, analyzing spectral data, and writing manuscript.

Switching between works, whenever possible, is a great idea to reduce monotony (at least for me). What do you say?

What kind of schooling/training/experience helped you get there?

I did my bachelor in Pharmacy. After my undergraduate, I got an opportunity to complete both my master and PhD in medicinal chemistry (subject of my interest) with same supervisor.

How does chemistry inform your work?

Well, it teaches me how to make new molecules, what functional groups or pharmacophores are essential for the biological activity and how to add or change these pharmacophores.

Finally, a unique, interesting, or funny anecdote about your career.

Among many funny situation, one that always come in my mind is the incident when I got scared by Liquid nitrogen tank. The incident took place when I was in my first semeter of Master course. I was learning LC/MS with my senior in the instrumental room. All of sudden, in the middle of the experiment, there was a loud noise. I started running to find the exit door. Immediately, my senior asked me to stop and started laughing loudly. Later, I realized that the sound was from the liquid nitrogen tank produced as a result of gas release to prevent excessive pressure build-up in the tank. Though it was scary and embarrasing moment, it always amuses me whenever I recall.

How to work-up reaction using separatory funnel?

2012-06-18T02:49:00.000+09:00

As you know, to get a pure compound is not an easy task. Here, I am going to write about the work-up process (liquid-liquid extraction) using separatory funnel, one of the methods for the purification of crude compound. I hope it will be helpful for you. In this method, two immiscible solvents, aqueous and organic solvent (ethyl acetate, methylene chloride etc) are used which allows the removal of water soluble impurities present in the reaction mixture.

Work-up procedure

Transfer the reaction mixture completely into the separatory funnel using the appropriate organic solvent. "Be cautious to close the stopcock". After that pour distilled water into the separatory funnel. Hold the stopper tightly and shake the reaction mixture gently. "Be sure to release the pressure- hold the stopper tightly, invert the funnel pointing outlet upwards and open the stopcock (See the video below)".

I want to share my bitter experience here. Once, while doing work-up (during shaking), I forgot to release the pressure. As soon as I kept the separatory funnel to stand, solvent splashed out of the separatory funnel through the stopper. Oh gosh! You can imagine the situation.:(

After gentle shaking, stand the separatory funnel for some time to see the clear separation of two layers i.e. organic and aqueous layer. Now comes the little trick. You need to determine the organic layer, where your desired compound remains. It can be done simply by comparing the density of two immiscible solvents used. For instance, ethyl acetate has lower density whereas methylene chloride has higher density than water. When you use ethyl acetate as organic solvent, it will remain at the upper layer. In case of methylene chloride it will remain at the lower layer. The organic layer is washed 2 or 3 times with water followed by saturated NaCl (brine). Check the TLC of all the washing to confirm the absence of your desired compound. After confirmation, you can discard the aqueous washing and collect the organic extract. Organic extract is then dried over magnesium sulfate or sodium sulfate. Remove the drying agent by filtration to get the clear organic extract. Evaporate the organic solvent using the rotary evaporator to get the concentrated product which can be further purified by recrsytallization or column chromatography, if necessary.

Things to remember while doing workup

Make sure to close the stopcock before transferring the reaction mixture into separatory funnel. It is one of the common mistakes to lose the compound. Keeping flask under separatory funnel will be a good idea.
Always remember to release the pressure while shaking the solvent mixture.
Sometime, there may not be clear separation of two layers i.e emulsion formation, in such case try to gently swirl the mixture and wait. If it does not work, add little saturated NaCl solution.
Make sure to differentiate the layers (see the density).
Check the TLC for all aqueous washings before discarding.
Sometime there may be formation of uniform black layers. In such case, you can add ice lump which will float in water (at the line between water and organic solvent).
For more troubleshooting, you may refer here and here.

Here is the diagrammatic illustration of work-up process.

And if you are still confused, please check out the video on how to do work-up.

If you have any queries, please leave them in the comment section below.

