Gururaj M. Shivashimpi's Blog: 2010

Thursday, July 8, 2010

From Molecule to Medicine

Following is the video made by NORVELL JEFFERSON, a Belgian audiovisual production company, which explains the various stages of drug discovery process.

Monday, May 10, 2010

Histone Deacetylase Inhibition and Cancer Therapy

Common cancer therapy technique like chemotherapy is taking the advantage of apoptosis to eliminate malignant cells within tumors. Epigenetic changes in living cell involve modulations in the expression levels of genes and are recognized as integral to the pathogenesis of many diseases including cancer, depression and various neurogenerative diseases. Reversible modification of histone protein carried out by histone acetyl transferase (HAT) and histone deacetylase (HDAC) enzymes, is involved in the chromatin remodeling and play important role in gene regulation. Over activity of certain HDACs was observed with several cancers, which mediate transcriptional repression by condensing the structure of chromatin and restricting the access of transcriptional factors and thus lead to gene silencing and tumor growth. Inhibition of their activity can induce cell cycle arrest, differentiation and/or apoptosis in cancer cells. Therefore, today HDACs are potential targets and identification of potent HDAC inhibitors possessing adequate ‘drug like’ properties is a considerable effort to develop therapeutics for the treatment of cancer.

Figure 1. Reversible histone acetylation mediated by HAT and HDAC.

Discovery of trichostatin A (TSA), isolated from Streptomyces hygriscipicus, as potent HDAC inhibitor by Yoshida and co workers (Riken, Japan) (J. Biol. Chem., 1990, 265, 17174–17179) and further X-ray crystallographic report of TSA bound histone deacetylase like protein (HDLP) by Finnin et al (Nature 401, 188-193), opened this new area of design and synthesis of HDAC inhibitors and their SAR study with HDAC paralogs. Several structurally unrelated natural and synthetic compounds have been reported so far as HDAC inhibitors (Figure 2) (J. Med. Chem., 2003, 46, 5097-5116). Major research groups contributing to this area of research are, Prof. Ronald Breslow (Columbia), Prof. Stuart Schreiber (Harvard), Prof. Alan Kozikowski (Illinois), Prof. Naoki Miyata (Nagoya City University, Japan), Dr. Thomas Miller (Merck), Prof. Norikazu Nishino (Kyushu Institute of Technology, Japan) and researcher from Methylgene (Canada). Prof. Nishino's research group is the pioneer in developing cyclic tetrapeptide based HDAC inhibitors. Their research is focused on both modification macrocylic cap group as well as incorporation of many zinc binding ligands to develop many analogs of natural cyclic peptides like chlamydocin, trapoxin and cyl-1 etc.

Figure 2. Natural and synthetic HDAC inhibitors.

The suberoylanilide hydroxamic acid (SAHA) also called Vorinostat, is another small molecular non-peptide class of HDAC inhibitor invented by Prof. Ronald Breslow and co workers (Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 5705-5708), which is the first HDAC inhibitor that was been approved by FDA in the year 2006 as an anticancer drug. This molecule is being manufactured and marketed by Merck and Co. with trade name Zolinza. It is used specially for the treatment of T-cell lymphoma (CTCL). In the following video one can see the animation of action of HDAC enzyme and its inhibition by Vorinostat molecule.

Apart from SAHA, many small molecular HDAC inhibitors are in pipeline, undergoing phase clinical trials and among them Panobinostat (LBH-589), developed by Novartis, is in phase clinical trial III. Panabinostat is being observed as potent active molecule against breast and prostate cancers. Hopefully this will be the second HDAC inhibitor coming to the market as anticancer drug in near future. Other HDAC inhibitors which are in clinical trial are Romidepsin, Mocetinostat and Belinostat etc.

Recently, Prof. H. Luesh and co-workers at University of Florida have isolated and characterized the depsipeptide named Largazole from a marine cyanobacterium Symploca sp (JACS, 2008, 130, 1806-1807), consisting of an unusual 16-membered macrocycle incorporated with linearly fused 4-methylthiazoline and thiazole with an ester of a 3-hydroxy-7-mercaptohept-4-enoic acid unit, which constitutes the side chain showing an essential unit for the potent HDAC inhibition (Figure 3).

Figure 3. Structure of Largazole.

