Shohei Tani

Antitumor agents—CLXVII. Synthesis and structure-activity correlations of the cytotoxic anthraquinone 1,4-bis-(2,3-epoxypropylamino)-9,10-anthracenedione, and of related compounds

1,4-Bis-(2,3-epoxypropylamino)-9,10-anthracenedione (3) was synthesized in this laboratory and was found to be a potent antitumor agent. Derivatives of this compound containing anthraquinone, naphthoquinone, and quinone skeletons were also prepared and evaluated for in vitro cytotoxic activity in several cell lines. These molecules were designed as bifunctional antitumor agents with the potential to act as (1) intercalating agents due to their planar backbones, and (2) alkylating agents due to the presence of alkylating moieties in their side chains. Compounds with an anthraquinone skeleton and propylamino side chains containing epoxides or halohydrins as the alkylating species showed greater activity than similar compounds with naphthoquinone or quinone skeletons. Compounds without these alkylating functionalities (e.g., with alkene or amino groups) were generally inactive. Hydroxy substitution on the planar skeleton in conjunction with alkylating side chains gave compounds with the most potent cytotoxic activity. The position of the hydroxy groups and side chains could be varied without substantially affecting activity. Activity was retained when an epoxypropyloxy side chain was substituted for the epoxypropylamino side chain in the parent compound.

Total synthesis of the alkaloids rhoeadine and alpinigenine

Rhoeadine (I) and alpinigenine (III) have been synthesised by a route involving the skeletal rearrangement of 1,2,3,4-tetrahydro-2-methyl-4′,5′,6,7-bismethylenedioxyisoquinoline-1-spiro-2′-indan-1′-ol (VII) into 5,6,7,7a-tetrahydro-2,3:10,11-bismethylenedioxy-7-methylbenz[d]indeno[1,2-b]azepine (VIII) by treatment with methanesulphonyl chloride and triethylamine. Oxidation of the indenoazepine (VIII) with osmium tetroxide gave 5,6,7,7a,12,12a-hexahydro-2,3:10,11-bismethylenedioxy-7-methylbenz[d]indeno[1,2-b]azepine-12,12a-diol (X), which was converted into (±)-rhoeagenine diol (XII) by treatment with sodium periodate followed by sodium borohydride. From 1,2,3,4-tetrahydro-2-methyl-4′,5′,6,7-tetramethoxy-1-spiro-2′-indan-1′-ol (XVII), (±)-alpinigenine diol (XXI) was synthesised. Oxidation of the diol (XXI) with manganese dioxide furnished (±)-alpinigenine (III).

Total synthesis of the alkaloid rhoeadine

Rhoeadine, an alkaloid from a variety of species of the genus Papaver, Papaveraceae, has been synthesised.