10. Patented Literature 2616 10.1. Esterification 2616 10.2. Ether Formation 2619 10.2.1. Etherification without Cyclization 2619 10.2.2. Etherification with Cyclization 2624 10.3. N-Alkylation 2625 10.4. Other Reactions 2627 11. Summary and Outlook 2628 12. Note Added in Proof 2628 13. Abbreviations Used in This Review 2629 14. Acknowledgments 2629 15. Supporting Information Available 2630 16. References 2630

Mitsunobu and Related Reactions: Advances and Applications

Despite over a century of applying organic synthesis to the search for drugs, we are still far from even a cursory examination of the vast number of possible small molecules that could be created. Indeed, a thorough examination of all 'chemical space' is practically impossible. Given this, what are the best strategies for identifying small molecules that modulate biological targets? And how might such strategies differ, depending on whether the primary goal is to understand biological systems or to develop potential drugs?

Navigating chemical space for biology and medicine

Fragment-based lead discovery is gaining momentum in both large pharmaceutical companies and biotechnology laboratories as a complementary approach to traditional screening. This is because fragment-based approaches require significantly fewer compounds to be screened and synthesized, and are showing a high success rate in generating chemical series with lead-like properties. Compared with traditional screening hits, the starting fragments have considerably lower molecular mass, and although the binding interactions of these fragments with a target protein are weak, they are structurally understood through X-ray crystallography or NMR, and they exhibit high 'ligand efficiency'. Here, we use examples from 25 different protein targets to describe chemical strategies that exploit this structural knowledge to rapidly develop fragments into high-affinity leads.

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Fragment-based lead discovery

Macrocycles occupy a unique segment of chemical space. In the past decade, their chemical diversity expanded significantly, supported by advances in bioinformatics and synthetic methodology. As a consequence, this structural type has now been successfully tested on most biological target classes. The goal of this article is to put into perspective the current applications, opportunities, and challenges associated with synthetic macrocycles in drug discovery. Historically, macrocyclic drug candidates have originated primarily from two sources. The first, natural products, provided unique drugs such as erythromycin, rapamycin, vancomycin, cyclosporin, and epothilone. Excellent reviews are dedicated to this class and how it inspired further synthetic and medicinal chemistry efforts; thus, it will not be covered here. From a molecular evolution standpoint, the medicinal chemistry of macrocyclic natural products usually involved direct use as a therapeutic agent or functionalization of the natural product scaffold by hemisynthesis. It parallels significant advances in the total synthesis of macrocyclic natural products during the past 2 decades. The second traditional source of macrocycles stems from peptides, some of which are natural products and, hence, also belong to the first category. Macrocyclization was recognized early in peptide chemistry as an efficient way to restrict peptide conformation, reduce polarity, increase proteolytic stability, and consequently improve druggability. Chemists accessed macrocyclic peptides with different geometries (head to tail, side chain to side chain, head to side chain), including the incorporation of nonpeptidic groups. Compelling examples of macrocyclic scaffolding of peptides include the works on somatostatins, melanocortins, and integrins, among others. Macrocyclic peptides generated several drugs from synthetic or natural sources, including octreotide, cyclosporine, eptifibatide, and caspofungin. Purely peptidic, depsipeptidic, and peptoid macrocycles will also not be covered in this article; the reader is instead referred to previous reviews. It is well understood that the boundary between synthetic macrocycles and the above categories is not always clear-cut; as a result, examples presented in the following sections could occasionally belong to one of these categories. In these cases, they were selected owing to their relevance to the perspective. Macrocycles are defined herein as molecules containing at least one large ring composed of 12 or more atoms. On the basis of standard molecular descriptors, macrocycles as a class are at the outskirts of the window generally considered optimal for good PK-ADME properties using these criteria. Indeed, their molecular weights tend to be on the higher end (often in the 500-900 g 3mol -1 range), their numbers of H-bond donors and acceptors, as well as their polar surface area (PSA), tend to be on the far side of the accepted druglike spectrum. For an equal number of heavy atoms, macrocycles inherently possess a lower number of rotatable bonds than their acyclic analogues, a beneficial feature for oral bioavailability (in the following, “acyclic” will be used in the sense of “nonmacrocyclic”). As a result, macrocycles are more conformationally restricted than their acyclic analogues, which potentially can impart higher target binding and selectivity and improved oral bioavailability (in this assessment, endocyclic bonds are considered to be nonrotatable, which is only an approximation; see ref 18). For a systematic chemoinformatic analysis of biologically active macrocycles, the reader is referred to the recent review of Brandt et al. Topologically, macrocycles have the unique ability to span large surface areas while remaining conformationally restricted compared to acyclic molecules of equivalent molecular weight. This characteristic makes them especially suited for targets displaying shallow surfaces, which can prove to be quite challenging for acyclic small molecules. Medicinal chemistry relies strategically on robust synthetic methods capable of producing an acceptable chemical diversity to adequately interrogate the chemical space of a biological target. Macrocycles are often (and rightly so) perceived as difficult to synthesize and hence deterred many medicinal chemists because of the lack of versatile synthetic platforms. The macrocyclization step is regularly plagued by low yields and often requires high dilution conditions to counterbalance entropic loss. In other words, the reduction in entropy responsible for beneficial conformational restrictions to the final molecule comes at a price during synthesis: what goes around comes around. Accordingly, the first part of this article is dedicated to the drug discovery aspects ofmacrocycles and highlights salient features of their medicinal chemistry. This section is organized by target class, a choice aimed at providing the reader an appreciation of the structural diversity generated for each class. To give the reader an appreciation of the tools available to construct macrocyclic scaffolds, the site and method of the pivotal macrocyclization step are indicated in the figures. Readers are referred to the source articles for further details. In the second part, the technologies and synthetic approaches that already have demonstrated utility or possess a high potential for macrocycle-based

Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery

The field of fragment-based drug discovery (FBDD) has developed significantly over the past 10 years and is now recognized as a tangible alternative to more traditional methods of hit identification, such as high throughput screening (HTS). The number of commercial and academic groups actively engaged in fragment-based research has increased, and as a consequence, there has been continued development and refinement of techniques and methods. From its inception, the fragment-based approach had two central tenets that were critical to its success and that have set it apart from HTS and other hit identification techniques. The first is the concept that chemical space can be more efficiently probed by screening collections of small fragments rather than libraries of larger molecules. The number of potential fragments with up to 12 heavy atoms (not including threeand four-membered ring structures) has been estimated at 10, whereas the number of potential druglike molecules with up to 30 heavy atoms is estimated at more than 10. Therefore, a much greater proportion of “fragment-like” chemical space can feasibly be screened in FBDD compared to “druglike” chemical space covered in a HTS where molecular size is much larger. The second idea is that, because by definition fragment molecules are small in size (typically less than 250 Da), they should typically bind with lower affinity to their target protein (micromolar to millimolar range) compared with druglike molecules that can form many more interactions (nanomolar to micromolar range) but that the binding efficiency per atom is at least as high as for larger hit molecules. Implicitly, the screening techniques employed in FBDD must be correspondingly much more sensitive than a HTS bioassay. Generally, sensitive biophysical techniques are employed to detect these weak binding events and to characterize the fragment interactions with the target active site. Nuclear magnetic resonance (NMR) and protein X-ray crystallography have been used extensively in fragment-based research because these techniques are highly sensitive in detecting low affinity fragment binding and also give information about the fragmentprotein interactions being formed. There have been a number of recently published general review articles that have discussed the various aspects of the FBDD field. In addition, there are now two books on the subject. In this journal in 2004, Erlanson et al. summarized the major developments in FBDD since the original publication by Fesik and co-workers of the “SAR by NMR” approach in the late 1990s. Particular note was given to the biophysical methods employed to screen for fragment binding and the merits and drawbacks of each of these techniques, along with the approaches that can be used to optimize fragments into lead molecules. Herein, the trends and developments over the past 4 years will be outlined and some selected examples that are illustrative of the approaches being utilized by those active in the field examined. Additionally, this review will look in some detail at representative protein-ligand complexes observed between fragment-sized molecules and their protein targets from the Protein Data Bank (PDB). Finally, some conclusions will be drawn from these data and the future of FBDD discussed.

Recent Developments in Fragment-Based Drug Discovery

A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a KD ∼100 μM to a 29-mer RNA model of Domain IIA was...

SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain

A technique for lead discovery vs RNA targets utilizing mass spectrometry (MS) screening methods is described. The structure−activity relationships (SAR) derived from assaying weak binding motifs a...

SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets.

http://ytlab.kmu.edu.tw/lecture/cabd/send_file_BMCL2008

Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors

The present disclosure relates to triazolopyridazine protein kinase modulators of Formula (I), methods of using these compounds to treat diseases mediated by kinase activity.

Triazolopyridazine protein kinase modulators

The present disclosure provides bicyclic triazole protein kinase modulators of formula I: and methods of using these compounds to treat diseases mediated by kinase activity.

Elizabeth A. Jefferson

Papers

SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain

SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets.

Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors

Triazolopyridazine protein kinase modulators

Bicyclic triazoles as protein kinase modulators