Unlike other cyclic tetrapeptide based macrocylic HDAC inhibitors, it was found inhibiting selectively the HDAC-1 paralog. Several research groups including Prof. H. Luesh have also reported the total synthesis of Largazole (JACS, 2008, 130, 8455-8459; JACS, 2008, 130, 11219-11222; Org. Lett. 2008, 10, 3907-3909; Org. Lett. 2010, 12, 1368-1371). This intriguing yet chemically tractable structure responsible for its interesting biological activity warrants further investigation for the therapeutic potential or its next-generation analogs. In recent years some research groups have reported synthesis of largazole analogs and their SAR studies (Org. Lett., 2008, 10, 4021–4024; Org. Lett., 2009, 11, 1301-1304; ChemMedChem. 2009, 4, 1269-1272). However there is still large scope for the development of its analogs and their SAR study to find potent and selective HDAC inhibitors.

Although the precise function of each HDAC paralog is unknown, evidence suggests that they are involved in diverse biological activities, like apoptosis. Therefore, finding selective inhibitor for these HDAC paralogs, either by modifying the cap group region inhibitor or investigating better ligand that can selectively co-ordinate with zinc ion present in the active site of HDAC paralogs, is the basic thrust in this area of research.

Tuesday, May 4, 2010

Top Books To Help You To Master Organic Chemistry

Text Books

"Advanced Organic Chemistry (Part A and B)" -------- Francis Carey and Richard J. Sundberg.
"Organic Chemistry" -------- T. W. Graham Solomons.
"Organic Chemistry" -------- Robert T. Morrison and Robert T. Boyd.
"Organic Chemistry (Vol. I and II)" -------- I. L. Finar.
"Virtual Textbook of Organic Chemistry" .

Reference Books

"Strategic Application of Named Reactions in Organic Synthesis" -------- Laszlo Kurti and Barbara Czako.
"Named reactions: A Collection of Detailed Reaction Mechanisms" -------- Jie Jack Lie.
"Organic Synthesis: The Disconnection Approach" -------- Stuart Warren.
"March's Advanced Organic Chemistry: Reactions, Mechanism and Structure" -------- Michael B. Smith and Jerry March.
"Modern Methods In Organic Synthesis" -------- W. Carruthers and Iain Coldham.
"Organic Synthesis" -------- Michael B. Smith.
"Principles of Organic Synthesis" -------- R. O. C. Norman.
"Greene's Protective Groups in Organic Synthesis" -------- Peter G. M. Wuts and Theodora W. Greene.
"Modern Organic Synthesis In The Laboratory (Experimental)" -------- Jie Jack Li.
"Sterechemistry of Organic Compounds" ------- Ernest L. Eliel.
"Spectroscopic Identification of Organic Compounds" -------- Robert M. Silverstein.
"Organic Spectroscopy" -------- William Kemp.

Tuesday, April 20, 2010

What Are The Career Options After PhD????

I am receiving many emails from young researchers and students, who took chemistry as major subject in their course, to know what to do after graduation or what are the possible options to make better career, etc. I know, one feels confused in choosing the career path after finishing his/her graduation. Therefore, I was thinking to write a brief and general write-up on this matter based on my experience. Fortunately, here is an interesting career guidelines link, that I found randomly. Taking some important points mentioned in this link, I tried to discuss by putting some of my views in my following description. I hope it will be a helpful information for many aspirants.

As mentioned in this link, depending on one's individual interest, he/she can choose following major options after PhD.

A fresh student have number of options, following are major options

Academic job in india (scientist/professor), earlier this is least preferred. Nowadays this profession also have reasonable salary with stable and tension free life. Only difficulty is to compete globally due number of reasons including working hands are PhD student rather than PDF.

PDF abroad, most preferred option so far, after reading status of PDF on forum/blog, some PhD students feel they are living better life during PhD than PDF abroad.

Joining private company in India, lot of students feel this is black box. Much more insecure than PDF, most of company are not doing great research so their is chance that student will not grow.

Although first option (Academics) is good, but it is not so easy to go for it just after finishing PhD. Because nowadays expectations are very high for academic jobs in India. So to start with, let me take the option of going for postdoctoral job after PhD. In the above said link, author has put some following points on purpose of doing postdoctoral research in abroad.

High salary (comparison to indian salary).

Status in society (complexity problem, person is considered superior if working abroad).

Exposure (opportunity to work with reputed scientist).

Good publications etc.

