Ansamacrolides

Abstract

The ansamacrolides or ansamycins are a family of antibiotics characterized by an aliphatic ansa‐bridge that connects two nonadjacent positions of an the aromatic nucleus. Ansamacrolides can be divided into two groups. One contains a naphthoquinoid nucleus and includes the streptovaricins, the rifamycins, tolypomycin, the halomycins, the naphthomycins, actamycin, the diastovaricins, kanglemycin, awamycin, and ansathiazin. The other contains a benzoquinoid nucleus and includes geldanamycin, the maytansinoids, the herbimycins, the macbecins, the mycotrienins, the trienomycins, the ansatrienins, and the maytansinoids and maytansides. Among the naphthoquinoids, the streptovaricins are produced by Streptomyces Spectablis n. sp. and all except streptovaricin D react with one mole of sodium periodate to yield the corresponding streptovals. The streptovaricins undergo thermal isomerization to the corresponding atropisostreptovaricins. The rifamycins were first isolated from a broth of Nocardia mediterranei. Only rifamycin B can be isolated easily as a stable crystalline compound. The structures of the rifamycins were arrived at by chemical degradation studies and confirmed by x‐ray crystallography. There have been thousands of rifamycin derivatives prepared in an attempt to obtain a broader‐spectrum antibiotic having good oral absorption. Several of the semisynthetic derivatives are therapeutically more effective than the parent antibiotics. Tolypomycin Y shows strong antibacterial activity against gram‐positive bacteria and Neisseria gonorrheae. The halomycins, a group of four antibiotics produced by Micromonospora halophytica, are active against gram‐positive bacteria. The halomycin complex exhibited high activity against bacterial strains resistant to penicillin G. The naphthomycins are a group of closely related antibiotics differing in the substituent at C‐2 and C‐30, and in the geometry about the C‐4 and C‐6 double bonds. The naphthoquinomycins, diastovaricins, and actamycin are all closely related to the naphthomycins. Kanglemycin is isolated from the fermentation broth filtrate of Nocardia mediterranei var. kanglensis and its structure determined by x‐ray crystallographic studies. The antibiotic is active against gram‐positive bacteria. Awaymycin and ansathiazin are produced by Streptomyces sp. No. 80‐217. Both are active against gram‐positive bacteria; awamycin is reported to have antitumor activity. Among the benzoquinoids, geldanamycin is isolated from the filtered beer of Streptomyces hygroscopicus var. geldanus var. nova. Unlike the naphthoquinoid ansamacrolides, geldanamycin has little antibacterial activity, being primarily active against protozoa and fungi, especially Tetrahymena pyriformis and Crithidia fasciculata. Geldanamycin also has herbicidal activity. Herbimycins A, B, and C along with some derivatives, are isolated from the fermentation broth of Streptomyces hygroscopicus AM‐3672. The herbimycins possess strong herbicidal activity and exhibit some antitumor and antiviral activity. Several derivatives of herbimycin A possess greater antitumor activity than the parent. Macbecin I and II are isolated from the fermentation broth of Nocardia sp. C‐14919. The macbecins are active against gram‐positive bacteria, fungi, and protozoa and exhibit in vitro antitumor activity against murine leukemia P 388 and melanoma B 16. The mycotrienins are produced by Streptomyces rishiriensis T‐23. They possess no antibacterial activity but are active against fungi and yeasts and exhibit weak antitumor activity. Trienomycins are isolated from Streptomyces sp. 83‐16. The trienomycins have no antimicrobial activity but have good antitumor activity. Trienomycin A is the most active. The ansatrienins are produced by Streptomyces collinus Tü 1982. The ansatrienins are active against fungi. The maytansinoids were the first ansamacrolides to be found in plants. The term maytansinoids refers to those ansamacrolides related to maytansine, whereas the term maytansides refers to maytansinoids lacking the ester side chain at C‐3 as well as the corresponding elimination products. Maytansine, colubrinol and colubrinol acetate, and normaytansine are maytansinoids. Another large group of maytansinoids are produced by the microorganism Nocardia sp. C‐25003 (N‐1) and are designated ansamitocins. Several semisynthetic maytansinoids have been prepared by acylating the C‐3 hydroxyl group of maytansinol. Some of these derivatives have antiprotozoal and antitumor activity similar to maytansine and ansamitocin P‐3. The maytansinoids possess antitumor activity, particularly against P 388 lymphocytic leukemia, B 16 melanocarcinoma, and Lewis lung carcinoma. A number of semisynthetic esters of maytansinol have been prepared and exhibit good antileukemic activity. The maytansides lack antitumor activity. Besides having antitumor activity, the ansamitocins have antiprotozoal and antifungal activity. The mode of action of the naphthoquinoid ansamacrolides is one whereby they inhibit bacterial growth by inhibiting RNA synthesis. This is accomplished by their forming a tight complex with DNA‐dependent RNA polymerase. The ansamacrolides form no such complex with mammalian RNA polymerase and thus have low mammalian toxicity. The antiviral activity of the ansamacrolides results from the inhibition of the assembly of the virus particles. The antitumor activity of geldanamycin and its derivatives appears to result from inhibition of DNA synthesis. The antitumor activity of the maytansinoids also appears to result from the inhibition of DNA synthesis. Rifampicin, the only commercially available ansamacrolide, is manufactured by Merrell Dow under the trade name Rifadin, and by CIBA under the trade name Rimactane. Rifampicin is also supplied in combination with isoniazid or pyrazinamide.