Getting macrocycles to their destination within cells

Macrocycles are organic compounds that contain a ring consisting of 12 or more atoms. They are found in many of our most valuable drugs. For instance, many antibiotics that combat bacterial infections, novel drugs that cure hepatitis C virus infections and drugs that prevent rejection of organ transplants are macrocycles. Recently, we have begun to gain a deepar understanding of the advantages they provide in drug discovery. Most importantly, they may allow high affinity binding to targets that have large and flat binding sites, for which conventional small molecule drugs do not provide sufficient potency and specificity. Interactions between proteins, as well as the binding sites of some enzymes, are examples of such difficult-to-drug targets.

The size of macrocycles often put them close to the upper limits of molecular weight and polarity above which they are unable to cross cell membranes and reach their targets within cells. In this publication we determined the ability of >200 drug-like macrocycles to penetrate cells an also their aqueous solubility. Our results provided an understanding of how molecular properties, such as the number of hydrogen bond donors, and specific functional groups govern their cell permeability. We also found that some macrocycles behave as molecular chameleons that expose polar groups in water and hide them in a lipophilic environment, e.g. by formation of intramolecular hydrogen bonds. Chameleons are particularly interesting as they may display both high aqueous solubility and high cell permeability, instead of one or the other.

Our work provides novel and fundamental understanding of the molecular properties of macrocycles that govern solubility and cell permeability; two key properties that also determine the oral absorption of drugs. Thereby our results provide important guidance for medicinal chemists involved in design of macocyclic drugs by clarifying which functional groups that should be included or excluded and how various descriptors influence drug-like properties. Last but not least, we demonstrated the benefits that may be reaped by design of chameleonic drugs.

Orginalartikel: Structural and conformational determinants of macrocycle cell permeability, Nature Chemical Biology volume 12, pages 1065–1074 (2016). Björn Over, Pär Matsson, Christian Tyrchan, Per Artursson, Bradley C Doak, Michael A Foley,  Constanze Hilgendorf, Stephen E  Johnston , Maurice D Lee IV, Richard J Lewis, Patrick McCarren,  Giovanni Muncipinto, Ulf Norinder, Matthew W D Perry, Jeremy R Duvall & Jan Kihlberg.

Jan Kihlberg undervisar på följande kurser på Institutionen för kemi:


Chemical Molecular Design 2019/2020 (10 credits)

Proteins and Drugs 2019/2020 (5 credits)

Current Trends in Chemistry 2019/2020 (5 credits)

Organic Synthesis 2019/2020 (15 credits)