Inhibition of focus formation of rat cells by mouse sarcoma virus by damavaricin Fc derivatives.

Sir: Streptovaricins were discovered by SIMINOFF et a!. and have been studied for their potential antitubercular activity1). A chemical study of streptovaricins was made by RINEHART and his colaborators and the relationship between chemical structure and biological activity was explored2). In addition to antibacterial activity, inhibition of reverse transcriptase of RNA tumour virus was observed in streptovaricins3). There is evidence that streptovaricins block the transformation of mouse cells by MOLONEY murine sarcoma-leukemia complex in vitro4). We have been interested in the various kinds of damavaricin C (DvC) derivatives which have been derived from streptovaricin C (SvC) as reported previously5). DvC has a newly formed phenolic hydroxyl group at the C-19 position of the naphthoquinone ring in the molecule, thus enabling us to prepare various derivatives having an alkyl ether linkage at this position. Thus obtained DvC derivatives retain their antibacterial activity, but acquire cell killing activity for mammalian cells, including viral transformed cells and human leukemia cells, in vitro6). Because of their cell killing activity, DvC derivatives have not yet been examined for an intriguing property, that is the inhibition of focus formation by RNA tumour virus. During the course of the preparation of DvC by treatment of SvC with oxygenated concentrated ammonia methanol (1: 2), at the same time was produced "damavaricin Fc" (DvFc, 1) which was found to be an atropisomeric mixture of two compounds, damavaricin Fc (1a) and atropisodamavaricin Fc (1b)7), at a ratio of 1: 3 [C36H43NO12, mp 224~226°C, [x]30D -532° (c 0.11, CHCl3)], the fact having been suggested from the peak intensities of the two phenolic hydroxyl protons in the pmr spectrum (unpublished data). Damavaricin Fc (1a), in which the ansa bridge lies above the aromatic nucleus, has the P helicity as well as natural streptovaricins, whereas atropisodamavaricin Fc (1b), in which the ansa bridge lies below the aromatic nucleus, has the M helicity as shown in Fig. 1. To avoid complicating nomenclature, hereafter we will use DvFc to refer to the atropisomeric mixture of damavaricin Fe. DvFc (1) has a 8-lactone ring between C-7 and C-10 of the ansa bridge which has been proved to produce a change in one of the biological properties. Specifically, the loss of antibacterial activity implies that DvFc has lost its capacity to bind RNA polymerase of prokaryotic cells. The inhibitory activity of the reverse transcriptase, however, is retained. These observations have prompted us to prepare various derivatives of DvFc as well as DvC and to examine their biological activity. DvFc has also an additional phenolic hydroxyl group at the C-19 position of the naphthoquinone ring, enabling the derivatization at this position as shown in Fig. 1. It is of interest that DvFc derivatives are less toxic against animal cells in vitro as compared with DvC derivatives. Therefore we were able to test whether or not any of the derivatives inhibited focus formation by MSV/MLV complex. As shown in Table 1, methyl (2), ethyl (3), and n-pentyl (4) ethers of DvFc were effective, whereas benzyl ether (7) was not effective.