Syntheses, drug molecules

Synthesize drug molecules using combinatorial chemistry and test with HTS assay system... 

Apart from the applications in synthesizing drug molecules with a triazole linkage, azide-alkyne cycloaddition reactions have also been used for various biological applications such as site-specific protein/viruses modifications and functionalization of cell surfaces. Use of transition-metal-catalyzed reactions for... 

A different approach reported recently (30) involves the synthesis and evaluation of polyphosphazenes that contain both aryloxy and imldazolyl side groups. Hydrolytic removal of the imidazolyl units takes place with a concurrent erosion of the solid polymer in a manner that is appropriate for the controlled release of entrapped drug molecules. 

As an example, we present in Exhibit 10.8 the synthesis of paditaxel (Taxol, Bristol-Myers Squibb), an important anticancer drug for breast and ovarian cancer and Kaposi sarcoma. It illustrates the complexity in the synthesis of drug molecules. 

The chiral separation of drug molecules and of their precursors, in the case of the synthesis of enantiomerically pure drugs, is one of the important application areas of HPLC in pharmaceutical analysis. Besides HPLC, capillary electrophoresis is another technique of choice for chiral separations. In this chapter we give an overview of the different modes (e.g., direct and indirect ones) by which it is possible to obtain a chiral separation in HPLC and CE. The direct approaches, i.e., those where the compound of interest is not derivatized prior to separation, are discussed in more detail since they are the most frequently used... 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

The structure of sulfa drug molecules, however, is very similar to that of the PABA molecule. Compare the structure of sulfanilamide, in part 2 of the diagram, with that of PABA. Notice how easily the sulfanilamide molecule can substitute for the PABA molecule in the synthesis of the bacterium s folic acid. The problem for the bacterium, however, is that folic acid produced from a sulfa drug molecule is... 

There are a number of problems associated with the use of peptides as drug molecules. Peptides are rapidly degraded by proteases and, therefore, their biological half lives are normally too short to be useful In a therapeutic sense. Most peptides exhibit more than one type of biological effect making lack of specificity a problem to be overcome. The size of even "small" peptides Is larger than most common drug molecules, and it is usually desirable, if for no other reason than ease of synthesis, to simplify the structures as much as possible. Finally, for the small number of peptides which have been studied by the oral route, poor bloavallablllty has been a problem. 

The synthesis of venlafaxine (1) as reported by the original inventors is straightforward (Scheme 14.1). As the drug molecule is commercialized as a racemate, the synthetic... 

Characterisation of some raw materials used in synthesis of drug molecules. 

Thus, there are some differences between a classical synthetic organic chemist and a synthetic medicinal chemist. The classical synthetic organic chemist is proud of a complex multistep synthesis which may, regrettably, have a low yield. The synthetic medicinal chemist is pleased to design a molecule that can be synthesized in as few steps as possible, hopefully with a high yield and few by-products. Figures 3.4.-3.6 present syntheses of three common drug molecules. 

APPENDIX 3.1 BASIC REACTIONS FOR DRUG MOLECULE SYNTHESIS... 

DESIGNING DRUG MOLECULES TO LIT RECEPTORS 56. Gabriel synthesis... 

Measures such as the number of compounds synthesized and the number of patents issued have been criticized on the grounds that they are more measures of R D activity (input) rather than of output.(11) Novelty of molecular structure represents a technically difficult assessment which, if performed at the time of synthesis, involves molecules with unknown pharmacologic and therapeutic properties. Novelty of pharmacologic action represents a fundamental measure of at least the potential for therapeutic innovation. In practice, however, this represents a judgmental issue and the necessary data on untested or unmarketed drugs would be difficult to obtain. 

---