Benzofuran-, benzothiophene-, indazole- and benzisoxazole-quinones: excellent substrates for NAD(P)H:quinone oxidoreductase 1

Abstract

A series of heterocyclic quinones based on benzofuran, benzothiophene, indazole and benzisoxazole has been synthesized, and evaluated for their ability to function as substrates for recombinant human NAD(P)H:quinone oxidoreductase (NQO1), a two-electron reductase upregulated in tumor cells. Overall, the quinones are excellent substrates for NQO1, approaching the reduction rates observed for menadione.

Figure 1

Some heterocyclic quinones.

Figure 2

E_redox values (v. Fc) for benzimidazole- and benzothiazole- quinones 11 and 25 compared to related indolequinones 46 and 47.^,

Scheme 1

Reagents and conditions: a, KH, MeI, DMF, rt (42%); b, fuming HNO₃, AcOH, rt (81% as 1:2 mixture of 4- and 6-nitro isomers); c, Sn, HCl, EtOH, reflux; d, NaBH₄, MeOH, rt; e, Fremy’s salt, NaH₂PO₄, aq acetone, rt (20% over 3 steps).

Scheme 2

Reagents and conditions: a, HNO₃, AcOH, rt; b, Sn, HCl, EtOH, rt; d, LiAlH₄, THF, 0 °C; d, Fremy’s salt, NaH₂PO₄, aq acetone, rt (53% over 4 steps).

Scheme 3

Reagents and conditions: a, POCl₃, DMF, CH₂Cl₂, 0 to 50 °C (20%, plus 40% of 4-formyl isomer); b, HNO₃, AcOH, rt (61%); c, Sn, HCl, EtOH, reflux (71%); d, NaBH₄, MeOH, rt; e, Fremy’s salt, NaH₂PO₄, aq acetone, rt (41% over 2 steps).

Scheme 4

Reagents and conditions: a, HNO₃, AcOH, rt (74%); b, Sn, HCl, EtOH, reflux (86%); d, LiAlH₄, THF, rt (80%); d, Fremy’s salt, NaH₂PO₄, aq acetone, rt; then aq HCl (2 M), acetone. (67%).

Scheme 5

Reagents and conditions: a, HNO₃, AcOH, reflux (87%); b, H₂, Pd/C, MeOH-THF (83%); c, Fremy’s salt, NaH₂PO₄, aq acetone, rt (75%); d, LiAlH₄, THF, rt (78%); e, Fremy’s salt, NaH₂PO₄, aq acetone, rt (88%); f, MnO₂, CH₂Cl₂, reflux (38%); g, Fremy’s salt, NaH₂PO₄, aq acetone, rt (79%); h, Ac₂O, pyridine, rt (69%); i, MsCl, Et₃N, CH₂Cl₂, rt; j, LiAlH₄, THF, rt (5% over 2 steps).

Scheme 6

Reagents and conditions: a, Cl₃CCH₂O₂CN=NCO₂CH₂Cl₃, BF₃•OEt₂, CH₂Cl₂, rt; b, Zn, AcOH, rt (35% over 2 steps); c, HNO₃, AcOH, rt (81%); d, MeI, KOH, DMSO, rt (49%); e, Sn, HCl, EtOH, reflux (96%); f, Fremy’s salt, NaH₂PO₄, aq acetone, rt (78%); g, NBS, AIBN, CCl₄; h, Ag-NO₃, aq acetone (36% over 2 steps).

Scheme 7

Reagents and conditions: a, NH₂OH•HCl, EtOH, pyridine, rt (98%); b, DIAD, Ph₃P, THF, rt (100%); c, HNO₃, AcOH, rt (91%); d, Sn, HCl, EtOH, reflux; e, Fremy’s salt, NaH₂PO₄, aq acetone, rt (20% over 2 steps).