Potential chemopreventive agents based on the structure of the lead compound 2-bromo-1-hydroxyphenazine, isolated from Streptomyces species, strain CNS284

Abstract

The isolation of 2-bromo-1-hydroxyphenazine from a marine Streptomyces species, strain CNS284, and its activity against NF-κB, suggested that a short and flexible route for the synthesis of this metabolite and a variety of phenazine analogues should be developed. Numerous phenazines were subsequently prepared and evaluated as inducers of quinone reductase 1 (QR1) and inhibitors of quinone reductase 2 (QR2), NF-κB, and inducible nitric oxide synthase (iNOS). Several of the active phenazine derivatives displayed IC₅₀ values vs QR1 induction and QR2 inhibition in the nanomolar range, suggesting that they may find utility as cancer chemopreventive agents.

Figure 1

Phenazine Natural Products

Figure 2

Structures of Sulforaphane (54) and Sulforamate (55)

Scheme 1^a

^aReagents and conditions: (a) o-chloranil, ether; (b) PhH, HOAc; (c) HBr, HOAc, reflux; (d) 1 eq NBS, PhCH₃; (e) 2 eq NBS, PhCH₃; (f) MeI, K₂CO₃, acetone.

Scheme 2^a

^aReagents and conditions: (a) 1 eq NBS, PhCH₃; (b) BBr₃, CH₂Cl₂.

Scheme 3^a

^aReagents and conditions: (a) PhH, HOAc; (b) HBr, HOAc; (c) NH4OAc, Br2, HOAc; (d) BBr₃, CH₂Cl₂.

Scheme 4^a

^aReagents and conditions: (a) Ag₂O, acetone; (b) PhH, HOAc.

Scheme 5^a

^a Reagents and conditions: (a) PhH, HOAc.

Scheme 6^a

^a Reagents and conditions: (a) Br₂, HOAc, NaOAc.

Scheme 7^a

^aReagents and conditions: (a) HBr, HOAc.

Scheme 8^a

^aReagents and conditions: (a) PhH, HOAc.

Scheme 9^a

^a Reagents and conditions: (a) PhH, HOAc.

Scheme 10^a

^a Reagents and conditions: (a) PhH, HOAc (b) HBr, HOAc (c) 2 eq NBS.