New approach could identify antiviral drugs against wide range of viruses

2012-05-09T21:37:00.000+09:00

Research team led by Michael J. Holtzman, MD, from Washington University, US, has recently reported the possibility of novel strategy to find small molecules that can enhance the host defense system against a broad range of viruses. The compounds were tested for their ability to increase the interferon signaling pathway (IFN-pathway) which mediates the host defense against a wide range of viruses. The team has conducted the cell-based high throughput screening of 2240 compounds which led to 64 hit compounds with significant interferon-stimulated response element ISRE) activity being idarubicin hydrochloride the most potent. Idarubicin, an anthracycline, is used as anti-cancer agent. DNA intercalation and topoisomerase II inhibition is responsible for its anti-cancer activity. To confirm that increased ISRE activity by idarubicin is independant of topoisomerase inhibitory effect, the team tested other three potent topoisomerase inhibitors (Etoposide, Hu-0331, and ICRF-193) for the ISRE activity. Interestingly, they found these compounds did not show significant increase in ISRE activity. Instead, two of them (etoposide and Hu-0331) caused decreased ISRE activity.

You may like to read Voreloxin as DNA intercalating topo II poison

Authors concluded that they validated the phenotypic screening strategy to identify small molecules that enhance the activity of the type I IFN signaling pathway and consequently improve antiviral host defense. They believed that this approach should thereby prove useful to discover drugs with activity against a broad range of viruses as well as other conditions (e.g., multiple sclerosis, melanoma) where the efficacy of IFN treatment might benefit from enhancing IFN signaling.

As you know, idarubicin, like other anticancer agents, has severe side effects; it cannot be easily used for antiviral purpose. But these findings have provided a new path in the antiviral drug discovery which enables the screening of more compounds to find potent one with less toxicity and side effects.

Source: Plos one

Pazopanib approved for soft tissue sarcoma

2012-04-28T21:16:00.001+09:00

Pazopanib (Votrient) from GlaxoSmithKline has been approved by FDA for the treatment of patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a rare cancer which begins in soft tissues such as muscle, fat, fibrous etc. Pazopanib is a potent anti-angiogenic agent, which means it interferes with the growth of new blood vessels essential for growth and survival of solid tumors.

You may like to read angiogenesis and anti-angiogenic foods

It was approved in 2009 for the treatment of advanced kidney cancer.

The common side effects of Votrient includes fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, a distorted sense of taste, shortness of breath, and skin discoloration.

For more details, here is FDA news release.

FDA approves Vismodegib for basal cell carcinoma

2012-02-01T19:31:00.000+09:00

Vismodegib (see structure) under trade name Erivedge from Roche has been approved by FDA for the treatment of basal cell carcinoma (BCC), the most common type of skin cancer. The drug is intended for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma who are not candidates for surgery and radiation. The drug works by inhibiting the hedgehog pathway, a pathway active in most basal cell cancers. It is the first FDA-approved drug for BCC that inhibits the hedgehog pathway.

Animation on Hedgehog signaling pathway.

“Our understanding of molecular pathways involved in cancer, such as the Hedgehog pathway, has enabled the development of targeted drugs for specific diseases,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approach is becoming more common and will potentially allow cancer drugs to be developed more quickly. This is important for patients who will have access to more effective therapies with potentially fewer side effects.”

Press release from FDA and Roche.

Novel drug for Alzheimer's Disease?

2012-01-28T01:39:00.000+09:00

Researchers have reported the novel compound with neurotrophic activity for cognitive enhancement and alzheimer's disease (AD). They previously found pyrazole derivative of curcumin called CNB001 (structure 1) with broad neuroprotective effects (J. Neurochem, 2008, 105, 1336). Due to the presence of hydroxyl groups in aromatic ring, the compound was believed to be modified by sulfation and carbohydrate addition in vivo which limits the brain penetration.

Therefore, the authors prepared the derivatives of CNB-001 without the hydroxyl groups but retaining neuroprotective activity. In this process, they discovered a new compound CNB-023 (structure 2). They did futher modifications to find more potent compound called J147 (structure 3) which has the ability to enhance memory in normal animals as well as to prevent memory deficits in AD transgenic mice.

Authors conclude that J147 has a potential as an alzheimer's disease therapeutic.

For experimental details please refer to PLOS one.

Happy new year 2012 and popular posts of 2011

2012-01-02T01:46:00.000+09:00

I wish all medchemblog readers a very very happy and healthy new year 2012. I hope this year brings a lot of success in your life. In this post I would like to take an opportunity to share the top 10 posts and the top 10 countries to visit the medchemblog in 2011.

