It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

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Fluorine in medicinal chemistry.

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small mole...

OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins

The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

Synopsis of some recent tactical application of bioisosteres in drug design.

III. Foldamer Research 3910 A. Overview 3910 B. Motivation 3910 C. Methods 3910 D. General Scope 3912 IV. Peptidomimetic Foldamers 3912 A. The R-Peptide Family 3913 1. Peptoids 3913 2. N,N-Linked Oligoureas 3914 3. Oligopyrrolinones 3915 4. Oxazolidin-2-ones 3916 5. Azatides and Azapeptides 3916 B. The â-Peptide Family 3917 1. â-Peptide Foldamers 3917 2. R-Aminoxy Acids 3937 3. Sulfur-Containing â-Peptide Analogues 3937 4. Hydrazino Peptides 3938 C. The γ-Peptide Family 3938 1. γ-Peptide Foldamers 3938 2. Other Members of the γ-Peptide Family 3941 D. The δ-Peptide Family 3941 1. Alkene-Based δ-Amino Acids 3941 2. Carbopeptoids 3941 V. Single-Stranded Abiotic Foldamers 3944 A. Overview 3944 B. Backbones Utilizing Bipyridine Segments 3944 1. Pyridine−Pyrimidines 3944 2. Pyridine−Pyrimidines with Hydrazal Linkers 3945

A field guide to foldamers.

CC-1065 and the Duocarmycins: Synthetic Studies.

BACKGROUND Over the past century, innovations in synthetic chemistry have greatly enabled the discovery and development of important life-changing medicines, improving the health of patients worldwide. In recent years, many pharmaceutical companies have chosen to reduce their R&D investment in chemistry, viewing synthetic chemistry more as a mature technology and less as a driver of innovation in drug discovery. Contrary to this opinion, we believe that excellence and innovation in synthetic chemistry continue to be critical to success in all phases of drug discovery and development. Moreover, recent developments in new synthetic methods, biocatalysis, chemoinformatics, and reaction miniaturization have the power to accelerate the pace and improve the quality of products in pharmaceutical research. Indeed, the application of new synthetic methods is rapidly expanding the realm of accessible chemical matter for modulating a broader array of biological targets, and there is a growing recognition that innovations in synthetic chemistry are changing the practice of drug discovery. We identify some of the most enabling recent advances in synthetic chemistry as well as opportunities that we believe are poised to transform the practice of drug discovery and development in the coming years. ADVANCES Over the past century, innovations in synthetic methods have changed the way scientists think about designing and building molecules, enabling access to more expansive chemical space and to molecules possessing the essential biological activity needed in future investigational drugs. In order for the pharmaceutical industry to continue to produce breakthrough therapies that address global health needs, there remains a critical need for invention of synthetic transformations that can continue to drive new drug discovery. Toward this end, investment in research directed toward synthetic methods innovation, furthering the nexus of synthetic chemistry and biomolecules, and developing new technologies to accelerate methods discovery is essential. One powerful example of an emerging, transformative synthetic method is the recent discovery of photoredox catalysis, which allows one to harness the energy of visible light to accomplish synthetic transformations on drug-like molecules that were previously unachievable. Furthermore, recent breakthroughs in molecular biology, bioinformatics, and protein engineering are driving rapid identification of biocatalysts that possess desirable stability, unique activity, and exquisite selectivity needed to accelerate drug discovery. Recent developments in the merging fields of synthetic and biosynthetic chemistry have sought to harness these molecules in three distinct ways: as biocatalysts for novel and selective transformations, as conjugates through innovative bio-orthogonal chemistry, and in the development of improved therapeutic modalities. The development of high-throughput experimentation and analytical tools for chemistry has made it possible to execute more than 1500 simultaneous experiments at microgram scale in 1 day, enabling the rapid identification of suitable reaction conditions to explore chemical space and accelerate drug discovery. Finally, advances in computational chemistry and machine learning in the past decade are delivering real impact in areas such as new catalyst design, reaction prediction, and even new reaction discovery. OUTLOOK These advances position synthetic chemistry to continue to have an impact on the discovery and development of the next generation of medicines. Key unsolved problems in synthetic chemistry with potential implications for drug discovery include selective saturation and functionalization of heteroaromatics; concise synthesis of highly functionalized, constrained bicyclic amines; and C-H functionalization for the synthesis of α,α,α-trisubstituted amines. Other areas, such as site-selective modification of biomolecules and synthesis of noncanonical nucleosides, are emerging as opportunities of high potential impact. The concept of molecular editing, whereby one could selectively insert, delete, or exchange atoms in highly elaborated molecules, is an area of emerging interest. Continued investment in synthetic chemistry and chemical technologies through partnerships between the pharmaceutical industry and leading academic groups holds great promise to advance the field closer to a state where exploration of chemical space is unconstrained by synthetic complexity and only limited by the imagination of the chemist, enabling the discovery of the optimal chemical matter to treat disease faster than ever before.

The importance of synthetic chemistry in the pharmaceutical industry.

Radicicol (1) exhibits potent anticancer properties in vitro, which are likely to be mediated through its high affinity (20 nM) for the molecular chaperone Hsp90. Recently, we reported the results of a synthetic program targeting radicicol (1) and monocillin I (2), highlighted by the application of ring-closing metathesis to macrolide formation. These efforts resulted in a highly convergent synthesis of radicicol dimethyl ether but failed in the removal of the two aryl methyl ethers. Simple exchange of these methyl ethers with more labile functionalities disabled a key esterification in the initial route. Through extended experimentation, a successful route to both natural products was secured, along with some intriguing results that emphasize the implications of this design on a broad range of fused benzoaliphatic targets, including analogues of these natural products.

Concise Asymmetric Syntheses of Radicicol and Monocillin I

Shape-Dependent Catalysis: Insights into the Source of Catalysis for the CC-1065 and Duocarmycin DNA Alkylation Reaction

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.

Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer

Robert M. Garbaccio

Papers

CC-1065 and the Duocarmycins: Synthetic Studies.

The importance of synthetic chemistry in the pharmaceutical industry.

Concise Asymmetric Syntheses of Radicicol and Monocillin I

Shape-Dependent Catalysis: Insights into the Source of Catalysis for the CC-1065 and Duocarmycin DNA Alkylation Reaction

Kinesin Spindle Protein (KSP) Inhibitors. 9. Discovery of (2S)-4-(2,5-Difluorophenyl)-N-[(3R,4S)-3-fluoro-1-methylpiperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide (MK-0731) for the Treatment of Taxane-Refractory Cancer