A scientific article by the Dr. "Omar Saeed Khalifa" entitled "Macrocyclic Drugs and Synthetic Methodologies toward Macrocycles"
Macrocyclic structures are prevalent in natural products and pharmaceutical compounds, serving as essential frameworks for medicinal chemistry efforts in contemporary drug development.
Historically and clinically, these molecules have profoundly influenced the realms of chemistry, biology, and medicine. A defining trait of macrocyclic natural products is their ring systems, which generally consist of 12 or more members.
Fig 1: Diagram of various applications of macrocyclic compounds
The distinctive structural attributes and conformational flexibility of macrocyclic rings provide significant functional benefits. These features can enhance potency and selectivity, particularly when critical functional groups interact with specific biological targets.
Furthermore, macrocycles often exhibit favorable drug-like characteristics, including high solubility, increased lipophilicity, improved membrane permeability, enhanced metabolic stability, and excellent oral bioavailability, along with desirable pharmacokinetic and pharmacodynamic profiles.
A prime example of successful macrocyclic drugs in clinical use is the macrocyclic antibiotics class, among which vancomycin stands out.
Vancomycin is a macrocyclic glycopeptide antibiotic effective against Gram-positive bacterial infections. Chemically, it comprises a hydrophilic glycopeptide structure with a glycosylated hexapeptide chain and aromatic rings interconnected by aryl ether bonds, forming a rigid molecular framework.
Additionally, two macrocyclic peptides within vancomycin have been synthesized using the TTN oxidation method. The macrocyclic tetrapeptide, an essential component of vancomycin, creates a binding pocket for the terminal carboxylate region, contributing to its functionality.
In conclusion, naturally derived macrocycles have demonstrated significant success in clinical applications. Newly developed macrocyclic chemotypes hold immense therapeutic potential and represent a vital class of medicinal agents. Macrocyclization has thus become a pivotal reaction in organic synthesis, with numerous approaches and methodologies enabling the construction of macrocyclic structures.