Top 10 posts
1. Angiogenesis and anti-angiogenic foods
2. Simple method of recording TLC data
3. Hydrogenation demonstration
4. Mitomycin, mode of action and synthetic approach
5. Purification technique-Column chromatography
6. Broccoli as a source of anticancer agents
7. Rotary evaporator vial adapter
8. Green tea: role in cancer prevention
9. Voreloxin: DNA intercalating topoisomerase II poison
10. Top 200 pharmaceutical products

Top 10 countries
United States
South Korea
Japan
India
Germany
United Kingdom
Canada
Russia
France
Netherlands

Source: Blogger stats

Breakthrough of 2011-HIV study

2011-12-30T11:51:00.004+09:00

The Journal Science has announced the top 10 breakthrough of the year 2011 and the winner is "HIV treatment as prevention". Check Science/AAAS | Special Issue: Breakthrough of the Year, 2011 to see the winner and the runner ups. You may also enjoy the video here Science - Video Portal.

Hyroxyl groups & Planarity of Quercetin- Essential for antioxidant activity

2011-12-07T13:13:00.000+09:00

It is the fact that polyphenols are considered as good antioxidants and have wide range of biological activities. In my earlier posts, role of polyphenol epigallocatechin-3-gallate in cancer prevention and neuroprotection were discussed. Recently, researchers have published the antioxidant activity and structure-activity relationship study (SAR) of polyphenol quercetin and its derivatives. They found that hydroxyl groups and planar conformation of the quercetin has an important role for antioxidant activity.

SAR study

For SAR study, authors have prepared various quercetin derivatives by methylation of hydroxyl groups or incorporation of bulky groups like rutinosyl and hydroxyethyl. O-methylation of all hydroxyl groups resulted in complete loss of antioxidant activity whereas O-methylation at 5 and 7 position has less effect on antioxidant activity. They found that the compound with rutinosyl group at 3-O position has less antioxidant capacity than the quercetin and 3-O methylated compound. They determine the dihedral angles (angle between the plane of the AC-ring and B-ring) for these three compounds. Quercetin, with highest antioxidant capacity, has the least dihedral angle and compound with rutinosyl group has the largest dihedral angle.

According to authors, the planar structure of quercetin allows the conjugated π-system of the AC-ring and B-ring to efficiently interact which distributes the electron donating effect of the OH groups over the whole molecules, enabling the cooperation of electron donors in the different rings. Bulky groups at 3-position forces the B-ring out of the plane of the AC-ring which diminishes the efficiency of the conjugated π-system found in Q, leading to a relatively low antioxidant activity.

Antiviral agents for Alzheimer's disease?

2011-11-03T23:58:00.000+09:00

Antiviral drugs, acyclovir, penciclovir and foscarnet, are found to reduce the formation of beta-amyloid (Aβ), and abnormally phosphorylated tau (P-tau). Accumulation of these proteins are thought to be responsible for the Alzheimer’s disease. You can go through my previous post (here)to see the video clip on Alzheimer disease (nice and informative animation).

This work was reported in PLoSOne by the researcher from the University of Manchester. Previously, they have shown that herpes simplex virus type 1 (HSV1) causes accumulation of the Aβ and P-tau. In this study, they have demonstrated that antiviral agents cause reduction in the accumulation of Aβ and P-tau, as well as HSV1. Among the tested antiviral agents, foscarnet was found to have the least effect. They believe that anti-HSV1 antiviral agents might slow AD progression. This provides a new insight for the usage of antiviral agents for the treatment of AD.

DRACOs: Cure for nearly any viral infection?

2011-08-25T19:02:00.001+09:00

A novel broad spectrum antiviral approach, DRACO, acronym for Double-stranded RNA Activated Caspase Oligomerizer has been developed by the researchers from Lincoln laboratory, MIT, USA. The work was published online in the Journal PLoS ONE. According to the study, DRACO, having two domains- one for binding to viral double stranded RNA (dsRNA) and another for inducing apoptosis when two or more DRACOs crosslink on the same dsRNA, are able to selectively induce apoptosis in cells containing viral dsRNA. This allows the killing of only infected cells without harming the healthy cells.

DRACOs with different dsRNA detection domain and apoptosis induction domains and transduction tags were prepared. It was shown to be effective against 15 different viruses including Rhinovirus, dengue flavivirus, tacaribe, amapari, and H1N1 influenza. It has been demonstrated that DRACO is nontoxic to 11 different mammalian cell types. It has also been tested in mice infected with H1N1 influenza. Treatment with DRACO has cured the infected mice.
Though further studies are needed, there is a great hope in the field of viral drug discovery. What do you say?

