Macrocycle Compounds

Growing interest towards medium- and large-sized macrocycles closely linked with the field of protein-protein interactions (PPI) as promising therapeutics targets.
ChemDiv used two methodologies for design and synthesis of macrocyclic peptidomimetic library.
One of them includes ring expansion employing Bormann-Wasserman strategy (BWS) and allows synthesising 10-12-membered lactams. This gives us access to unique functionally enriched, spiro and fused scaffolds.
The other one is based on click-macrocyclization of linear peptidomimetics bearing acetylene and azide functionalities at the ends to provide 14-22 membered macrocyclic peptidomimetics.
That allowed us to obtain novel, IP clean, diverse set of macrocyclic scaffolds that we offer for synthetic proposal.

 Please contact us at chemdiv@chemdiv.com to obtain database of novel scaffolds for evaluation and discussion of final macrocycles compounds for production.

Macrocyclic Peptidomimetics

 Our Goals:

• The scaffolds and final compounds should be peptide mimetics;

• The scaffolds should have at least two points of diversification, preferably in peptoid moiety;

• The scaffolds and final compounds should be single diastereomers and, optionally, single

• enantiomers with known configuration;

• Selected synthetic tool for macrocyclization should be high yielding, preferably applicable for

• liquid phase synthesis (LPS) and, optionally, for solid phase synthesis (SPS) if LPS fails to provide

• target macrocycles in reasonable yields;

• Reported data about structural features that are able to improve cell permeability for macrocyclic

• peptide mimetics should be considered in the library design.

Synthetic Tool Selection:

• Click-macro-cyclization (CMC) has obvious advantages if compared to other most used approaches such as macro-lactamization or RCM.

• CMC is less sensitive in relation to size of cycle formed;

• CMC is highly region-controlled with no stereo-chemical impact (in contrast to MCR that usually lead to

• formation of cis- and trans-isomers in various ratio);

• Triazole ring formed as a result of CMC is pharmacologically relevant: to the best of our knowledge at least no negative records for this structural moiety have been published so far;

• There are numerous commercially/synthetically available bifunctional intermediates (azides, alkynes)

• compatible with peptide synthesis to form linkers at CMC-step with variable linker (macrocycle formed)

• size;

• CMC tolerates many functional groups in pre-CMC intermediates;

• CMC is less sensitive in relation to stereochemistry of peptoid moiety (in contrast to macro-lactamization

• that often requires opposite configuration for amino acids to be coupled at the macrocycle formation step).

Despite obvious advantages, some issues are still actual for CMC:

• High risk of di-, tri-meric (and even more) macrocycles formation in both, LPS and SPS.

• High dilution technique is required at CMC-step; however, it does not guarantee only monomer cycle formation

• Success or failure of each specific scaffold synthesis becomes known only at very late steps of the challenging multi-step synthesis    

Nevertheless, our experience on validated and pre-validated series allows us to predict the most acceptable linkers and choose preferable CMC conditions to minimize mentioned side reactions and therefore to make the chemistry feasible in liquid phase.