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Updated: Jul 23, 2025
Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1
Samuël Demin1, Aldo Peschiulli1, Adriana I Velter1
1Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse B-2340, Belgium.
Abstract:
Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds (Ra)-10 and (Ra)-15, possessing remarkable cellular potency and properties.
Insights
Researchers explored macrocyclic indoles to inhibit myeloid cell leukemia-1 (MCL-1), a protein promoting cancer. They discovered novel compounds with improved potency and solubility, offering a promising new therapeutic strategy for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Myeloid cell leukemia-1 (MCL-1) is an antiapoptotic protein crucial for mitochondrial homeostasis.
- MCL-1 overexpression in cancer cells drives tumor progression, making it a key therapeutic target.
Purpose of the Study:
- To investigate the impact of pyrazole and indole isomerism on macrocyclic indole compounds targeting MCL-1.
- To discover novel MCL-1 inhibitors with enhanced cellular potency and drug-like properties.
Main Methods:
- Synthesis and structural modification of macrocyclic indole derivatives.
- Evaluation of cellular potency and physicochemical properties (e.g., solubility) of synthesized compounds.
- Structure-activity relationship (SAR) analysis to identify key structural features for activity.
Main Results:
- Incorporation of a fluorine atom on the naphthalene moiety significantly improved cellular potency.
- Introduction of diverse side chains on the pyrazole ring enhanced compound solubility.
- Discovery of potent MCL-1 inhibitors, compounds (Ra)-10 and (Ra)-15, with favorable properties.
Conclusions:
- Macrocyclic indoles represent a promising scaffold for developing novel MCL-1 inhibitors.
- Strategic structural modifications, including fluorination and pyrazole side-chain diversification, are effective for optimizing inhibitor potency and solubility.
- Compounds (Ra)-10 and (Ra)-15 demonstrate significant potential for further development as anti-cancer therapeutics targeting MCL-1.
