Current Topics in Medicinal Chemistry - Volume 10, Issue 14, 2010

Macrocyles are essential features of more than one hundred important drugs currently in the market. The remarkable success of several of these drugs justifies a sustained interest in exploring macrocyclic scaffolds for the discovery of new therapeutic agents. Broadly defined as cyclic templates with twelve or more atoms, macrocycles generally do not conform to the popular “rule of 5” restrictions, a set of proposals that sought to define properties essential for favorable pharmacokinetic profiles of small molecules [1]. Additionally, most macrocylic compounds, especially those derived from natural sources, have structural complexity that made their de novo synthesis a challenge. And where the syntheses have been worked out, such are not usually feasible for commercial production of these molecules. The lack of both compliance with the “rule of 5” and tractable synthetic approaches are principally responsible for the under-utilization of macrocyclic scaffolds in the drug discovery process [2]. This special issue of Current Topics in Medicinal Chemistry discusses recent progress in in silico understanding of the druggable attributes of macrocycles, their (semi)-synthesis, and also highlights challenging intracellular molecular recognition systems for which macrocycles might be particularly suited as drug development templates. In the first contribution, Brandt et al. [3] (Leibniz Institute, Germany) reviewed various chemoinformatic approaches for the analysis of bioactive macrocycles. They surmised that studies over the decades have shown that, unlike most “rule of 5” compliant small molecules, the membrane permeability (and subsequent bioavailability) of macrocycles could be enhanced through protection of their key pharmacophores from energetically costly interactions via internal hydrogen bonding, selfaggregation and restricted rotation. Additionally, the restricted conformation of macrocycles could significantly influence bioactivity by locking the crucial pharmacophores in conformation(s) that optimize their interactions with their intracellular targets. Using the interaction of Heat Shock Protein 90 (HSP90) with its retinue of client proteins as a model system, Johnson et al. [4] (San Diego State University, USA) showed that macrocycles are indeed preferred by nature to modulate or perturb proteinprotein interactions, a system that is rather challenging for small molecules due to extensive contacts between the interacting proteins. Macrocycles provide the requisite extensive complementary surface recognition motifs sufficient to interfere with protein-protein interaction and consequently elicit a desired biological effect, which in the case of the perturbation of HSP90- client proteins interaction is antitumor activity. In the third contribution, Avolio and Summa [5] (IRBM, Italy) reviewed efforts aimed at the discovery of inhibitors of hepatitis C virus NS3-4A protease based on macrocyclization of appropriate small molecule leads. In this and other systems, chemists have demonstrated that macrocyclization of appropriate small molecules could ameliorate many of the shortcomings of their acyclic congeners. Avolio and Summa's review aptly demonstrated how application of the understanding of structural attributes that engender naturally occurring macrocycles with attractive qualities could be used in the discovery of wholly synthetic, druggable macrocycles. The structural complexity of many macrocycles, particularly those of natural origin, often endowed them with a richness of chemistry that is unparalleled relative to acyclic compounds of comparable molecular weights. Specifically, the spatialdistribution of functional groups on macrocyclic templates may influence their reactivity. This appreciation is used in semisynthetic transformation of many natural macrocycles. In their reviews, Mwakwari et al. [6] (Georgia Institute of Technology, USA) and Ying and Tang [7] (Enanta Pharmaceuticals, USA) showed that macrocyclic templates derived from 14- and 15- membered macrolides are susceptible to selective chemical transformations in the presence of functional groups that will otherwise interfere with such reactions in simpler molecules. In their contribution, which aims at updating the progress on the discovery of macrocyclic histone deacetylase inhibitors, Mwakwari et al. discussed the use of this semi-synthetic approach to “erase” standard bioactivity (i.e. antibacterial activity) and then impact new bioactivity (i.e. antiproliferative activity through histone deacetylase inhibition) on macrolides. Ying and Tang further elaborated on the use of semi-synthetic approaches (within the last six years) to obtain a new generation of macrolide-derived antibiotics which are able to overcome much of the resistance developed against the starting macrolide templates.

