Biological properties of streptonigrin derivatives. II. Inhibition of reverse transcriptase activity.

Reverse transcriptase of RNA tumor viruses plays an important role in the integration of the viral genome into host cell DNA1,2) and specific inhibitors of this enzyme might provide chemotherapeutic agents against infection by retro viruses. In the course of our screening for enzyme inhibitors against reverse transcriptase of avian myeloblastosis virus (AMV), the novel substances, retrostatin3) and chromostin4), and limocrocin5) which had been reported as a pigment produced by Streptomyces limosus6), were isolated as specific enzyme inhibitors. In addition, another potent inhibitor coproduced with retrostatin by S. retrostaticus was found to be identical with streptonigrin (1)8), an antitumor antibiotic produced by S. floculus7). Although 1 showed strong antitumor activity8,9), clinical application of 1 was discontinued due to its marked side effects on the gastrointestinal tract and especially on the bone marrow. As the methyl ester of 1 (2) showed some improvement in chemotherapeutic coefficient10,11), modification of the carboxyl group on C2' was carried out12) (Table 1). The antibacterial and cytocidal activities of the derivatives against various bacteria and tumor cells were reported previously13) and the results are summarized in part in Table 2. 1 was also recognized by CHIRIGOS et al. to be an inhibitor of reverse transcriptase14). Several known antibiotics of different groups were tested for their inhibitory activities against AMV reverse transcriptase and 1 showed the most potent activity. In this note, the effects of 1 and its derivatives (2•`11, Table 1) on the activities of