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
Copyright © 2020 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:97 |
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| Enthalten in: |
Bioorganic chemistry - 97(2020) vom: 16. Apr., Seite 103691 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Thirupataiah, B [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.03.2021 Date Revised 01.03.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2020.103691 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM307314324 |
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| 245 | 1 | 0 | |a Synthesis of 11,12-dihydro benzo[c]phenanthridines via a Pd-catalyzed unusual construction of isocoumarin ring/FeCl3-mediated intramolecular arene-allyl cyclization |b First identification of a benzo[c]phenanthridine based PDE4 inhibitor |
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| 500 | |a Date Revised 01.03.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Benzo[c]phenanthridine | |
| 650 | 4 | |a FeCl(3) | |
| 650 | 4 | |a Isocoumarin | |
| 650 | 4 | |a PDE4 | |
| 650 | 4 | |a Pd-catalyst | |
| 650 | 7 | |a Benzene Derivatives |2 NLM | |
| 650 | 7 | |a Isocoumarins |2 NLM | |
| 650 | 7 | |a Phenanthridines |2 NLM | |
| 650 | 7 | |a Phosphodiesterase 4 Inhibitors |2 NLM | |
| 650 | 7 | |a Palladium |2 NLM | |
| 650 | 7 | |a 5TWQ1V240M |2 NLM | |
| 650 | 7 | |a Cyclic Nucleotide Phosphodiesterases, Type 4 |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 650 | 7 | |a PDE4B protein, human |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 700 | 1 | |a Reddy, Gangireddy Sujeevan |e verfasserin |4 aut | |
| 700 | 1 | |a Ghule, Shailendra S |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Jetta Sandeep |e verfasserin |4 aut | |
| 700 | 1 | |a Mounika, Guntipally |e verfasserin |4 aut | |
| 700 | 1 | |a Hossain, Kazi Amirul |e verfasserin |4 aut | |
| 700 | 1 | |a Mudgal, Jayesh |e verfasserin |4 aut | |
| 700 | 1 | |a Mathew, Jessy E |e verfasserin |4 aut | |
| 700 | 1 | |a Shenoy, Gautham G |e verfasserin |4 aut | |
| 700 | 1 | |a Parsa, Kishore V L |e verfasserin |4 aut | |
| 700 | 1 | |a Pal, Manojit |e verfasserin |4 aut | |
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