To some extent I agree with him, but purpose of doing postdoctoral research in abroad is not just for high status in society or for high salary. It is actually an opportunity to learn how to become an independent researcher. One should learn, how to propose new research idea, how to create some new direction for ongoing research and also to get publications. One should not go for PDF, just because his/her senior has gone to do. There are many laboratories in abroad where, Professors ask a proposed research plan on which the person wants to work. For that one needs deep understanding on what's the current area of research in that lab and what new ideas can be implemented to redirect or to progress the ongoing research in that lab. Accordingly one should make a research proposal. This is what many postdocs working in NIH and NSF projects are told to do, before joining the research group in US. Same is the case for JSPS postdoctoral program in Japan also. Next question, how to get or how to apply for postdoctoral position?? Actually there are some links (You can find those links in my blog), in which one can see postdoctoral job advertisements. Otherwise, easiest way is, get the contact address of Professors from research papers and send an inquiry email, containing a cover letter and CV, asking for postdoctoral position. The cover letter should include brief description of your current research interests, purpose of joining that research group and career goals.

Coming to third option, Industrial jobs (Pharmaceutical/Biotech companies). Although industrial jobs are considered as mindless repetitive tasks, but due to high pay scale, more and more students are attracted towards these jobs. Unfortunately it is triumph of materialism that has infected every part of our culture, but not a bad option to choose. Basically there are two type of chemical companies in India, that is Generics and CROs (Contract research organizations). First type of companies are working on production and marketing of generic drugs, where as CROs are service based companies, manufacturing and supplying active pharmaceutical ingredients (APIs), bulk drug intermediates and other chemical intermediates to bigger pharma companies abroad (Pfizer, Merck, Novartis, etc), to fasten the drug development process. Regardless of what type of products they are making, both companies need well trained chemists to work in their R & D and process development units. A person with good exposure to advanced synthetic reactions, multistep synthesis, analytical techniques and with handling experience of scientific instruments have greater demand in these companies. One can join these companies just after PhD or he/she can spare 1-2 years in abroad as postdoctoral researcher and then go for these kind of jobs. To lead a comfortable life this option is always better.

I tried to explain all the points as career guidance for future aspirants after PhD. Please leave your comments or share your views on how you found this information. Also if you have any question, please don't forget to post below, so that we can discuss further if needed.

Saturday, April 3, 2010

How to get new research ideas from Scientific literature ???

Coming up with an idea for original research project will probably be the most challenging part of a research job. Knowing how to get new ideas for a research project is very important. Till date, scientific literature (Articles, Reviews, Monographs, etc) is the only major resource to get ideas, but how to extract a new idea from it, is again a question. Nowadays one can find many blogs and forums, where in many tips, suggestions and guidelines have been told by experts. For example, following is an interesting blog written by a fellow teacher, who made a thorough discussion on the same topic. He has given some following guidelines on how to read a research article to extract new ideas from it.

Basics:

What did the authors conclude?

What alternate conceptual models, explanations, or hypotheses did the authors consider? Why did they prefer the explanation in their conclusion?

What methods did they use to approach the problem?

What's the context? How does this work fit with other work that's been done and questions being asked? Why does anyone care about this research?

Getting ideas for future work:

Do you accept the author's conclusions? If not, are there other approaches that could allow you to test their conclusion?

Does this research suggest new ways to interpret a different problem? (Could something like this model explain other areas? Other periods of time? Other types of processes?).

Are there other problems that could be studied using the same methods? (And what equipment or expertise is necessary to use these methods?).

One can see many worth reading views and comments below this blog by many experts, where in lot much has been discussed on this topic. Among them following comment drawn my attention, in which the commenter has put a very important word, "Skeptical".

Of course. My experience with graduate students learning how to read the scientific literature is that they do a perfectly fine job of understanding what the authors are saying, but tend to forget that their job is to be skeptical about it.

Yes, it is very true that if we keep on praising other's work or just understand what they did in a particular research article, we will never extract new ideas from it. Therefore, it is very important to read skeptically and questioning everything. Most of the time it is the negative results in a research article which give us the way to generate new ideas. What new thing can you develop from highly focused good results?? Good results are focused only to convince the reviewer of a particular journal to make him agree to accept the work for publication.

Well the bottom line is, after reading 10-15 papers of a particular area of research, you will begin to see that there are gaps in our knowledge that need to be filled, and that is where you get ideas for new research projects.

Useful links

Tips and suggestions to master organic chemistry.

Links for organic reactions and synthetic problems.

Links for organic chemistry research.

Links for postdoctoral jobs in abroad.