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

B. Thirupataiah, Gangireddy Sujeevan Reddy, Shailendra S. Ghule, Jetta Sandeep Kumar, Guntipally Mounika, Kazi Amirul Hossain, Jayesh Mudgal, Jessy E. Mathew, Gautham G. Shenoy, Kishore V.L. Parsa, Manojit Pal

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number103691
JournalBioorganic Chemistry
Volume97
DOIs
Publication statusPublished - 04-2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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