10 制癌活性物質カルチノフィリンの合成研究(口頭発表の部)

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Carzinophilin (1) is an antitumor antibiotic isolated from Streptomyces sahachiroi by Hata et al. in 1954. While the structure of 1 has been revised several times over 30 years, Armstrong et al. reported in 1991 that the ^1H- and ^<13>C-NMR spectra of 1 were superimposable on these of azinomycin B. The latter compound is an antitumor antibiotic bearing a characteristic 1-azabicyclo[3.1.0]hexan-2-ylideneglycine system. It is also disclosed that 1 is one of the strand cross-linking reagents for DNA. These unique history, novel structure, and potent antitumor activity make 1 as well as its related compounds the attractive targets for total synthesis. In the course of our synthetic studies on the model compounds 10 and 23 of 1, we have achieved in developing several methods useful for the synthesis of1: (1) synthesis of 2-methylidene-1-azabicyclo[3.1.0]hexanes 10 and 23 by the aziridine formation under basic conditions; (2) stereoselective construction of the C12, C13-dioxygenated (carzinophilin numbering) pyrrolidine 15 from 2,3,5-tri-O-benzylarabinofuranose (12) by employing the Nicotra's protocol; (3) elaboration of pyrrolidin-2-ylideneglycine 20 by the coupling reaction of thioimidate 15 with 4-phenylazlactone followed by activation of the azlactone ring by introducing an Alloc group into the N9 position (carzinophilin numbering) and subsequent ring opening with amine 19; and (4) construction of β-hydroxyenamide system by deprotection of protected 2-N-acylamino-3-ketoaldehyde. Based on the results accumulated in these model studies, the synthesis of 13-desacetyl-12,13-O-dibenzyl-4-O-methykarzinophilin (2) was achieved. However, subsequent deprotection of the two benzyl groups in 2 to obtain 1 met with failure. In this synthesis, the stoichiometric asymmetric dihydroxyation of allylic alcohol 26 employing (DHQ)_2PHAL, the Sharpless ligand, effected stereoselective introduction of the C18 and C19 oxygen functionalities in 2. The synthesis of 2 constitutes the first example which successfully constructed the full carbon framework involved in 1. It was also revealed that the 1-azabicyclo[3.1.0]hexan-2-ylideneglycine system corresponding to the central core skeleton of 1 is quite reactive, and that 2 and 10 readily alkylate two molecules of thiophenol at the C10 and C21 positions. These results seem to mimic the reactivity of 1 which behaves as an alkylating reagent for DNA. Some carzinophilin congeners synthesized in these studies were found to exhibit potent in vitro cytotoxicity [for example, IC_<50> (P388)=0.0032μg/mL (9) and 0.0021μg/mL (10)] which is almost equal to that of adriamycin. In antitumor activity assay (in vivo), 9 clearly reduced the volume of Sarcoma 180 similarly to mitomycin C while a decrease of body weight was observed for the tested mice.
天然有機化合物討論会の論文
1997-07-20

10 制癌活性物質カルチノフィリンの合成研究(口頭発表の部)

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