Synthesis of a regio-isomer of kealiiquinone, a marine benzimidazole alkaloid

Abstract

Treatment of 1,3-dialkyl-2-(phenylthio)benzimidazolium salts 3 and 1,3-dialkyl-2-phenylthio-1H-imidazolium salts 7 with aq. K 2 CO 3 gives 1,3-dialkyl-1,3-dihydrobenzimidazol-2-ones 4 and 1,3-dialkyl-1,3-dihydroimidazol-2-ones 8, respectively, in 22-94% yield. A regio-isomer 17 of kealiiquinone, a marine benzimidazole alkaloid, where the 4-methoxyphenyl group at the 4-position migrates to the 9-position, is synthesized by application of the reaction. Cytotoxity of 17 and kealiiquinone against 39 human cancer cells is evaluated. They have weak activity but a unique mechanism of action.

Total syntheses and cytotoxicity of kealiiquinone, 2-deoxy-2-aminokealiiquinone and analogs

“…Such activity patterns an observation reported by Ohta's group where isokealiiquinone is more active than kealiiquinone. 13 As far as our studies with the benzoquinone group are concerned, kealiiquinone is the least active with the 2-amino derivative 2 and the C2-deletion analog 2-deoxykealiiquinone ( 10 ) being comparably active. At the present time no information is available regarding the mechanism of action of these compounds.…”

“…12 At the time of this report, no bioactivity data were reported, but in a subsequent synthetic effort it was determined that it was cytotoxic, with potentially a unique mechanism of action based on the inhibition profile in a multi cell line screen. 13 Schmitz reported the isolation of 2-deoxy-2-aminokealiiquinone ( 2 ), but no bioactivity was reported for this molecule. 14 More recently, Proksch and coworkers reported the isolation of three related naphthimidazole derivatives for which only limited investigations were performed using the brine shrimp toxicity assay.…”

“…In their report of the synthesis of kealiiquinone and isokealiiquinone, the Ohta lab suggest that these molecules act via a unique mechanism, based on the profile these compounds exhibit in a Japanese version of the NCI 60 cancer cell line panel. 13 Likewise, the Looper group has ruled out some of the common pathways for cytotoxicity for kealiinine B ( 4 ). 17 …”

Synthesis, anti-bacterial, anti-asthmatic and anti-diabetic activities of novel N-substituted 2-(4-styrylphenyl)-1H-benzimidazole and N- substituted-3[4-(1H-benzimidazole-2-yl)-phenyl]-acrylic acid tert-butyl ester

“…It is noteworthy to mention here that, in an alternative approach, compound 4a has also been prepared by condensing N-methyl-OPDA dihydrochloride 11 (1a) with 4-bromobenzoic acid (2) in the presence of polyphosphoric acid at 180 o C (Scheme 3). The structure of compound 4a…”

Synthesis and Biological Evaluation of Some Novel [4-(1H-Benzoimidazol-2-yl)-thiazol-2-yl]-benzylidene-amines and N-[4-(1H-Benzoimidazol-2-yl)-thiazol-2-yl]-N'-benzylidene-hydrazines

“…Thiazoles have been incorporated into a wide variety of therapeutically interesting candidates. Benzimidazoles are among the important heterocyclic compounds found in several natural and non-natural products such as Vitamin B 12 , 13 marine alkaloid kealiiquinone, 14 benzimidazole nucleosides. 15 Some of their derivatives are marketed as anti-fungal agents such as Carbendazim, 16 antihelmintic agents such as Mebendazole and thiabendazole 17 and anti-psychotic drug such as Pimozide.…”