Indolocarbazole analogs of staurosporine and methods of synthesis thereof
Inventors
Wood, John L. • Kong, Ke • Gayler, Kevin
Assignees
Publication Number
US-12173012-B2
Publication Date
2024-12-24
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 present disclosure relates to indolocarbazole analogs of staurosporine and their methods of synthesis. The invention introduces a methodology for direct aromatic C—H functionalization to access previously inaccessible regions (C2 and C10) of the indolocarbazole aromatic region, specifically through C—H borylation chemistry. This approach allows the preparation of equipotent indolocarbazole-derived analogs of staurosporine using regioisomeric boronate intermediates as diversification points, enabling the generation of a range of aromatically substituted staurosporine analogs.
The problem addressed is that, although many modifications of staurosporine have been reported, available chemical methods have limited derivatization of the indolocarbazole core, restricting functionalization to only two accessible locations (upper half of the ICZ moiety) due to the limitations of electrophilic aromatic substitution (EAS) chemistry. Thus, functionality at the C2 and C10 positions could not be introduced, preventing structure-activity relationship (SAR) studies and biological evaluations of such analogs. The invention overcomes these challenges by employing C—H activation borylation, influenced primarily by steric congestion, which allows regioselective access to these previously inaccessible positions.
The disclosed methodology has demonstrated that introducing functionality at the C2 and C10 positions does not abrogate kinase activity and does in fact alter the selectivity profile, as verified with synthesized analogs. The methods enable the preparation, isolation, and further functionalization of new staurosporine derivatives, expanding the chemical space and therapeutic potential of this important class of kinase inhibitors.
Claims Coverage
There is one independent claim describing the main inventive feature covered by the patent.
Method for synthesizing staurosporine analogs via Boc protection, borylation, functional group transformation, and deprotection
The inventive feature comprises the following steps: 1. Reacting staurosporine with Boc2O to produce Bis-Boc staurosporine, wherein Boc is tert-Butyloxycarbonyl. 2. Reacting the Bis-Boc staurosporine with B2Pin2 to produce boron pinacol esters of Bis-Boc staurosporine, wherein B2Pin2 is bis(pinacolato)diboron. 3. Oxidizing or chlorinating the boron pinacol esters of Bis-Boc staurosporine to produce staurosporine analog intermediates. 4. Deprotecting the staurosporine analog intermediates to remove Boc groups and yield the final staurosporine analogs. The focus is on a chemical synthesis method for creating a set of novel staurosporine analogs by introducing chemical diversity at previously inaccessible positions on the indolocarbazole core.
The claims provide coverage for a method to synthesize novel staurosporine analogs using Boc protection, C—H borylation, functional transformation, and Boc deprotection steps, resulting in compounds with new functionalities at the C2 and C10 positions of the indolocarbazole core.
Stated Advantages
The disclosed method allows for the preparation of staurosporine analogs with functionality introduced at previously inaccessible positions (C2 and C10) of the indolocarbazole core.
The introduction of new functionalities at these positions does not abrogate kinase activity and is shown to change the selectivity profile.
The methodology enables access to new regions of chemical space for structure-activity relationship studies and potential therapeutic improvements.
Documented Applications
Prevention or therapy for protein kinase related diseases or conditions such as inflammatory and autoimmune conditions, cancer, mood disorders, and cardiovascular diseases through administration of a preferred staurosporine analog.
Use in the manufacture of a medicament comprising a therapeutically effective amount of a staurosporine analog for administration to a subject.
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