Impact factor 2010

2011-07-16T16:28:00.004+09:00

Thomson Reuters has released the Journal Citation Report 2010. You can check out the link below;

"2010 Journal Citation Reports® Science Edition (Thomson Reuters, 2011)"

Total synthesis

2011-06-25T15:33:00.002+09:00

Check out the nice and informative documentary on total synthesis entitled “Total synthesis-From chemistry to medicine”. This video was prepared by Professor Matt McIntosh and his students of chemistry department at the University of Arkansas. He himself is involved in the total synthesis of various biologically important natural compounds.

As Professor Matt McIntosh mentioned, total synthesis has very important role in the discovery of new medicine. Most of the clinically used medicines are derived from natural products. For e.g. Camptothecin, a well-known topoisomerase I inhibitor for cancer treatment is first isolated from the Camptotheca acuminata. It’s hard and almost impossible to scale up the production of biologically active compounds from the natural resources. To provide those compounds in large scale, preventing the natural resources, total synthesis is a good option. At the same time, different analogues can be prepared to find out more potent compounds.

Looking forward to see the making of total synthesis (Phase II) from the group.

So, what do you think? Please leave your opinion.

Top 200 pharmaceutical products

2011-02-12T23:04:00.001+09:00

It’s obvious that most people related to pharma world are interested in knowing popularity of drugs in market. If you haven’t seen one, it’s worthwhile going through this list (Njarðarson research group at the University of Arizona) of top 200 pharmaceutical products by worldwide sales in 2009. Atorvastatin, sold by Pfizer under the trade name Lipitor tops the list. The attractive poster in pdf contains information like chemical structure, company name and the sales amount.

Make your guess and find out how many of them are in the list.

Rotary evaporator vial adapter

2010-12-11T23:26:00.002+09:00

For the purpose of transferring sample (synthesized compound) into vial and evaporate the solvent, rotary evaporator vial adapter is used. It can be purchased from various suppliers. But, what to do if ready-made vial adapter is not available at the time you need it? No worry, you can easily make it by yourself. For this, you just need rubber septum, capillary tube, and connector or bump trap.

Procedure: Appropriate sized rubber septum is selected and attached to the one end of the connector or bump trap (As shown in picture). Thereafter, make sure to avoid air leakage by sealing joint with parafilm. Finally, capillary tube is inserted right through the middle of the rubber septum. Be careful, capillary tube may break and hurt you. So, it’s suggested to prick the rubber septum with other strong sharp materials (for instance syringe) before inserting capillary. Caution:While operating rotary evaporator, hold the vial until enough pressure is developed, otherwise it may fall into heating bath.

So, how do you transfer your sample into vial and evaporate solvent? Leave your view in the comment section below.

4-oxo-fenretinide: Anticancer activity via two independent mechanisms

2010-10-23T17:25:00.001+09:00

Retinoids are structurally related to vitamin A and has been reported to modulate fundamental cellular processes including cell proliferation, differentiation and apoptosis. In this post anticancer activity of the 4-oxo-fenretidine or 4-oxo-N-(4-hydroxyphenyl) retinamide (4-oxo-4-HPR), which is a polar metabolite of fenretinide or 4-hydroxyphenyl retinamide (4-HPR), will be discussed as reported in PLOS one by Tiberio et. al.

Authors have identified 4-oxo-4-HPR from the analysis of plasma samples of 4-HPR treated patients (participating in Phase III breast cancer prevention trial). This metabolite has been associated with antiproliferative and apoptotic effects in various cancer cell lines and is two to four times more effective than 4-HPR in inhibiting cell growth. Interestingly, 4-oxo-4-HPR is also effective in 4-HPR-resistant cells and, in combination with 4-HPR, has a synergistic effects. 4-HPR and 4-oxo-4-HPR has several similar signaling intermediates like ROS generation, increase of intracellular ceramide levels, and activation of caspase-3 and -9. But its (4-oxo-4-HPR) effectiveness towards 4-HPR resistance cells indicates that it has additional mechanism of action compared to 4-HPR. From the study, it is found that it targets microtubules and inhibits tubulin polymerization causing mitotic arrest and formation of multipolar spindles without loss of centrosome integrity.

In this study, they have found that the mitotic arrest and the coupled formation of multipolar spindles induced by 4-oxo-4-HPR were independent from ROS-related signaling cascade. 4-oxo-4-HPR induced ROS generation occurred earlier than the mitotic arrest. The result was further supported by the finding that inhibition of ROS-related pathway by vitamin C or PLAB silencing did not prevent the ability of 4-oxo-4-HPR to exert its antimicrotubule activity. The ability of 4-oxo-4-HPR to act through at least two independent mechanisms has probably been the explanation behind its higher potency than the 4-HPR and effectiveness to 4-HPR resistant cell lines.

