Damavaricins

The streptovaricins inhibit the reverse transcriptase of some RNA oncogenic vimses that may be involved in the process of viral transformation (see Antiviral agents). The atropisostreptovaricins again have similar activities to the corresponding natural isomers. The streptovals and streptovarone exhibit gready improved activity against reverse transcriptase relative to the streptovaricins (85), but their in vitro activities were low (86). The damavaricins also inhibit reverse transcriptase (4) as well as tumor cell growth (87). 

The streptovaricins differ from each other mainly in the different extent of oxidation of the ansa bridge20. Very recently, protostreptovaricins I-V21 and damavaricin C and D22 have been isolated and structurally analyzed (Fig. 8). It has been postulated that these compounds are biosynthetic precursors of the streptovaricins21 (cf. Chap. 2.). Damavaricin C can also be generated from streptovaricin C by oxidative hydrolysis2 3 ... 

Investigations of the biosynthesis of the rifamycins, streptovaricins and geldanamycin proved that the ansa chain of the ansamycins is synthesized as proposed by Woodward. The isolation of the precursors rifamycin W, damavaricin C and D and the protostreptovaricins, together with the fact that rifamycin B and tolypomycin Y are cosynthesized by Streptomyces tolypophorus26 make it probable that the rifamycins, streptovaricins and tolypomycin Y have a common progenitor. 

As possible biogenetic precursors of the streptovaricins, damavaricin C and D and the protostreptovaricins I-V have been isolated and characterized (Fig. 8)21,22. Streptovaricin C and D are the precursors of the other streptovaricins22. Figure 13 summarizes the various supposed routes of biosynthesis of the streptovaricins. 

The structure of the ansamycins determines not only their activity on RNA polymerase, but also other important characteristics such as their ability to penetrate into bacteria and their pharmacokinetics and absorption in the host. To cite just a few examples rifamycin B, containing a free carboxylic acid group, has no antibacterial activity, although it inhibits RNA polymerase as strongly as rifampicin. Damavaricin C behaves similarly to rifamycin B, whereas its 6-methyl ether inhibits RNA polymerase to a lesser extent, but has good antibacterial activity23. Rifampicin owes its widespread clinical use to the fact that, in contrast to most other rifamycin derivatives, it is well absorbed when given orally. 

A panoply of protecting groups was enlisted in the synthesis of Damavaricin by Roush and co-workers.242 Here we show 2 steps [Scheme 8.100] towards the end of the synthesis in which a Teoc group and a 2-(trimethylsilyl)ethyl ester were cleaved simultaneously with TAS-F to liberate an amino group and a carboxyl group that served as partners in a macrolactamisation reaction. 

In their synthesis of (-i-)-damavaricin D (Fig. 11-24), Ronsh and co-workers used crotylboronate methodology three times in the assembly of the C(I)-C(13) polypropionate segment 250 [178, 204, 205]. The synthesis of 250 was designed so that chain growth occurs from C(13) to C(l) and such that the mismatched reaction necessary to install the C(10)-C(12) anp. anfl-dipropionate stereotriad could be dealt with early in the synthetic sequence, when the aldehyde substrate had a relatively modest diastereofacial bias (Scheme 11-9). 

Ansamycins - The structures, reactions, physical properties and biosynthe-sis of these antibiotics were reviewed.98 Protostreptovaricins I-IV were described as precursors of the streptovaricins.99 Also, the biosynthetic sequence damavaricin D - SvD -> SvC SvB, SvJ was determined.100 The isolation and structure of actamycin was reported.101 An immunosuppresent effect in mice of rifamycin and streptovaricin a..alogues correlated with toxicity but not with in vitro activity.102 The plasma decline of ethynyl-estradiol after administration of rifamycin was quantified in humans.103... 

A similar strategy has been followed for the preparation of the naphthoquinone nucleus (118) [202], a precursor of awamycin (119), another ansamycin antibiotic isolated from several Streptomyces species and active against Gram-positive bacteria, protozoa and marine tumors in vivo. The compound is also cytotoxic to Hela cells in vitro [203]. The structure of awamycin (119) has been determined by X-ray analysis [204] and it is structurally similar to damavaricin D (120), a degradation product and biosynthetic precursor of streptovaricin D (108). 

Damavaricins C (40) and D (41) are biologically active precursors of the streptovaricins and were isolated from the culture broth of a mutant of Nocardia mediterranei [86]. Damavaricin C (40) could be also obtained by... 

On the other hand, the damavaricins are regarded as precursors of the streptovaricins [86], protorifamycin I (34), which is structurally related to the protostreptovaricins, and to rifamycin W (20) [83]. Washed mycelium of a rifamycin B (1) producing Nocardia mediterranei transformed C-rifamycin W (20) into C-rifamycin B (1). Consequently, it was suggested that rifamycin W (20) was the normal precursor of other rifamycins [75]. 

Damavaricin Fc (133) is an atropisomeric mixture of two isomers produced by the alkaline degradation of streptovaricin C (44) [237]. Although the HIV-specificity is low as compared to that of HIV-selective inhibitors, including AZT (azidothymizine zidovudine), n-pentyldamavaricin Fc (134) showed inhibitory activity on HIV replication... 

Recently, Sasaki, e/ al. (112a), have prepared a series of 19-O-alkyl derivatives (14) of damavaricin C (Fig. 5) by reaction of damavaricin C... 

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