Editorial [ The Use of Selective Fluorination in Drug Design and Development Guest Editor: Dr. Kenneth L. Kirk ]

The small size and high electronegativity of fluorine are among the special properties that contribute to the well-recognized importance of this element in the field of medicinal chemistry. The sometimes predictable effects of fluorine substitution on the biological behavior of biologically active molecules have been used increasingly effectively in drug design, dating from such early examples as the important anticancer agent fluorouracil. Increasing interest in fluorinated pharmaceutical and medicinal agents helped spur development of new fluorinating agents that, in turn, produced yet more applications in medicinal chemistry. As newer approaches to drug development evolved, rapid accumulation of compound inventories through such strategies as combinatorial and parallel synthesis combined with high throughput screening commonly included fluorine substitution as an important trial substituent in lead development. The biological consequences of fluorine substitution now often become rationalized after the fact. Interpretation of such data in turn has added to our understanding of how fluorine interacts with macromolecular recognition sites, and this has aided further drug design. We review in this issue several aspects of the use of fluorine in drug design and development. Organization of this subject matter may be approached by 1) an examination of how fluorine has facilitated drug development in specific biological targets/disease states 2) a discussion of fluorinated analogues of different classes of compounds (e.g. fluorinated amino acids, ketones, nucleosides, steroids, etc.) with respect to their applications to drug development, 3) or a mechanistic approach that stresses the special properties of fluorine (electrophilic character, effects on pKa, resistance to enzymatic defluorination, etc.) with examples of how such properties are exploited in drug design. In this issue we employ a combination of these approaches. Thus, we present reviews that feature a specific functional group (fluorophosphonates), compound class (natural products, nucleosides, peptides), biological targets (antitumor and antiviral agents, central nervous system agents) and theory (effects of fluorine on the interactions of small molecules with macromolecules). An introductory summary of biochemical rationales and recent developments is also presented to give the reader an overview of progress in this exciting area of medicinal chemistry. The editor wishes to thank the authors for their outstanding contributions. This project was sported in part by the NIDDK intramural research program.