In the world of pharmaceuticals, bigger rings are opening doors to previously "undruggable" targets.
Imagine a key that's not rigid and stiff, but flexible and adaptable, able to mold itself perfectly to a lock that no traditional key could ever open. This is the promise of macrocyclic drugs, a class of molecules that is pushing the boundaries of modern medicine.
For decades, drug discovery was dominated by small, rigid molecules. But many disease-causing proteins have large, flat surfaces with no obvious pockets for these small drugs to bind to, rendering them "undruggable." Macrocycles, with their unique combination of size, flexibility, and power, are now cracking these locks, offering new hope for treating a wide range of diseases.
At their simplest, macrocycles are organic molecules containing a ring of at least 12 atoms4 . This large ring structure sets them apart from traditional small-molecule drugs and gives them a special set of skills.
They occupy a sweet spot in molecular design. They are larger and more powerful than typical small-molecule drugs, allowing them to bind to expansive protein surfaces. Yet, they are often still small enough to be administered as a pill, unlike large biologic drugs like antibodies that require injection6 9 .
Their superpower lies in their ability to disrupt protein-protein interactions (PPIs). Many critical biological processes are controlled by proteins interacting with each other on large, shallow surfaces. Traditional drugs are ineffective here. Macrocycles can wedge themselves into these interactions and block them6 .
Animated representation of a macrocyclic structure with diverse atoms forming a large ring.
The impact is already being felt in the clinic. Since 2014, the U.S. Food and Drug Administration (FDA) has approved 19 new macrocyclic drugs for conditions ranging from bacterial and viral infections to cancer and chronic obesity3 .
| Drug Name (Generic) | Brand Name | Year Approved | Primary Use |
|---|---|---|---|
| Lorlatinib | Lorbrena | 2018 | ALK-positive metastatic non-small cell lung cancer3 |
| Glecaprevir | Mavyret | 2017 | Hepatitis C virus (HCV) infection3 |
| Simeprevir | Olysio | 2013 (2014 in EU) | Hepatitis C virus (HCV) infection3 |
| Plecanatide | Trulance | 2017 | Chronic idiopathic constipation3 |
| Bremelanotide | Vyleesi | 2019 | Hypoactive sexual desire disorder3 |
| Sugammadex | Bridion | 2015 | Reversal of neuromuscular blockade3 |
| Moxidectin | - | 2018 | Anthelmintic (parasitic worms)3 |
Creating these complex ring-shaped molecules in the lab is no easy feat. The process of macrocyclization—forming the large ring—is a major hurdle. The molecule must contort into the correct conformation for the ends to meet and react, a process often hampered by ring strain and unfavorable spatial interactions1 . For a long time, this limited macrocyclic drugs to derivatives of naturally occurring compounds.
However, synthetic strategies have advanced dramatically. Today, chemists have a powerful toolkit for building these macrocyclic scaffolds1 3 :
Early macrocyclic drugs were primarily derived from naturally occurring compounds with limited structural diversity.
Development of macrolactamization and macrolactonization techniques enabled creation of peptide-based macrocycles.
Introduction of Ring-Closing Metathesis (RCM) and transition metal-catalyzed coupling reactions expanded synthetic possibilities.
Microwave-assisted synthesis, solid-phase synthesis, and AI-driven design are now revolutionizing macrocycle production.
One of the most significant innovations in macrocycle synthesis is the application of microwave irradiation. Moving from traditional heating methods to microwave-assisted organic synthesis (MAOS) is like upgrading from a conventional oven to a high-speed air fryer.
Microwave heating is more efficient, transferring energy directly to the molecules rather than slowly heating the reaction vessel from the outside. This leads to spectacular improvements2 7 :
Hours or days of conventional heating can be shortened to mere minutes.
More of the starting material is converted into the desired macrocyclic product.
Faster, more direct reactions often result in fewer unwanted byproducts.
| Synthesis Step | Conventional Heating | Microwave-Assisted | Benefit of Microwave |
|---|---|---|---|
| Paal-Knorr Reaction | 24 hours | 10 minutes | 144x faster |
| Alkylation Reaction | 5 hours | 20 minutes | 15x faster |
| Linstead Macrocyclization | 120 minutes | 8 minutes | 15x faster, yield increased from 19% to 28% |
To understand the real-world impact, let's examine a pivotal study that helped pioneer this method for creating macrocyclic diaryl ethers—structures common in many natural products with potent biological activity2 .
