Publisher： Bentham Science Publishers
E-ISSN： 1873-4294|10|14|1359-1360
ISSN： 1568-0266
Source： Current Topics in Medicinal Chemistry, Vol.10, Iss.14, 2010-10, pp. : 1359-1360
Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.
Abstract
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 d
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