Authors believed that modification in position 4 of the cyclohexene ring is responsible for 4-oxo-HPR antimicrotubule activity, but does not affect the ability of the retinoid to induce ROS generation and to activate the ROS-related signaling cascade.

Solvent impurities in NMR spectra

2010-09-13T09:57:00.002+09:00

In my previous post 'here', I have written on how to clean NMR tube to get clean spectra. If NMR tube is not properly dried in oven before use, there will be many confusing solvent peaks in the spectra. Also, when the sample is not properly dried and the NMR solvent is contaminated, you can easily get those unwanted solvent peaks. To make your work easy to differentitate the solvent peaks, paper including chemical shift values of common laboratory solvents has been reported. It's nice update to this paper published back in 1997.

But it is suggested to properly dry NMR tube, sample and prevent NMR solvent from contamination to avoid these solvent peaks. What do you think? Let us know your view.

Gallotannin (Penta-O-Galloyl-beta-D-glucose) against Breast Cancer

2010-09-10T10:33:00.006+09:00

Breast cancer (BCa) is one of the major causes of cancer-related deaths in women. Most of BCa express estrogen receptors (ER) and/or progesterone receptors, and some have amplified human epidermal growth factor receptor (HER-2) proto-oncogene and express high levels of the HER-2 protein. In some cases, BCa lacks all these expressions referred as “triple negative BCa”. This subtype is clinically characterized as more aggressive and less responsive to standard treatment and associated poorer overall patient prognosis.

Various drugs like BSI 201 and SN-38 are in clinical trials for the treatment of triple negative BCa.

BSI 201, also called as Iniparib is 4-iodo-3-nitrobenzamide. It inhibits the nuclear enzyme poly ADP ribose polymerase (PARP), which is involved in multiple cellular processes, including DNA repair. SN-38 is an active metabolite of irinotecan.

Recently, Penta-1, 2, 3, 4, 6-O-galloyl-beta-D-glucose (PGG), naturally occurring gallotannin polyphenolic compound found in oriental herbs was reported to have significant inhibitory activity on BCa cells especially triple negative BCa cells both in vitro and in vivo.

In this study, PGG treatment (in cell culture) caused P53-ser¹⁵ phosphorylation and caspase-mediated apoptosis in MCF-7 BCa cells. In P53-mutant MDA-MB231 triple negative BCa cells, PGG caused not only apoptosis, but also autophagic responses. Independent of P53 or ERα status of the BCa cells, PGG induced S-arrest and G1 arrest. There was no induction of P21^cip1and P27^kip1 expression. Downregulation of Cyclin D1 by PGG has been an important mediating event for the G1 arrest action.

In vivo study showed that PGG given by oral administration was quite safe to the host nude mice and had greater than 60% inhibition of a triple negative BCa (MDA-MB231) xenograft model.

MDA-MB231 was injected subcutaneously into the right flank of athymic nude mice. After 4 days, PGG was delivered by oral gavage at the dose of 20 mg/kg body weight.

Purification technique-Column Chromatography

2010-08-04T14:37:00.002+09:00

Sorry guys, it has been quite busy days so couldn't connect with you often. Today's post will be on column chromatography (demonstration on how to make column). As a medicinal chemist, I can't imagine my work without column chromatography at least single run a day.

Actually, this post is especially for the freshmen who still are not sure on how to make column. At the same time, I have great expectation from expertise to share the information which they think is missing in this post.

Column chromatography, technique for purification or separation of single compound from mixture of compounds, contains two phases i.e. stationary and mobile phase. Stationary phase are solid materials, commonly silica and alumina, through which compounds are allowed to run down by the help of appropriate solvents called as mobile phase. Usually mixture of solvents is used as mobile phase. The most common solvent combination is ethyl acetate/ hexane and Methylene chloride/ methanol.

Process of making column

First put small piece of cotton or glass wool into the column (to outlet). Support the column with clamps. Little sea sand is poured into the column (0.5 to 1.0 cm in height). Cotton wool and sand are used to prevent silica falling from the column. Solvent, usually less polar, is poured into the column (for e.g if you are using solvent mixture of Ethyl acetate and hexane as mobile phase, it's better to make column in less polar solvent i.e. hexane). Silica slurry is prepared in appropriate solvent and poured into the column while stirring. The valve is opened to allow the dripping of solvent. The adsorbed silica is rinsed down the column using pipette. Silica is allowed to settle down for a while. Thereafter valve is closed, silica level is marked and gently tapped with soft materials like cork rings or hand. Slight pressure can be applied (but be sure to open the valve). Small amount of sea sand is poured (In case of wet loading, I put sea sand first and then sample but in case of dry loading I put sample first and then sea sand on the top of sample). That’s it; your column is ready. Dry loading is demonstrated in the video embedded below.

