The Natural and The Unusual: Protein-forming œ-amino acids are a group of 20 naturally occurring amino acids encoded by DNA, and obtained by the hydrolysis of proteins. In addition to these, a large number of amino acids, variously known as unusual, unnatural, synthetic, non-standard or non-coded œ-amino acids have been synthesized. They are used to prepare several therapeutically useful compounds. For example, D-phenylglycine and its derivatives are used as building blocks in the synthesis of popular antibiotics such as, ampicillin, cefalexin, and amoxycillin. Combined with carbidopa, L-Dopa, an analogue of the amino acid phenylalanine, is widely used in the treatment of Parkinson's disease. Incorporation of unusual œ-amino acids into peptides has led to unique analogues, which are biologically active and relatively stable. Hence, the preparation of unusual a-amino acids extends the availability of building blocks for the synthesis of natural products and drugs. Moreover, some of them are themselves biologically active.

Constrained œ-amino acids: In constrained œ-amino acids, the side-chain flexibility of proteinogenic œ-amino acids is restricted. The figure shows the phenylalanine molecule (1), along with its constrained analogues (2 and 3). When phenylalanine is replaced with a constrained analogue such as 2, in peptide modifications, the resulting peptidomimetics (compounds that mimic peptides) show enhanced pharmacological properties.

The Building Block Approach: The 'building block approach' generates a large number of compounds starting from a common precursor, by processes that are flexible enough to generate various unusual œ-amino acid derivatives. These building blocks can be incorporated into small peptides, and similar transformations can be performed at the peptide level, thereby providing a large number of modified peptides in lesser time. These compounds can be used for in vivo and in vitro optimization studies on therapeutic targets. Since unnatural peptides are prepared in a step-wise fashion, development of methods based on chemical modification of the intact oligo-peptides, will deliver them without having to repeat the entire sequence of peptide synthesis.

Research at IIT Bombay

Our group has been working in this area since 1994. We have demonstrated that various types of reactions can be useful tools for the preparation of a library of unusual a-amino acid derivatives. In addition, it is feasible to modify peptides using these unusual a-amino acids in a post-translational manner. Such methodologies have direct applications in drug design.

We have developed several new methods for the synthesis of cyclic amino acids, beyond the few being used since 1930. Around 250 unusual œ-amino acid derivatives have been prepared, most of which are not accessible in a direct manner by known methods. Additionally, various synthetic methods developed in our laboratory have been used in materials science applications and in crystal engineering studies. Details of the work are reported in ‘Recent applications of the Suzuki-Miyura cross-coupling reaction in organic synthesis’, (Tetrahedron 2002, 58, 9633-9685, S. Kotha, K. Lahiri, and D. Kasinath; http://www.tetrahedron.info/tet)*

With its seemingly inexhaustible inventory including fabrics, fuels, dyes, perfumes, pharmaceuticals and polymers, the products of organic synthesis will continue to provide many benefits for humanity.

* The paper was rated as the third most requested paper during the 2nd and 3rd quarter of 2003, by the Chemical Abstract Services (CAS) in Columbus, Ohio. Prof Kotha has been recently awarded the CRSI Bronze medal by the Chemical Research Society of India. - Editor

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