Derivatives of a PARP Inhibitor TIQ-A through the Synthesis of 8-Alkoxythieno[2,3- c]isoquinolin-5(4 H)-ones

Mirko M Maksimainen; Antti Nurmesjärvi; Reima A Terho; Michael D Threadgill; Lari Lehtiö; Juha P Heiskanen

doi:10.1021/acsomega.0c01879

Derivatives of a PARP Inhibitor TIQ-A through the Synthesis of 8-Alkoxythieno[2,3- c]isoquinolin-5(4 H)-ones

ACS Omega. 2020 May 28;5(22):13447-13453. doi: 10.1021/acsomega.0c01879. eCollection 2020 Jun 9.

Authors

Mirko M Maksimainen¹, Antti Nurmesjärvi², Reima A Terho², Michael D Threadgill³, Lari Lehtiö¹, Juha P Heiskanen²

Affiliations

¹ Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu FI-90014, Finland.
² Research Unit of Sustainable Chemistry, University of Oulu, P.O. Box 4300, Oulu FI-90014, Finland.
³ Drug & Target Discovery, Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, U.K.

Abstract

Thieno[2,3-c]isoquinolin-5(4H)-one is known for its potential as an anti-ischemic agent through the inhibition of poly(ADP-ribose) polymerase 1 (PARP1). However, the compound also inhibits many other enzymes of the PARP family, potentially limiting its usability. The broad inhibition profile, on the other hand, indicates that this molecule backbone could be potentially used as a scaffold for the development of specific inhibitors for certain PARP enzymes. These efforts call for novel synthetic strategies for substituted thieno[2,3-c]isoquinolin-5(4H)-one that could provide the needed selectivity. In this article, an efficient synthetic strategy for 8-alkoxythieno[2,3-c]isoquinolin-5(4H)-ones through eight steps is presented and other tested synthetic pathways are discussed in detail. Synthesis of 7-methoxythieno[2,3-c]isoquinolin-5(4H)-one is also demonstrated to show that the strategy can be applied widely in the syntheses of substituted alkoxythieno[2,3-c]isoquinolin-5(4H)-ones.