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

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

Mirko M Maksimainen  1 , Antti Nurmesjärvi  2 , Reima A Terho  2 , Michael D Threadgill  3 , Lari Lehtiö  1 , Juha P Heiskanen  2
Affiliations

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

Mirko M Maksimainen et al. ACS Omega. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structures of TIQ-A and its structural isomer.
Scheme 1
Scheme 1. Previous Syntheses of 9-Methoxythieno[2,3-c]isoquinolin-5(4H)-one
Scheme 2
Scheme 2. Synthetic Routes to 8-Alkoxythieno[2,3-c]isoquinolin-5(4H)-ones
Reagents and conditions: (a) Pd(PPh3)4, K3PO4, dioxane, H2O, 90 °C, and 24 h; (b) NaOH, EtOH, H2O, reflux, and 1 h; (c) SOCl2, toluene, dimethylformamide (DMF), 80 °C, and 105 min; (d) NaN3, tetrahydrofuran (THF), H2O, ice bath, and 20 min; (e) 1,2-dichlorobenzene, 210 °C, and 20 h; (f) BBr3, CH2Cl2, rt, and 2 h; (g) BBr3, CH2Cl2, rt, and overnight; (h) MeOH, conc. H2SO4, 85 °C, and 19 h; (i) 3-bromobenzyl bromide, K2CO3, DMF, rt, and 19 h; (j) 2-bromopropane, NaH, DMF, 60 °C, and 19 h; and (k) MeOTf, NaH, DMF, 60 °C, and 19 h.
Scheme 3
Scheme 3. Route B: Potential Strategy for the Synthesis of 9a from Compound 4 via Lactam Protection
Scheme 4
Scheme 4. Synthesis of 7-Methoxythieno[2,3-c]isoquinolin-5(4H)-one (12)
Reagents and conditions: (a) Pd(PPh3)4, K3PO4, dioxane, H2O, 90 °C, and 24 h; (b) NaOH, EtOH, H2O, reflux, and 1 1/2 h; (c) SOCl2, toluene, DMF, 80 °C, and 105 min; (d) NaN3, THF, H2O, ice bath, and 25 min; and (e) 1,2-dichlorobenzene, 210 °C, and 12 h.
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