Things to remember while making column,

1. Make sure the column is dry (keep the column in oven prior to use).

2. Appropriate amount of cotton wool or sand should be used. Excess amount makes the opening tight resulting slow rate of solvent dripping.

3. Silica slurry should be stirred enough to remove any air bubble. It is advisable to make the column one night before using so that silica will be well settled and avoids trapping of any air bubbles.

4. While making silica slurry, be careful to avoid inhalation of light silica particles (Always put on the mask and do your work in fume hood).

5. Make sure to remove any air bubble trapped in the column by tapping or applying slight pressure.

6. Be careful while applying pressure. Pressure should be released slowly to prevent formation of cracks in the column.

7. Be sure that silica is settled properly before adding sand. Otherwise the sand, being heavier will sink into the silica.

8. While loading sample (wet loading), make sure the level of solvent is just in middle of sand layer.

9. You can add your point. Leave it in comment section and it will be updated here.

Angiogenesis and anti-angiogenic foods

2010-07-02T15:28:00.008+09:00

This post shares the natural way of preventing cancer by eating healthy anti-angiogenic foods. William Li’s talk on topic “Can we eat to starve cancer?” has been an inspiration behind this post.

In his talk, he has mentioned many natural diets with antiangiogenic substances that can help to prevent cancer. Beside cancer, there are more than 70 major diseases in total that affects billions of people worldwide due to abnormal angiogenesis.

Angiogenesis, a hallmark of cancer, is a fundamental process by which new blood vessels are formed from existing vessels. It is essential in reproduction, development and wound repair. Under these conditions, angiogenesis is highly regulated, i.e. turned on for brief periods (days) and then completely inhibited. In 1971, Dr. Folkman proposed that tumor growth and metastasis are angiogenesis-dependent and hence, blocking angiogenesis could be a strategy to arrest tumor growth. Without blood vessels, tumors cannot grow beyond a critical size or metastasize to another organ.

William Li’s research team has conducted anti-angiogenic therapy on various species and has obtained the positive results. As Li explains, their present interest is on various diets that can be used in antiangiogenic therapy. They have prepared list of more than 30 antiangiogenic foods and beverages. You can check the list here. After watching the list, I realize that we, knowingly or unknowingly, are eating many anti-angiogenic foods that can prevent the cancer. Yes, Mother Nature has a huge database of compounds that can be used for medicinal value. But for this purpose we need more research and great efforts.

Check out the informative and very nice talk by William Li, MD.

Novel Protein Kinase D inhibitors

2010-06-19T22:49:00.010+09:00

As we are going to talk about the Protein Kinase D inhibitors, let’s understand the basic about the protein kinases. Actually they are the enzymes which catalyze protein phosphorylation, i.e., the transfer of the gamma-phosphoryl group of ATP to tyrosine, serine and threonine residues in protein substrates. Phosphorylation can result in activation / inhibition of an enzyme, conformational changes or creation of surface with distinct binding properties. Thus, protein phosphorylation has great role in various cellular processes and defect in this process can result in many diseases including cancer and inflammation.

Recently, researchers from University of Pittsburgh has reported the Novel protein kinase D inhibitors that cause arrest in prostate cancer cell growth and motility.

Protein kinase D is a novel family of serine/threonine kinases and Diacylglycerol (DAG) receptors. Three isoforms has been idenfied as PKD1, 2 and 3. Since its discovery, PKD has been implicated in various cellular functions significant to tumor development including proliferation, survival, apoptosis, angiogenesis, and motility.

In this study, they have synthesized the analogues of CID755673 (previously reported PKD inhibitor) by modifying their core structures and side chains.

SAR study

Design of CID755673 analouges was based on the modification of 4 major structural zones (I, II, III and IV) as shown in figure (right side).

In zone I, phenolic substituent was modified as well as the alpha position on the aromatic ring.

Most of the derivatives were considerably less active than parent compound in the PKD screening.

In zone II, oxygen was changed with sulfur and nitrogen

Nitrogen replacement results in loss of activity, whereas sulfur substitution increases the activity.

In zone III, ring size was modified by adding or removing methylene groups, as well as substituting the benzylic positions.

