Synthesis of 11,12-dihydro benzo[c]phenanthridines via a Pd-catalyzed unusual construction of isocoumarin ring/FeCl3-mediated intramolecular arene-allyl cyclization: First identification of a benzo[c]phenanthridine based PDE4 inhibitor
| Autor: | Gangireddy Sujeevan Reddy, B. Thirupataiah, Shailendra S. Ghule, Jetta Sandeep Kumar, Jessy Elizabeth Mathew, Manojit Pal, Gautham G. Shenoy, Kazi Amirul Hossain, Jayesh Mudgal, Guntipally Mounika, Kishore V. L. Parsa |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Phenanthridine
010405 organic chemistry Stereochemistry Organic Chemistry Sonogashira coupling Ring (chemistry) 01 natural sciences Biochemistry 0104 chemical sciences Catalysis Isocoumarin 010404 medicinal & biomolecular chemistry Concentration dependent chemistry.chemical_compound chemistry Intramolecular force Drug Discovery polycyclic compounds Molecule Molecular Biology |
| Zdroj: | Bioorganic Chemistry. 97:103691 |
| ISSN: | 0045-2068 |
| Popis: | In spite of their various pharmacological properties the anti-inflammatory potential of benzo[c]phenanthridines remained underexplored. Thus, for the first time PDE4 inhibitory potential of 11,12-dihydro benzo[c]phenanthridine/benzo[c]phenanthridine was assessed in vitro. Elegant synthesis of these compounds was performed via a multi-step sequence consisting of a Pd-catalyzed unusual construction of 4-allyl isocoumarin ring and FeCl3-mediated intramolecular regio- as well as site-selective arene-allyl cyclization as key steps. The overall strategy involved Sonogashira coupling followed by isocoumarin and isoquinolone synthesis, then chlorination and subsequent cyclization to afford a range of 11,12-dihydro derivatives. One of these dihydro compounds was converted to the corresponding benzo[c]phenanthridine that showed concentration dependent inhibition of PDE4B affording an initial hit molecule. The SAR study suggested that 11,12-dihydro analogs were less potent than the compound having unsaturation at the same part of the ring. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect