Naphthalenoid ansamycin antibiotics

Naphthalenoid Ansamycin Antibiotics with Cj Ansa Chains... 

Naphthalenoid ansamycins with C i ansa chains can be further classified into three groups, namely, the rifamycin group, the proto-streptovaricin group and the streptovarlcin group, based on the difference of their chromophores. Awamycin [34,35] is an example of the naphthalenoid ansamycin antibiotics and belongs to the protostrepto-varicin group with a sulphur atom in the molecule. 

Rifamycin W (20), a naphthalenoid ansamycin antibiotic with a Cjy ansa chain was isolated from a mutant strain of Nocardia mediterranei. Unlike... 

Awamycin (26) was isolated from the cultured broth of Streptomyces sp. 80-217 [34,35] as an antitumor antibiotic. Awamycin (26) is one of the naphthalenoid ansamycin antibiotics containing a sulphur atom in the molecule at the C-3 position of the chromophore, and its structure is closely related to rifamycin W (20). 

Other examples of naphthalenoid ansamycin antibiotics with a sulphur atom are CP-50833 (28), obtained from the culture broth of Streptomyces nigellus subsp. africanus ATCC31496 [80], and the semisynthetic antibiotics derived from rifamycin S (2), i.e., 3-thiomethylrifamycin S and 3-thiomethylrifamycin SV (4) which were obtained by repeatedly treating rifamycin S with MeSH [81]. The double bond at the C4-C5 position of 28... 

It was also found that when [r- C]-AHBA (118) was administered to a streptovaricin C (44) producing culture, C-21 (the quinone methide carbonyl at 188.3 ppm) of 44 was specifically labelled (Fig. 5) [93], and the existence of 118 itself in the fermentation broth was reported [186,187]. It was also reported that the biosynthesis of the naphthalenoid ansamycin antibiotic actamycin (69) was markedly increased by the... 

Thus, naphthalenoid ansamycin antibiotics with a Cjy ansa moiety, naphthalenoid ansamycin antibiotics with a C23 ansa moiety, followed by the naphthalenoid ansamycin antibiotics with a C9 ansa moiety will be discussed. 

Naphthalenoid Ansamycin Antibiotics with a C 17 Ansa Moiety... 

If the carbons derived from a propionate unit are indicated as P and carbons derived from an acetate unit are indicated as A, the common biosynthetic building units and their sequence in the naphthalenoid ansamycin antibiotics with a Cn ansa moiety (and a part of the chromophore) are presented as P-A-P-P-P-P-P-P-A-P (Fig. 8). 

As examples of other naphthalenoid ansamycin antibiotics, rubradirin (70) and protorubradirin (71) were isolated from the fermentation broth of Streptomyces achromogenes var. rubradiris [109-114,117]. As indicated previously, protorubradirin (71) is the C-nitroso-analogue of 70, and it seems that 71 is the true secondary metabolite produced by S. achromogenes var. rubradiris. Thus, rubradirin (70), reported earlier, is the photo-oxidation product of protorubradirin (71). The ansa moiety of these compounds possesses a C9 chain, instead of a C or a C23 chain. 

The ansa moiety and part of the chromophoric unit of 70 and 71 consist of nine carbons, and the biosynthetic building units of this part, and their sequence are considered to be P-A-P-P-A-P (Fig. 12). Through a comparison of the ansa moiety of this compound with that of the ansa chains of the naphthalenoid ansamycin antibiotics with a Cp ansa chain (P-A-P-P-P-P-P-P-A-P), it seems that the first two to four biosynthetic units (P-A, P-A-P or P-A-P-P), and the last two to four units (A-P, P-A-P or P-P-A-P), are involved in the formation of the antibiotic, whereas the four biosynthetic units (P-P-P-P) in the center of the sequence are missing. 

It appears that the starting three units in the biosynthetic process (P-A-P) are universal to the naphthalenoid ansamycin antibiotics which possess an ansa moiety consisting of the Cp and C23 ansa chains, and also the C9 chains and even an early intermediate such as 72. 

Among the naphthalenoid ansamycin antibiotics, the streptovaricin complex was reported to inhibit focus formation by MSV (MLV murine leukaemia virions) and to inhibit the splenomegaly-induced Rauscher leukaemia by virus selectively [226,227]. On the other hand, awamycin (26) [34,35] was shown to possess activity against HeLa S3 cells and antitumor activity against experimental murine tumors. Antitumor activity tests on streptovaricin C (44) were conducted [226,227]. 

Among the naphthalenoid and benzenoid ansamycin antibiotics, some ansamycins possess a 1,4-naphthoquinone or a 1,4-quinone unit as a chromophore, and others possess a 1,4-hydroxynaphthalene or a 1,4-hydroquinone units (or their derivatives) as a chromophore. Since these two types of chromphore are in most cases reversible, it is not appropriate to classify by the difference of the oxidation stage of the chromophore. In this review, benzenoid and naphthalenoid ansamycins are further divided according to the difference of the length of their ansa chains. Thus, naphthalenoid ansamycins are divided into 3 groups, i.e., naphthalenoid ansamycins with C17 ansa chains, naphthalenoid ansamycins with C23 ansa chains, and naphthalenoid ansamycins with C9 ansa chains. The benzenoid ansamycins are divided into 2 groups, i.e., benzenoid ansamycins with C15 ansa chains and benzenoid ansamycins with Ci7 ansa chains. The relationships between, and the antibiotics within these groups are indicated in Scheme 2. 

Naphthalenoid ansamycins with C9 ansa chains consist of two compounds, rubradirin and protorubradirin. These antibiotics possess a C9 ansa chain moiety and a C-nitroso-sugar or a C-nitro-sugar in the structure, respectively. As will be described below, rubradirin appears to be a photooxidation product of protorubradirin. 

Funayama et al. suggested the possibility of the application of this model for the determination of the stereochemistry and biosynthetic pathway of the known ansamycin antibiotics [202]. According to this proposal, it is important to consider that, of the C17 ansa chain naphthalenoid ansamycins, the absolute configurations of rifamycins S (2) [16, 194] and B (1) [33, 42], and streptovaricin C (44) [94], were established by X-ray analysis. The rigorous biosynthetic studies of rifamycin S (2) indicated P-A-P-P-P-P-P-P-A-P as the biosynthetic sequence of the ansa chain and a part of the naphthalenoid moiety [197]. 

About 70 naphthalenoid ansamycins have been reported until now. In most of these ansamycins, the ansa part is composed of 17 carbons, like the rifa-mycins, and in other instances the ansa moiety is composed of 23 carbons, like the naphthomycins [1]. Models for the biosynthesis and stereochemistry (Celmer s model), as applied to macrolide antibiotics [2], have been developed for these two types of ansamycins [3]. 

AnsamacroHdes. Antibiotics in the ansamacrolide family are also referred to as ansamycins. They are benzenoid or naphthalenoid aromatic compounds in which nonadjacent positions are bridged by an aliphatic chain to form a cyclic structure One of the aliphatic-aromatic junctions is always an amide bond, Rifampin is a semisynthetically derived member of this family and has clinical importance, it has selective antibacterial activity and inhibits RNA polymerase. 

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