Biochemically active molecules, development

Cobalt is one of twenty-seven known elements essential to humans (28) (see Mineral NUTRIENTS). It is an integral part of the cyanocobalamin [68-19-9] molecule, ie, vitamin B 2> only documented biochemically active cobalt component in humans (29,30) (see Vitamins, VITAMIN Vitamin B 2 is not synthesized by animals or higher plants, rather the primary source is bacterial flora in the digestive system of sheep and cattle (8). Except for humans, nonmminants do not appear to requite cobalt. Humans have between 2 and 5 mg of vitamin B22, and deficiency results in the development of pernicious anemia. The wasting disease in sheep and cattle is known as bush sickness in New Zealand, salt sickness in Florida, pine sickness in Scotland, and coast disease in AustraUa. These are essentially the same symptomatically, and are caused by cobalt deficiency. Symptoms include initial lack of appetite followed by scaliness of skin, lack of coordination, loss of flesh, pale mucous membranes, and retarded growth. The total laboratory synthesis of vitamin B 2 was completed in 65—70 steps over a period of eleven years (31). The complex stmcture was reported by Dorothy Crowfoot-Hodgkin in 1961 (32) for which she was awarded a Nobel prize in 1964. 

For testing the biological activity of such a large number of molecules, development of fast assays and with a read-out as simple as possible is essential. These assays can be performed on molecular targets (biochemical assays) or target cell (cell-based assays). 

Recently, various schemes have been developed where a gel can undergo phase transition when a particular kind of molecule is present. This transition is achieved by embedding biochemically active elements such as enzymes or receptors within a gel that is placed near the transition threshold. When target molecules enter the gel, the active element either converts them into other... 

Today research does no longer focus on the dendrimer itself but on the multiplication of functional components attached to a dendritic skeleton and new materials with specific properties (redox, ligand, and liquid crystalline properties, biochemical activity. ..) are anticipated. [9] Industry has also shown increasing interest in functional cascade molecules for applications in diverse areas such as medical engineering, agrochemistry, and the development of photocopier toner additives. Concrete applications include nanoscale catalysts [2a],... 

The neurotransmitters and hormones are good examples based on the approach of starting with a biochemically active substance as the prototype molecule. This group of compounds combine with specific receptors, and therefore, provide the basic structure for synthetic modification in order to obtain more specific activity or even antagonistic response. The following will serve as examples of this approach at developing bioactive molecvdes. 

Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

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