Indolocarbazole analogs of staurosporine and methods of synthesis thereof
Inventors
Wood, John L. • Kong, Ke • Gayler, Kevin
Assignees
Publication Number
US-11993611-B2
Publication Date
2024-05-28
Expiration Date
2041-06-30
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Abstract
Equipotent indolocarbazole-derived analogs of staurosporine identified herein are prepared through C—H borylation chemistry. Functionality resides at C2 and C10 of the indolocarbazole aromatic region. Introducing functionality in this previously inaccessible region does not abrogate kinase activity and is shown to change the selectivity profile.
Core Innovation
The invention is directed to the preparation and identification of equipotent indolocarbazole-derived analogs of staurosporine by employing C—H borylation chemistry. This method enables the introduction of functional groups at the C2 and C10 positions of the indolocarbazole aromatic region, an area of the molecule that was previously inaccessible to modification through existing chemical methods such as electrophilic aromatic substitution. The new chemical approach provides access to regioisomeric boronate intermediates, which allow further diversification and generation of various aromatically substituted staurosporine analogs.
The problem addressed by this invention arises from the historical limitations in modifying the indolocarbazole core of staurosporine, particularly at the C2 and C10 positions. Prior methods restricted substitution primarily to other parts of the aromatic system, limiting structure-activity relationship (SAR) studies and hindering the exploration of analogs with potentially improved kinase selectivity and potency. Notably, previous SAR efforts did not include synthetic analogs with C2 and C10 functionalization due to electronic and steric constraints in available reactions.
By utilizing aromatic C—H functionalization, specifically borylation guided by steric congestion, the invention succeeds in generating staurosporine analogs with new substitution patterns at C2 and C10. The methodology is validated by the preparation of 13 new analogs, and biological studies confirm that modifications in these newly accessible positions do not abolish kinase inhibitory activity but do influence selectivity profiles. This approach therefore provides a platform for generating analogs that can be assessed for improved therapeutic properties.
Claims Coverage
There is one main independent claim providing a new class of compounds and dependent claims specifying preferred substituents.
Compound having novel substitution pattern on indolocarbazole core
A compound with a structure based on the indolocarbazole core of staurosporine, wherein substituents R1, R2, and R3 are each independently selected from OH, H, OMe (OCH3), or Cl. This structure encompasses analogs functionalized at previously inaccessible positions (C2 and C10) as described. - The main feature is the provision of indolocarbazole analogs of staurosporine with defined substituents at these positions. - The claim also encompasses compounds wherein the substituent comprising boron is pinacolato borane.
The claims protect indolocarbazole analogs of staurosporine characterized by novel functional group substitution patterns, specifically allowing for boron-based or other substituents (OH, OMe, Cl, H) at defined positions on the aromatic region.
Stated Advantages
The method allows introduction of functionality in previously inaccessible regions of the indolocarbazole aromatic system (C2 and C10), thus enabling new structure-activity relationship studies.
Introducing functionality at C2 and C10 does not abrogate kinase inhibitory activity and changes the selectivity profile.
The new chemical approach provides a route to analogs with potentially improved therapeutic properties.
Documented Applications
Methods of prevention or therapy for protein kinase related diseases or conditions such as inflammatory and autoimmune conditions, cancer, mood disorders, and cardiovascular diseases, including the administration of a preferred staurosporine analog compound.
Inclusion of synthesized analogs in pharmaceutical compositions for oral administration (tablet, capsule, powder, or liquid), injection (cutaneous, subcutaneous, intravenous), or dry powder inhaler.
Use in the manufacture of a medicament for administration to a subject with a protein kinase related disease or condition.
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