Thioether insertion exo to the five-membered heterocycle and an additional methylene group were well tolerated.

In zone IV, functional group interconversions as well as replacement of the amide with heterocyclic groups.

Showed unsatisfactory activity thus amide function of parent compound was retained.

After initial screening and the SAR analysis on ca 50 analogues, five novel compounds with equal or greater potency for PKD compared to parent compound were selected for further testing.

Among the analogues, kb-NB142-70 was the most potent compound which inhibited PKD1 with nearly 7-fold greater potency compared to parent compound (CID755673). It also, inhibited PKD2 and PKD3 about 4-fold stronger than parent compound

It has been found that these analogs showed increased cytotoxicity and dramatic arrest in cell proliferation (prostate cancer cells) compared to parent compound. In addition, authors reported that the analogues, Kb-NB142-70 and Kb-NB165-09, in particular, are potent inhibitors of prostate cancer cell migration and invasion.

From their experimental data, researchers concluded that Kb-NB142-70 and Kb-NB165-09 are the most potent and specific analogues in vitro and in cells. They are doing further testing for these compounds in order to find potential anti-cancer agents in the treatment of prostate cancer.

Quick look at Drug discovery opinion (DDO)

2010-06-02T15:39:00.006+09:00

This post includes candid talk with Mr. Bill Harris, founder of Drug discovery opinion (DDO). Last month, medchemblog conducted polling for favorite blog. Drug discovery opinion (DDO) got the highest vote (42%). Let me introduce the blog. It’s a nice blog with recent updates on drug discovery and development. It was established in 2008 by medicinal chemists, Mr. Bill Harris and Ms. Sally Redshaw to provide consultancy services to Pharma and Biotech companies. They have many years experience in drug discovery and development working with companies like Roche, GSK and De Novo pharmaceuticals. Authors have clear and concise way of presenting the subject matter. Click on the banner to visit their page.

It’s a great pleasure to present views/opinion from one of the founder of DDO, Mr. Bill Harris. Medchemblog is thankful for his wonderful support and valuable time. Ok, let’s take a look at what he says;

Medchemblog: Welcome sir, would you please introduce your blog (DDO) in your way?
DDO: Sally Redshaw, another medicinal chemist, and I decided to form a consultancy business. We aimed to exploit our long careers in Pharma and biotech companies to provide support in med chem and drug discovery, particularly to biotech companies. When setting up a website to inform about our business activities, we wanted something that was a little more interesting than a static ‘corporate’ site. Since we were already reading broadly in the primary literature, to keep up with developments in med chem and drug discovery, it seemed a small step to share some of the more interesting scientific developments in a concise form. Although many institutions provide press releases, we found these a little simplistic (and sometimes inaccurate) for a medicinal chemist readership, so thought we could provide something more informative in bite-size pieces.

Medchemblog: What is the main goal of DDO?

DDO: Of course a main goal for DDO is to establish business relationships with clients. The blog aspect of the site, we hope, provides a route for us to engage with fellow scientists in the drug discovery and development arena – maybe at some point in the future that will turn into a professional relationship.

Medchemblog: How much contribution do you think DDO has in the field of drug discovery and development (on the basis of your viewers feedback)

DDO: We have had very kind feedback from readers of the blog, who seem to like the concise nature of the articles – enough information in easy to digest form with the ability to follow up in more depth if it is an area of interest to them. If it helps people keep up with the huge information flow, that would be great.

Medchemblog: Beside DDO, which is your favorite blog/site in the field of drug discovery and development?

DDO: Probably has to be In the Pipeline. Derek Lowe’s take on our industry is always an enjoyable read.

Medchemblog: Blogs/ site you follow and read regularly?

DDO: The news sites, like Science Daily and Eureka, we try to keep up with. When we get time, we do like to read a variety of chemistry/medicinal chemistry sites (including medchemblog!)

Medchemblog: Suggestions for the beginners, who want to pursue their career in the field of drug discovery and development?

DDO: This has to be the toughest question! It is really difficult to offer good advice when our industry is going through so much change. I suppose that the response to such change has to be flexibility and mobility, both of which are easier said than done. One thing is certain – society’s need for medicines is not going to diminish, and we are far from having solved many of the pressing health problems.

Medchemblog: Few words or suggestions for medchemblog.

DDO: You will not go far wrong if you continue to write about those things that interest you – your enthusiasm will be recognised and appreciated by your readers.

Medchemblog: Thank you sir.

