Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 6, Number 14, 2006

Contents

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


Editorial Pp. 1445


Selective Fluorination in Drug Design and Development: An Overview of Biochemical Rationales Pp. 1447-1456
Kenneth L. Kirk
[Abstract]


Fluorinated Molecules as Drugs and Imaging Agents in the CNS Pp. 1457-1464
Shengguo Sun and Adeboye Adejare
[Abstract]


Design and Synthesis of Phosphonodifluoromethyl Phenylalanine (F₂Pmp): A Useful Phosphotyrosyl Mimetic Pp. 1465-1471
Terrence R. Burke, Jr.
[Abstract]


The Strength of Weak Interactions: Aromatic Fluorine in Drug Design Pp. 1473-1482
Stephen G. DiMagno and Haoran Sun
[Abstract]


How C^α -Fluoroalkyl Amino Acids and Peptides Interact with Enzymes: Studies Concerning the Influence on Proteolytic Stability, Enzymatic Resolution and Peptide Coupling Pp. 1483-1498
René Smits and Beate Koksch
[Abstract]


Fluorinated Nucleosides as Antiviral and Antitumor Agents Pp. 1499-1528
Wei-Dong Meng and Feng-Ling Qing
[Abstract]


Fluorinated Natural Products with Clinical Significance Pp. 1529-1543
Craig J. Thomas
[Abstract]


Peptidyl Fluoro-Ketones as Proteolytic Enzyme Inhibitors Pp. 1545-1566
Monica Sani, Roberta Sinisi and Fiorenza Viani
[Abstract]




Abstracts
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Editorial

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.

Dr. Kenneth L. Kirk, Ph.D.
Laboratory of Bioorganic Chemistry
National Institute of Diabetes,
and Digestive and Kidney Diseases
National Institutes of Health,
Department of Health and
Human Services
Bethesda, MD 20892
USA


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Selective Fluorination in Drug Design and Development: An Overview of Biochemical Rationales
Kenneth L. Kirk

Several strategies used in the rational design and synthesis of fluorinated compounds as potential therapeutic agents are reviewed. Applications of fluorine substitution in empirical SAR studies for lead development also are discussed, along with the implications with respect to fluorine target interactions that can be derived from biological activities.


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Fluorinated Molecules as Drugs and Imaging Agents in the CNS
Shengguo Sun and Adeboye Adejare

The strategic use of fluorine substitution in drug discovery and drug development is well documented. The small size and high electronegativity of fluorine are among properties of this element that lend special advantages. Applications in drugs targeted to the central nervous system (CNS) have been particularly fruitful in addition to favorable properties seen in many peripherally acting drugs. Fluorine substitution can be used to solve problems unique to the CNS, such as blood brain barrier (BBB) penetration. Likewise, use of the positron emitting isotope, ¹⁸F, provides a unique tool for non-invasive imaging and diagnoses in the CNS. In this review, fluorine in CNS drugs and drug discovery are discussed.


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Design and Synthesis of Phosphonodifluoromethyl Phenylalanine (F₂Pmp): A Useful Phosphotyrosyl Mimetic
Terrence R. Burke, Jr.

Hydrolytically-stable phosphotyrosyl (pTyr) mimetics can be useful tools for the study of cellular signal transduction processes. Among pTyr mimetics reported to date, phosphono(diflouromethyl)phenylalanine (F₂Pmp) has shown particular utility when dealing with protein-tyrosine phosphatases (PTPs). The current overview presents the development of F₂Pmp and a summary of approaches toward its synthesis and use.


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The Strength of Weak Interactions: Aromatic Fluorine in Drug Design
Stephen G. DiMagno and Haoran Sun

Selective aromatic fluorine substitution can increase the affinity of a molecule for a macromolecular recognition site through non-covalent interactions. These effects are evaluated most accurately by direct comparison of binding affinities of selectively fluorinated compounds with their corresponding hydrocarbons. In cases where structural data confirm similar binding geometries for the fluorocarbon and hydrocarbon analogues, reliable estimates for the impact of fluorination upon arene-π•••X and C-F•••X interaction energies are possible. Existing studies show that fluorination’s impact on any individual molecular interaction is quite modest. Upon binding to a protein receptor, cumulative fluorinated aromatic quadrupolar and C-F•••X dipolar interaction energies rarely differ from those the corresponding hydrocarbons by more than 1.3 kcal/mol, and most individual interactions appear to be in the 0.1-0.4 kcal/mol range. Similarly, non-ideal selective fluorination is rarely associated with a dramatic decrease in affinity, because the impact of weak repulsive interactions in the bound state is counterbalanced by increased lipophilicity.


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How C^α-Fluoroalkyl Amino Acids and Peptides Interact with Enzymes: Studies Concerning the Influence on Proteolytic Stability, Enzymatic Resolution and Peptide Coupling
René Smits and Beate Koksch

Combination of the unique physical and chemical properties of fluorine with proteinogenic amino acids represents a new approach for the design of biologically active peptides with improved pharmacological parameters that carry a powerful label for spectroscopic analysis. However, the general consequences of amino acid fluorination on structure and activity of peptides and proteins are still controversially discussed. Studying the interaction of fluorinated amino acids with enzyme active sites provides valuable information on how fluoroalkyl groups of peptide-based drugs might interact with target proteins or receptors. Therefore, different enzymatic approaches including proteolysis studies, enzymatic resolutions and peptide bond couplings were studied by our group.


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Fluorinated Nucleosides as Antiviral and Antitumor Agents
Wei-Dong Meng and Feng-Ling Qing

The synthesis of nucleosides and analogues with fluoride modifications on the surgar moiety are reviewed, and their biological activities as potential antiviral and anti-tumor agents are also discussed.


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Fluorinated Natural Products with Clinical Significance
Craig J. Thomas

The modification of natural products in an effort to alter their biochemical capacity is a common technique utilized by synthetic and medicinal chemists. Fluorine substitution imparts unique and advantageous physiochemical properties that can be shrewdly employed to constructively alter pharmacological agents. The adornment of natural products with fluorine has proven beneficial in several examples. This overview discusses several of the most relevant fluorinated natural products under current examination.


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Peptidyl Fluoro-Ketones as Proteolytic Enzyme Inhibitors
Monica Sani, Roberta Sinisi and Fiorenza Viani

Proteolytic enzymes are involved in many important physiological processes. Because of the critical roles played by these enzymes, aberrations in regulation of their activities can lead to pathological conditions. For this reason, finding inhibitors selective for a proteolytic enzyme that is contributing to a medical problem can be an effective therapeutic strategy. The introduction of fluorine in the backbone of proteolytic enzyme substrates can lead to active and selective inhibitors belonging to the peptidyl fluorinated ketone family. Fluorine not only can influence the mechanism of substrate/enzyme recognition events but also can modify the in vivo profile of the substrate. Although prediction of the total effects of fluorine on the pharmacokinetic parameters can be difficult, the pharmaceutical interest in the synthesis and biological evaluation of peptidyl fluorinated ketones highlights the potential of this family of molecules as therapeutically useful inhibitors.