Aureolic acid

Aureolic acid group of antibiotics We have given below an extended summary of the work done with this group of antibiotics, because we have been actively involved in understanding the mode of action of these DNA-binding antibiotics. The summary also illustrates the model example of how different biophysical and biochemical approaches were undertaken to characterize the association of these drugs with chromosomal DNA and the sequential effect of this binding upon the chromatin structure. 

To date, few carbohydrate interactions with DNA have involved interactions within the major groove. Among the classes of compounds known to exhibit DNA binding are enediyne antibiotics, anthracydines, pluramycins, indolocar-bazoles, and aureolic acids. Of the limited number of carbohydrates known for DNA binding, only a select few have displayed major groove contacts. These... 

The present contribution centers on stereoselective syntheses of mono- and in particular oligo-saccharides of the 2-deoxy- and the 2,6-dideoxy series as well as some branched-chain species. These are the principal sugar portions in a large number of important natural glycosides, such as the cardiac glycosides (3), the orthosomy-cins (D, the tetronic acids (5), the aureolic acids (6, see below), and the anthracyclines (2, see below), to name just a few. 

Mithramycin A. (Aureolic acid, Plicamycin) [18378-89-7] M 1085.2, m 180-183°, [a]p° -51° (c 0.3, EtOH). Purified from CHCI3, and is soluble in MeOH, EtOH, Me2CO, EtOAc, Me2SO and H20, and moderately soluble in CHCI3, but is slightly soluble in C Hg and Et20. Fluorescent antitumour agent used in flowcytometry. [Thiem and Meyer TET 37 551 1981 NMR Yu et al. Nature 218 193 7965]. 

Complex glycosylated compounds like macrolides, anthracyclines, aureolic acids, cardiac glycosides, orthosomycines and tetronic acids are of considerable scientific as well as pharmaceutical interest. Obviously, each of them is responsible for certain therapeutic effects with respect to different diseases. Anthracyclines and aureolic acids are applied in cancer chemotherapy, orthosomycines are active as antibiotics against Gram-positive bacteria, and the cardiac glycosides are used in the treatment of cardiac insufficiency. 

In all cases, 2,6-dideoxy sugars of the d- or L-series are common and important parts of these various molecules. In general, the specific therapeutic effect is thought to be caused by the aglycone, and the sugar residue to be responsible mainly for regulating the pharmacokinetics. Thus, parameters like bioavailability, resorption, distribution, or therapeutic width are influenced by the carbohydrate moieties. By modification of the carbohydrate moiety it is, e.g., possible to enhance the efficacy of unspecific aglycones like anthracyclines or aureolic acids, or also to reduce possible side effects. Such as approach is followed in the field of class-I and -II anthracyclines in order to decrease their considerable cardiotoxicity. 

Scheme 19. Structure of members of the aureolic acids family of antitumor drugs.

J. Thiem and M. Gerken, Synthesis of the E-D-C trisaccharide unit of aureolic acid cytostatics, J. Org. Chem., 50 (1985) 954-958 and references therein. 

J. Rohr, C. Mendez, and J. A. Salas, The biosynthesis of aureolic acid group antibiotic, Bioorg. Chem., 27 (1998) 41-54. 

S. O Connor, Aureolic acids Similar antibiotics with different biosynthetic gene clusters, Chem. Biol., 11 (2004) 8-10. 

Members of this group feature tricyclic carbon framework decorated with two oligosaccharide chains. Mithramycin 48 and chromomycin A3 49 are two aureolic acids that have found their use in cancer chemotherapy. These compounds, interacting with Mg2+, bind GC-rich DNA in a nonintercalative way, and sugar chains are indispensable in stabilizing metal-antibiotic complexes. Carbohydrates are... 

Lombo F, Menendez N, Salas JA et al (2006) The aureolic acid family of antitumor compounds structure, mode of action, biosynthesis and novel derivatives. Appl Microbiol Biotechnol 73 1-14... 

Scheme 13. The antitumor antibiotics daunomycin (29 = daunorubicin) and adiiamycin (30 = doxorubicin) are polyketides with an attached deox ugar moiety. Polyketide oligodeoxy-saccharides characterized by one or more deoxysaccharide chains include the anthracyclines arugomycin (31) [73a] and viriplanin (32), the angucyclines landomycin A (see 12 in Scheme 6) and vineomycin A, (33 = P1894B [74]), and the aureolic acid antibiotics mithramycin (34) and UCH9 (35).Also,orthosomydn antibiotics, such as avUamycin A (36) can be considered as polyketide oligodeoxysaccharides...

Antitumor antibiotics are amongst the most important of the cancer chemodierapeutic agents, which include members of the anthracycline, bleomycin, actinomycin, mitomycin and aureolic acid families. Clinically useful agents from these families are the daunomycin-... 

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