Donald E. Nettleton

Isolation and structure of rebeccamycin ― a new antitumor antibiotic from Nocardia aerocoligenes

The isolation and structure elucidation of rebeccamycin 1, a new antitumor agent from , is described. The NMR spectra of 1 and its peracetate 2 are discussed.

Antitumor agents from the bohemic acid complex. 4. Structures of rudolphomycin, mimimycin, collinemycin, and alcindoromycin

The structures of four new anthracyclines (rudolphomycin (1 1) , collinemycin (12), mimimycin (13), alcindoromycin (14)) have been determined by a combination of chemical degradations and spectral interpretation. The use of 13C NMR spectroscopy has been extensive and assignments to the 13C NMR spectra of these compounds have been made. The marked clinical effectiveness of the antitumor antibiotics adriamycin and daunomycin (1 and 2) (Figure 1) has led to an intensive search for new members of this interesting class of compounds.* This search has resulted in the isolation and characterization of a number of new agents: carminomycin3 (3), cinerubins A and B,4 aclacinomycins A and B,5 the rhodirubins,6 b a ~ m y c i n s , ~ nogalamycin,* and marcellomycin and musettamycing from our own laboratories. Recent work from these laboratories has shown that some of the t-pyrromycinone-based anthracyclines as well as aclacinomycin A (10) (based on 1-deoxypyrromycinone) possess a mode of action which distinguishes them from the adriamycin class of anthracyclines.I0 In the preceding paper’’ of this series we have described the isolation of several new members of this unique class of agents. It is the purpose of this paper to give the structure determination of these compounds as well as to provide further details of the structure elucidations of musettamycin and m a r c e l l ~ m y c i n . ~ The structures are illustrated i n Table I. Structures of Musettamycin (7) and Marcellomycin (8) The structural assignments to musettamycin and marcellomycin which were made earlier were based on a number of lines of evidence as outlined below. Both compounds were reddish-orange solids having elemental formulas C36H45N014 and C42H55N017, respectively. Total acid hydrolysis of either 7 or 8 led to the isolation of 6-pyrromycinone (4) in addition to trace amounts of 17-pyrromycinone (21) (Scheme I) which possessed identical properties with those reported by Brockmann and Lenk for compounds 4 and 21.12 Mild alcoholysis of 7 or 8 gave t-pyrromycin ( 6 ) , the N M R spectrum of which was identical with that reported for the partial hydrolysis product of cinerubin A (9).4 Thus the aglycone as well as the first sugar for both these products was established. From the nonanthracycline portion of the methanolysis experiments the methyl glycoside of 2-deoxy-~-fucose (22) as a mixture of a and p anomers was obtained with the a anomer predominating. The [ H N M R spectrum of musettamycin exhibited three signals in the anomeric region at 6 5.50,5.24, and 5.00 as broad singlets which have been assigned to the C-1’, C-7, and C-1” protons, respectively, by comparing the line positions for a series of related compounds (Table 11). The small coupling constants indicated that the protons in question were equatorial rather than axial. Thus the structure of musettamycin was

Structure-activity relationships in chemically modified coumermycin

ABSTRACT Coumermycin A1 was early recognized as a potentially useful antibiotic because of its very good spectrum of activity against gram-positive organisms (particularly against staphylococci), in addition to appreciable activity against a variety of gram-negative bacteria. However, in spite of its excellent in vitro activity, the insoluble character of coumermycin A1 made parenteral administration unsatisfactory. Poor oral absorption was also observed. Because of these shortcomings, coumermycin A1 was chemically modified either by an acyl interchange reaction or by direct condensation with 3amino-4-hydroxy-8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl)noviosyloxy] coumarin (PNC-amine), which was produced by chemical degradation of coumermycin A1. A large number of semisynthetic derivatives were so prepared, and interesting structure-activity patterns will be discussed. A number of the new semisynthetic derivatives possessed markedly improved oral absorbability in mice. This improvement in some cases was >25 fold over the parent compound and more than compensated for the lower antibacterial potency possessed by most of the derivatives. Further, some of the more active compounds showed a significant improvement in the in vivo antistaphylococcal therapeutic effect, and marked improvement in oral efficacy in experimental D. pneumoniae and Streptococcus pyogenes mouse infections. Compounds demonstrating the broadest spectrum of antibacterial activity were members of the 3-substituted-4-hydroxybenzoic acid class. Among the aliphatic derivatives, 3-isobutyramido-4-hydroxy-8-methyl-7{3-O-(5-methyl-2-pyrrolylcarbonyl)noviosyloxy]coumarin (designated as BLC43) was by far the most interesting. Characterized by its overall trend toward improved in vitro activity, and its significant in vivo activity, this compound was selected for extensive pre-clinical evaluation. The results of these investigations will be discussed.