Ansamycins benzenoid

As described in the introduction, macrocyclic lactams can be classified as ansamycins and other compounds, and the ansamycins consist of an ansa-chain and a chromophore-containing moiety. The ansamycins are typically divided into two groups, i.e., the naphthalenoid ansamycins and the benzenoid ansamycins, according to their chromophores. 

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. 

Benzenoid Ansamycin Antibiotics with Cis Ansa Chains... 

Maytansine (73) was the first example of a benzenoid ansamycin with a Ci5 ansa chain. Maytansine was isolated originally from the higher plant Maytenus ovatus (Celastraceae). Subsequently, antibiotics related to maytansine were isolated from the fermentation broth of Nocardia sp. as well as other higher plants. Compounds belonging to the maytansinoid group possess a 1,3,5-trisubstituted benzene moiety as a chromophore. 

Among other benzenoid ansamycins with C15 ansa chains, geldanamycin, the macbecins and the herbimycins are classified in this category. These compounds possess a 1,4-quinone or a 1,4-hydroquinone moiety as a chromophore. 

Trienomycins A (111), B (112), C (113), D (114), E (115) and F (116), which possess cytotoxic and anti-tumor activity, were isolated from the fermentation broth of Streptomyces sp. 83-16 and their structures determined [169-172]. Unlike most of the other benzenoid ansamycin... 

The biosynthetic precursor of the chromophoric moiety was studied vigorously by several research groups. As a result it was established that during the biosynthesis of the ansamycins, a W-C7N unit (Fig. 4) was incorporated into the chromophores of both the benzenoid ansamycins, such as geldanamycin (85) [177, 178] and ansamitocin P-3 (81) [179], and also the naphthalenoid ansamycins, such as the rifamycins [22,180-182] and actamycin (69) [183]. 

Regarding the biosynthesis of the benzenoid ansamycin antibiotic ansamitocin P-3 (81), it was reported that the C-NMR signal of the benzyl carbon of ansamitocin was enhanced by feeding [1 -13C]-AHBA (118) [179]. 

As described in the introduction to this chapter, the chromophoric moiety of the benzenoid ansamycin antibiotics are biosynthetically derived from a "w-CyN unit" via the shikimate pathway, and the ansa chain moieties are derived from a "polyketide" chain via the condensation of acetate or glycolate (C2 unit) and propionate (C3 unit) moieties. 

Because the biosynthesis of the w-CyN unit was discussed previously, only the biosynthesis of the ansa moiety of the benzenoid ansamycin antibiotics with a C15 ansa moiety and the benzenoid ansamycin antibiotics with a C17 ansa moiety will be discussed here. 

Benzenoid Ansamycin Antibiotics with Cjs Ansa Moiety... 

Funayama et al. reported the possibility for the application of their model to the stereochemistry and biosynthesis of the Imown benzenoid ansamycin antibiotics [202]. According to the analysis, herbimycin A (86) seemed to possess the same biosynthetic building units as those of... 

Maytansine is an alkaloid first isolated from Maytems ovatus (Celastraceae) [1], and maytansine is classified as a benzenoid ansamycin. The structure, including absolute stereochemistry, was determined by x-ray crystallography of its 3-bromopropyl ether derivative [2], and a total synthesis has been achieved [3]. 

Other benzenoid ansamycins, geldanamycin [9,10] and herbimycin [11,12], are also known. Herbimycin was first isolated as a herbicidal antibiotic and was subsequently found to normalize tumor cells [13]. 

The origin of the chromophore moiety of these benzenoid ansamycins is the m-CyN unit, and no unit(s) derived from the polyketide pathway are concerned in the biosynthesis of the chromophore, unlike the naphthale-noid ansamycins. Therefore, in the benzenoid ansamycins, it can be more clearly seen how the m-CyN unit is incorporated into the chromophore. This matter will be discussed in Section 13.4. 

In the benzenoid ansamycin antibiotics, the ansa chains of herbimycin A, geldanamycin, and macbecin I [7] are similar. It was shown that the ansa moiety of geldanamycin consisted of four molecules of propionic acid (P), two... 

Fig. 2. Structures of naturally occurring benzoquinonoid and benzenoid ansamycins...

The basic ansamycin structure consisting of a naphthoquinone or naphthohydroquinone ring and its spanning chain with its various substituents is required for antibacterial activity and E. coli RNA polymerase inhibition. Neither the rifamycin aromatic chromophore alone (18, Fig. 12) 126) nor streptovarone (Fig. 6) 104) has much activity, nor does the aliphatic ansa chain of rifamycin by itself (19, Fig. 12) or varicinal A (Fig. 6) 109). Cleavage of the ansa chain, as in the streptovals (Fig. 6) or rifarubin S (Fig. 20) (5), also leads to loss of activity. Benzoquinonoid and benzenoid ansamycins are not potent antibacterial agents. 

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