Rifamycin biological activities

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

Chemical Properties and Derivatives. There have been thousands of rifamycin derivatives prepared in an attempt to obtain a broader-spectrum antibiotic having good oral absorption. Rifamycins B, O, and S have served as starting materials tor the preparation of numerous classes of derivatives. Several of the semisyntheUc derivatives are more active, have a broader spectrum of biological activity, and are therapeutically more effective than the parent antibiotics. 

Manufacture and Processing. Although fermentation procedures have not been reported, assumptions concerning fermentation media and optimal conditions have been made. The transformation of the biologically inactive rifamycin B to the biologically active rifamycin S is usually accomplished chemically. Several rifamycin B oxidases have been isolated that can enzymatically transform rifamycin B to rifamycin O, which is hydrolyzed in the fermentation medium to rifamycin S. The enzymes from Monocilliim spp. ATC 20621 and Humicold spp. ATCC 20620 are intracellular, whereas... 

Several hundred semisynthetic derivatives have been prepared in an effort to obtain substances with better biological activities (for references see Ref.s)). Particularly positions 3 and 4 of the naphthoquinone ring system (numbering system as proposed by Prelog7 8) have been extensively substituted, since it has been shown that structural changes in these two positions do not critically affect the action of the substance on the target enzyme, the bacterial RNA polymerase (cf. Chapter 3.). They can, however, influence other parameters such as its ability to penetrate into cells, its pharmacokinetic properties and resorption, which are all important for clinical use as an antibiotic. Rifampicin (U.S. rifampin), which is a widely used orally active tuberculostatic agent, is a 3-(4-methyl piperazinyl)-iminomethyl derivative of rifamycin SV, synthesized via the 3-formyl derivative (Fig. 5)10 ... 

Brufani, M., Cerrini, S., Fedeli, W., Vaciago, A. Rifamycins, an insight into biological activity based on structural investigations. J. Mol. Biol. 87, 409 (1974)... 

It is possible that the biological activity of these compounds is due to their interaction with the hybrid RNA-DNA (hy-DNA), single-stranded DNA (ss-DNA), or the DNA-DNA duplex (ds-DNA). It was therefore, interesting to locate the site of action of tilorone in the viral DNA-polymerase system. It is still not clear whether a particular site or target in the DNA-polymerase system, other than the true RNA-dependent reaction, can be correlated with the biological role of the oncornaviruses. The key role of the RNA-directed reaction in in-vivo leukemogenesis using purified enzyme and rifamycin derivatives, has been nicely demonstrated by Wu eta/63. ... 

Polyketide and non-ribosomal peptides produced by bacteria and fungi often attain the conformations that establish biological activity by cychzation constraints introduced by tailoring enzymes. This includes heterocychzation of cysteines, serines and threonines in non-ribosomal peptides. The second cychzation constraint is macrocychzation in polyketides, such as the above-mentioned antibiotic erythromycin and the antitumor epothilones. Regio- and stereospecific macrocychzation usuaUy occurs at the end of the polyketide and non-ribosomal peptide assembly hnes during chain release by thioesterase domains [49]. However, in the case of antibiotics of the ansamycin class, like the antitubercular drug rifamycin, the final... 

If a drug fails to meet present day standards because of low in vitro potency, metabolic, or chemical instability, poor oral absorption or high degree of serum and tissue binding, experience teaches that the prospects for improvement via structural modification are good—if systematic structural modification with retention of biological activity is feasible. The clinically established semisynthetic cephalosporins, rifamycin SV and rifampicin represent precisely this kind of improvement, while laboratory data indicate that it has also been achieved in the coumermycin series as well (96, 97). 

The biological activity of rifamycins has been described [179b]. Rifamycin S (102) results from the oxidation of rifamycin B (98) to rifamycin O (101) and final hydrolysis, and rifamycin SV (103) is given by reduction of rifamycin S (98) to the corresponding hydroquinone. The biological activity is retained by all compounds. Rifampicin, a hydrazone derivative of 3-formyl rifamycin SV, is a widely used orally active tuberculostatic agent [182]. 

Treatment of rifamycin S with formaldehyde and secondary amines yields the 3-aminomethyl derivatives (38, X = CH2NR2) which are not of therapeutic interest (125). However, upon oxidation in acidic medium, the aminomethyl derivatives yield 3-formylrifamycin SV, also known as rifaldehyde [13292-22-3] (38, X = CHO), C3gH47N023. Treatment of rifaldehyde with amines, hydrazines, hydroxylamines, and hydrazides yields a number of derivatives of the 3-fomiyl group having exceUent biological activity (109,126—128). The most therapeuticaUy usehjl derivative is the A/-amino-iV-methylpiperazine hydrazone of rifaldehyde known as rifampin in the United States and rifampicin elsewhere. 

Rtfamycin B is not biologically active but is spontaneously converted in aqueous solution to the active rifamycins O, S, and SV. Rtfamycin SV was chosen for further studies because of its good in vivo activity, low toxicity, and solubility properties. Rifamycin SV is effective against a variety of infections as weU as being active against tuberculosis and leprosy (168). Rifamycin P is the most active of the naturally occurring rifamycins (174). 

Rifamycin B (1), the main fermentation product from cultures of Nocardia mediterranei, displayed very poor biological activity. However on... 

Standing in aqueous solution, it was transformed into the highly biologically active rifamycin S (2). It was this compound which became the most important starting material for the production of semi-synthetic derivatives, including rifampicin (rifampin) (19). 

Rifamycin P (14) was synthesized, and the biological activities of 14 and some derivatives of this compound were reported [66]. According to the report, the derivatives were more active than 14 against the Mycobacterium avium complex and other slowly and rapidly growing non-tuberculous mycobacteria. These organisms frequently cause systemic infections in patients with AIDS, and it was suggested that 2 -(diethylamino)rifamycin P appeared suitable for further investigation. 

Figure 8 Biologically active rifamycins produced by a mutant strain of A.

Subsequently, 25-deacetyl-25-ep/-hydroxy-rifamycin S (8), an example of a rifamycin S epimer, was synthesized with the aim of increasing the intrinsic activity of rifamycin S (2). However, the biological evaluation did not confirm this hypothesis [57]. 23- p/-25-deacetylrifamycin S and 21-ep/-rifamycin S were also prepared [58, 59]. 

Aside from the derivatives described thus far, involving substitution at C-24 and C-25, almost no derivatives of the rifamycins have been found to have superior biological properties. Mono-acyl derivatives of rifamycins B, O, S and SV derived by acylating the phenolic hydroxyl at C-21 showed only very slight changes in antibacterial activities from those of the parent compounds (7 79, 722, J24, 126). On the other hand, acetylation of both the hydroxyl groups on C-7 and C-9 gave an inactive derivative and the C-7 hydroxyl also appears to be required for activity from the results with rifamycin Y (Fig. 1), which is inactive (9, 752). 

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