Bioactive Macrocycles from Nature

DAVID J. NEWMAN AND GORDON M. CRAGG

1.1 Introduction

Natural products have been an important source of pharmacologically active molecules throughout the history of medicinal chemistry and a selection of these molecules has advanced to provide clinically validated, marketed therapeutics for numerous indications, most notably as antibiotics, immunosuppressives and anti-tumor agents. Among these, structurally diverse and complex naturally derived macrocycles have demonstrated an impressive record of efficacy as pharmaceutical agents, and are playing an increasingly important role in the treatment of a range of serious diseases. These macrocycles have received intense recent interest from the medicinal chemistry community driven in part by their activity in biological systems, such as those mediated by protein–protein interactions, that are difficult to prosecute with more typically drug-like small molecules. In addition, the selectivity afforded by their complexity and the remarkable ability of some of these macrocyclic natural products to provide significant systemic exposures on oral dosing despite physical properties that lie substantially outside of normal parameters for achieving oral bioavailability, make them an attractive chemical class. Thus, these macrocyclic natural products and related biosynthetically and semi-synthetically derived macrocycles are of great value not only for their own intrinsic pharmacological activity but also or their potential as tools used to understand how to design molecules with he properties necessary to produce highly effective therapeutics for the treatment of human disease.

Further testaments to the current level of focus on macrocycles in drug discovery are the excellent reviews published over the last five years on key aspects of the medicinal chemistry of this chemotype. The most recent of these reviews, by Giordanetto and Kihlberg, provides an analysis of the physical properties of macrocyclic drug molecules, including cLogP, polar surface area, hydrogen bond donor count and molecular weight, in relationship to their ability to be orally efficacious. In addition, in 2008, Driggers et al. provided an excellent overview of macrocycles as drug leads and candidates at that time. This was followed by a review in 2011 by Marsault and Peterson showing the use of macrocycles over a wide area of medicinal chemistry and, in 2012, a review from Mallinson and Collins focusing primarily on potential anticancer agents.

In their 2014 review Giordanetto and Kihlberg reported 68 registered macrocyclic drugs approved for human use (identified through mining of the GVK BIO online structure-activity relationship database (GOSTAR)), along with a set of 35 macrocyclic drug candidates in clinical development (identified using the Adis R&D Insight database). The latter set did not include compounds in early clinical trials whose structures were not in the public domain. Most of these drugs, which have macrocyclic rings comprised of 12 or more atoms, fall into three chemical classes, namely macrolidic antibiotics, macrolides that have antitumor or immunological effects, and cyclic peptides that may or may not contain lactone (depsipeptide) linkages.

Of the 68 identified macrocyclic registered drugs, 34 are used for the treatment of infections, mainly of bacterial origin, while 10 are used for the treatment of a variety of cancers; the remaining 28 are applied in cardio-vascular, gynecological and immunological therapeutic areas, as well as in a range of indications, including anesthesiology and pain (these numbers do not total 68 since some agents have two or more activities). The majority of these molecules are natural products or directly derived from natural products (48 and 18, respectively), while eribulin (vide infra) is totally synthetic but modeled on the marine natural product, halichondrin B, and Sugammadex is a modified γ-cyclodextrin. Nineteen of the 68 drugs are administered orally, with 15 of these belonging to the macrolide classes. The parenterally administered macrocyclic drugs include all of the cyclic peptides, with the exception of cyclosporin A which is orally delivered.

As with the registered drugs briefly discussed above, of the 35 macrocycles identified as agents in clinical development 14 are under investigation for the treatment of various cancers, 10 are in infectious disease trials, and the remaining 11 are under investigation for indications ranging from endocrinology to ophthalmology. While these agents are also predominantly natural products (17) or natural product-derived molecules (8), with the largest chemical class being cyclic peptides (11), 10 of the clinical candidates are of de novo design. A total of 43% of these clinical candidates are administered orally, a significant increase over the 28% of all registered macrocyclic drugs that are orally administered, and nine of the 10 de novo designed macrocycles in trials are orally bioavailable. The increasing numbers of orally active macrocyclic drug candidates indicates that organic and medicinal chemists are learning to apply the lessons provided by bioactive natural macrocyclic agents, such as those presented in this chapter, for the design of fully synthetic molecules having desirable pharmacological properties, including oral bioavailability.

In strongly endorsing the impressive therapeutic record of natural product-derived macrocycles reported in earlier reviews and commentaries, the following sections will expand on the discussion of the macrocyclic chemical classes mentioned above, while adding a number of other chemical compounds that fall under the general description of "macrocycles" that have originated from plant and marine sources. Some of these compounds have arisen from the assessment of biosynthetic clusters that has led to the identification of novel agents, frequently not associated with the "expected" macro-organism source.

Also included are two short sections covering natural product macro- cycles, which are described in detail in two later chapters...