I hope you enjoyed the discussion. As most of the medchemblog viewers like DDO, I think it’s a proper way of introducing DDO and its founder through this post.

Please feel free to share your views!

ACS meetings content online

2010-05-25T13:48:00.011+09:00

It’s good news for those who had missed the opportunity to attend American Chemical Society (ACS) meeting in San Francisco, CA (Spring 2010), Washington, D. C and Boston MA (Fall 2010). ACS has provided the contents from the meetings online. It’s great to see and hear the presentation with a sip of coffee just sitting in front of your computer. They have synchronized the audio with power point slide. Great job indeed!

Check out the link here.

So, which is your favorite presentation? Hope to see your opinion.

Voreloxin: DNA intercalating topoisomerase II poison

2010-05-18T11:38:00.002+09:00

As we know, topoisomerases are the nuclear enzymes that change the topology of DNA by transiently breaking one or two strands of DNA. They have important role in number of vital cellular processes like replication, transcription, recombination, repair, chromatin assembly, and chromosome segregation. Many anticancer drugs that target topoisomerase have been developed. For instance, Camptothecin and Etoposide, well known anticancer agents, inhibit topo I and topo II respectively.

Recently, Voreloxin, a quinolone derivative, which is completing phase 2 clinical trials for acute myeloid leukemia (AML) and platinum-resistant ovarian cancer, has been reported as a DNA intercalating topo II poison.

Discovery of Voreloxin has occurred while optimizing the class of compounds bearing a 1, 8 –naphthyridine core. Voreloxin has no antibacterial activity, but interestingly shows potent cytotoxicity towards eukaryotic cancer cell lines. Moreover, its activity was not affected by common mechanism of drug resistance, including P-gp overexpression, when evaluated in etoposide and anthracycline-resistant nonclinical models. Authors claimed Voreloxin as a first-in-class topo II poison and inhibitor that intercalates DNA and induces site selective DNA DSB, G2 arrest, and apoptosis.

Structure-activity relationship (SAR) study

It was found that coplanarity of the naphthyridine core and the N-1 thiazole ring was required for antineoplastic activity. Two derivatives of Voreloxin, replacing thiazole ring with fused phenyl ring (A) and phenyl ring (B) has been evaluated for their intercalative activity in topo I intercalation assay, using either negatively supercoiled or relaxed DNA as a substrate. It was found that phenyl derivative did not show intercalation whereas fused phenyl analog has greater DNA intercalation activity than Voreloxin. Similarly in cytotoxicity assay, phenyl derivative has weaker cytotoxicity whereas intercalative fused phenyl analogue was more cytotoxic than Voreloxin.

Amyloid beta-protein: Not just a culprit

2010-04-10T14:08:00.006+09:00

The amyloid beta-peptide (Aβ) is the main component of beta-amyloid plague in the brains of Alzheimer’s disease (AD) patients. It is formed by the cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein with no normal physiological function. β and γ- secretase act susccessively to produce number of Aβ isoforms of which Aβ40 and Aβ42 are the most common.

Aβ accumulates outside and around the neurons giving rise to amyloid plague. These plagues are able to cause the neuronal cell death responsible for various neurodegenerative diseases like alzheimer’s disease (AD). So, it is seen as a culprit behind the AD. But recently, Soscia et.al.has reported the importance of Aβ as an antimicrobial peptide (AMP).

AMPs are potent, broad spectrum antibiotics that target gram-negative and gram-positive bacteria, enveloped viruses, mycobacteria, fungi, protozoans and in some cases, transformed or cancerous host cells. They are also called as “host defense peptides” with great role in the innate immune system.

In vitro study shows that Aβ is active against at least eight (out of twelve tested) common and clinically relevant microorganisms, including the bacteria S.pneumoniae (leading cause of bacterial meningitis) and C. Albicans, (common cause of neurocandidiasis). The antimicrobial activity (MICs) of beta amyloid peptide (Aβ40 and Aβ42) against various microorganisms has been compared with LL-37. The antimicrobial activity of Aβ peptide was equivalent to or greater than LL-37 for seven of the pathogens tested.

LL-37 belongs to the cathelicidins family of mammalian AMPs. It is the only member in the family that has been identified in humans.

Also, authors have shown that the AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that the AMP action correlates with tissue Aβ levels. Consistent with Aβ-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Aβ antibodies. From this data, they believe that the Aβ function in vivo as an AMP and play an important role in innate immunity.

For refreshment and to understand progression of A.D, check out the video. Nice presentation!