Research News

Striking Gold with Sugars

Srinivas Hotha leads a research group working on chemical glycosylation at IISER-Pune. Learn more about his research in this article.

Srinivas Hotha obtained M.Sc. from the School of Chemistry at University of Hyderabad and a Ph.D. from Osmania University while working at the Indian Institute for Chemical Technology (IICT) in Hyderabad and at the National Chemical Laboratory (NCL) in Pune, India.  After completing postdoctoral work at the Rockefeller University, USA, he returned to join NCL, Pune as a faculty in 2003. He moved to IISER-Pune as an Associate Professor in 2010. Srinivas Hotha has received Young Scientist awards from Council of Scientific & Industrial Research, Indian National Science Academy,and A V Rama Rao Foundation and is a Swarnajayanti Fellow of the Department of Science and Technology, India.

Srinivas Hotha started off his research career as an independent investigator using carbohydrates in a combinatorial synthesis approach. He thought they would make great templates for combinatorial synthesis due to their high oxygen and chiral contents and a multicyclic framework—favorable features that natural products seemed to have over synthetic molecules. The broader aim was to hit upon carbohydrate derived natural product-like molecules with biological applications.

It was during this phase that he came across a gold compound (AuCl3) ordered by one of his graduate students and waiting in the shelf to be used.  He did not think it would be of much use considering relatively inert characteristics of gold, but he chose to throw it anyway in one of the reactions that are routinely set up in his laboratory. This curiosity proved rather valuable as AuCl3 seemed to activate a glycosidation reaction. Further testing on more substrates suggested that Aucl3 was actually kicking out a propargyl group from the substrate and if you performed the reaction in presence of a substituent group, you could chemically modify a carbohydrate molecule.

A few practical issues plaguing glycosidation reactions have been finding stable donors and reducing unwanted byproducts which only make it so much more difficult to purify the desired product. Propargyl glycosides fit like a glove into the description of a good donor: stable and easy to prepare; yields traceless or no byproducts.

This discovery opened a whole new field for him and his research group to work on and presented to the scientific community a promising new donor for glycosidation reactions. There was great excitement in having generated a novel glycosyl donor, and why not, chemists have been trying to fine tune glycosidation reactions since the 1900s. The persistent nature of these trials speaks of the much needed substrates and methodologies in efficiently making carbohydrate molecules.

Hotha’s group has since exploited this reaction to generate stereoselective glycosides and found that methyl glycoside (in addition to propargyl glycoside) could also be used as a glycosyl donor in the presence of a gold salts to generate glycosides, disachharides, and oligosaccharides.

“Carbohydrate synthesis is fundamentally different from peptide or nucleic acid synthesis due to the presence of several similarly reactive hydroxyl groups in carbohydrate molecules,” says Srinivas Hotha, who is finding newer and simpler strategies toward this endeavor at IISER-Pune (Photo credit: Shanti Kalipatnapu).

More recently, Hotha’s group, in collaboration with Sayam Sen Gupta’s group at the National Chemical Laboratory (NCL) in Pune, has directed its efforts to make glycopolymers such as glycopeptides (Pati et al. (2011) Polymer Chemistry 2:805). As Hotha describes, there are two ways of achieving this: (i) generate a polymer and then attach sugar moieties at specific locations to yield a glycopolymer, or (ii) polymerize a glycomonomer. Each of these methodologies have had varying degrees of success in the past, but a modified version of the latter technology proposed by Hotha’s team presents certain advantages. As Hotha puts it, “The key to successful glycopeptide synthesis seems to lie in our choice and design of an appropriate glycosylated amino acid”. For example, it would help for the sugar and amino acid moieties in a glycosylated amino acid to be sufficiently far (sterically) from each other to ensure high polymerization efficiency. Hotha and collaborators thus synthesized O-glycosylated lysine-N-carboxyanhydride in a gold catalyzed reaction using a stable glycosyl donor and a commercially available protected amino acid. This strategy has allowed producing monomers in a high yield providing a promising start-up material for making glycopeptides.

Hotha’s group continues to discover various applications of the novel glycosyl donors they have developed in synthesis of glycomimetics and that of complex carbohydrates. Given the technical challenges in carbohydrate synthesis and its commercial relevance, Hotha’s group seems to have its path chalked out.

Most of the work described here has been published and can be accessed here.

-Reported by Shanti Kalipatnapu

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s