The classical Ullmann coupling reaction, used to form these ethers, typically requires very high temperatures and long reaction times, often leading to low yields. This made it inefficient for creating diverse libraries of macrocycles for drug discovery.
Researchers used a model compound, a 1,7-diarylheptan-3-one, and subjected it to macrocyclization under different conditions2 :
The reactions used a simple catalytic system of copper oxide (CuO) and a base (K2CO3) in pyridine solvent2 .
The results were striking. While conventional heating for 20 hours gave only a 33% yield of the desired macrocycle, the microwave-assisted reaction at 220°C was completed in just 35 minutes with an excellent 85% yield2 .
This experiment demonstrated that microwave irradiation is not merely a faster heating method. It provides a more efficient energy transfer that overcomes the kinetic and thermodynamic barriers of macrocyclization, making a challenging reaction practical and high-yielding. This opened the door to rapidly synthesizing a wide panel of macrocycles with different ring sizes and substitution patterns, a crucial capability for drug optimization2 .
The synthesis and study of macrocycles rely on a suite of specialized reagents and tools. The following table details some of the key components in a macrocycle researcher's arsenal.
| Reagent / Tool | Function in Macrocycle Research | Example Use Case |
|---|---|---|
| Grubbs/Hoveyda-Grubbs Catalysts | Catalyzes Ring-Closing Metathesis (RCM), a premier method for forming large rings from diene precursors. | Key for creating carbon-based macrocyclic scaffolds without the need for high-dilution conditions. |
| PyBOP/HATU | Peptide coupling reagents that facilitate the formation of amide bonds, essential for macrolactamization. | Used to cyclize linear peptide sequences into macrocyclic peptides, improving their metabolic stability3 . |
| Copper/Palladium Catalysts | Enable key carbon-carbon and carbon-heteroatom bond-forming reactions essential for ring closure. | Copper catalysts are used in intramolecular Ullmann diaryl ether synthesis; Palladium catalysts are used in cross-couplings2 . |
| Solid-Phase Supports | Insoluble polymer resins to which a growing molecule is attached, simplifying purification and automation. | Enables the rapid synthesis of vast "one-bead-one-compound" libraries of macrocyclic peptides for high-throughput screening3 . |
| mRNA Display | A display technology that links a macrocyclic peptide to its genetic code, allowing screening of vast libraries. | Used to discover initial lead compounds that bind to a specific protein target from libraries containing trillions of unique members9 . |
The field of macrocyclic drug discovery is accelerating rapidly, fueled by technological advances. Two areas, in particular, point toward a transformative future:
Researchers are now using artificial intelligence to design macrocycles from scratch. In one groundbreaking study, scientists used an AI-assisted approach to generate and model 14.9 million never-before-seen macrocyclic peptides in silico. Several of these designed molecules showed promising results in the lab, inhibiting cancer-linked proteins and key viral proteins5 .
This moves the field from painstakingly testing a few compounds to intelligently exploring a virtually infinite chemical space.
For decades, drug discovery was guided by the "Rule of Five," a set of principles that suggested molecules beyond a certain size and complexity would not be orally bioavailable. Macrocycles are shattering this dogma.
of macrocyclic drugs are orally bioavailable
break traditional drug-like property rules
It is now known that close to 40% of macrocyclic drugs are orally bioavailable, proving that larger, more complex molecules can indeed be developed into convenient pills4 6 .
From their humble origins as natural products to their current status as a frontier in drug design, macrocyclic drugs have come of age. They represent a powerful new modality, blending the best properties of small molecules and biologics to target the root causes of disease in ways previously thought impossible.
With innovations like microwave-assisted synthesis accelerating their creation and AI opening new design horizons, the macrocycle revolution is just beginning. As research continues to untangle the complexities of their synthesis and behavior, these adaptable molecular keys are poised to unlock a new era of medicine.