In this review, macrocycles are defined as organic molecules containing at least one non-bridged cycle of 12 or more covalently connected atoms. Common statistical aspects as well as structure activity relationships (SAR) of macrocycles based on chemoinformatics methods are discussed. Can macrocyclic structural features be linked to activities against cancer cells, viruses like HIV, or bacteria? General challenges and problems in using chemoinformatics for more detailed analyses of macrocycles based on large compound databases are outlined.

Heat shock proteins (HSP) are a family of highly conserved proteins, whose expression increases in response to stresses that may threaten cell survival. Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer as it plays a vital role in normal cell maturation and acts as a molecular chaperone for proper folding, assembly, and stabilization of many oncogenic proteins. To date, a majority of Hsp90 inhibitors that have been discovered are macrocycles. The relatively rigid conformation provided by the macrocyclic scaffold allows for a selective interaction with a biological target such as Hsp90. This review highlights the discovery and development of nine macrocycles that inhibit the function of Hsp90, detailing their potency and the client proteins affected by Hsp90 inhibition.

Hepatitis C virus (HCV) is a major cause of acute hepatitis and chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). No vaccine is currently available to prevent hepatitis C, and the current standard of care (SOC) - pegylated interferon-α (PEG-IFN-α) in combination with ribavirin (RBV) - is only partially effective and it also presents side effects. Novel treatment options now under intensive development are focused on the discovery of inhibitors of HCV-specific enzymes. The HCV NS3 protease plays an essential role for viral replication and it is recognized as one of the most attractive targets for developing novel anti-HCV therapies. After two decades of research efforts a number of potent active-site inhibitors of the NS3 protease have been generated and some of them are in late stage of clinical trials. A particularly interesting class of HCV NS3 protease inhibitors are based on depeptidized macrocyclic structures. The article reviews the recent progresses made in the discovery and development of macrocyclic inhibitors of the HCV NS3 protease as described in the most recent scientific literature (patent excluded), from a medicinal chemistry perspective.

Histone deacetylase inhibitors (HDACi) are an emerging class of novel anti-cancer drugs that cause growth arrest, differentiation, and apoptosis of tumor cells. In addition, they have shown promise as anti-parasitic, antineurodegenerative, anti-rheumatologic and immunosuppressant agents. To date, several structurally distinct small molecule HDACi have been reported including aryl hydroxamates, benzamides, short-chain fatty acids, electrophilic ketones, and macrocyclic peptides. Macrocyclic HDACi possess the most complex cap-groups which interact with HDAC enzyme's outer rim and have demonstrated excellent HDAC inhibition potency and isoform selectivity. This review focuses on the recent progress and current state of macrocyclic HDACi.

Development of novel erythromycin-based antibiotics has been one of the most studied topics in the past three decades. Such tremendous efforts have generated a number of beneficiary drugs such as clarithromycin, azithromycin and telithromycin. However, widespread application of antibiotics in clinical practice has triggered an increasing emergence of bacterial resistance. Therefore, discovery of novel macrolide antibiotics to suppress the resistance is urgent for human healthcare. This review focuses on advances in the area since 2004.

Macrolides currently play a major role in the management of severe infections. Evidence derived from several retrospective studies have shown a significant reduction of mortality from community-acquired pneumonia upon treatment with a macrolide. Apart from other explanations, their effect is probably mediated through modulation of the immune function of the host. Supporting this inference are results from various studies which have shown that macrolides, such as clarithromycin, prolonged survival and modulated monocytes functions in both animal models and clinical presentation of pyelonephritis and sepsis of Gram-negative pathogens. The present review focuses on how the concept of macrolide function within the human immune system has evolved in recent years. Particular emphasis is on the role of macrolides in the treatment of sepsis syndrome. Many of the findings herein discussed have created a novel perspective for the management of sepsis syndrome with 14-membered macrolide, specifically clarithromycin.