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

被引：17

作者：

Thirupataiah, B. ^{[1
,2
]}

Reddy, Gangireddy Sujeevan ^{[1
,2
]}

Ghule, Shailendra S. ^{[1
]}

Kumar, Jetta Sandeep ^{[1
,2
]}

Mounika, Guntipally ^{[1
]}

Hossain, Kazi Amirul ^{[1
]}

Mudgal, Jayesh ^{[2
]}

Mathew, Jessy E. ^{[2
]}

Shenoy, Gautham G. ^{[2
]}

Parsa, Kishore V. L. ^{[1
]}

Pal, Manojit ^{[1
]}

机构：

[1] Dr Reddys Inst Life Sci, Univ Hyderabad Campus, Hyderabad 500046, India

[2] Manipal Acad Higher Educ, Manipal Coll Pharmaceut Sci, Manipal 576104, Karnataka, India

来源：

BIOORGANIC CHEMISTRY | 2020年 / 97卷

关键词：

Isocoumarin; Benzo[c]phenanthridine; Pd-catalyst; FeCl3; PDE4; CONCISE SYNTHESIS; TOPOISOMERASE-I; ALKALOIDS; DERIVATIVES; ANTITUMOR; ULTRASOUND; NITIDINE; DESIGN;

D O I：

10.1016/j.bioorg.2020.103691

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Mphenanthridine/benzoklphenanthridine 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.

引用

页数：17

共 55 条

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