Anthracyclines isolation

Anthracyclines isolated from stieptomyces show a 2,3,6-trideoxy-3-amino-L-/yxo-configurated sugar oc-attached to the aglycon. Therefore, the first interest centered on the synthesis of aminodeoxy sugars in the l-lyxo series, e.g., daunosamine [46-50]. Several new glycosides were prepared [51] in order to evaluate structure-activity relationships. 

As the benzylic hydroxy group in position 7 is removed easily, and further hydroxylation and/or oxidation in other positions can occiu, at least 15 D-ring modifications (5-19) can be distinguished (Fig. 1), which gave rise to nearly 500 natmal anthracyclines isolated to date. However, as the nitrogen-free sugar residues are split off easily already under weakly acidic conditions during the isolation process, not aU of them may be truly natoal. 

The anthracyclines represent a broad family of antibiotics that exhibit activity in numerous tumors. The first anthracyclines, doxorubicin (DOX) and dau-notubicin (DNR), were isolated from Streptomyces var peucetius they were shown to be composed of a tetracyclic ring system with adjacent quinone-hydro-quinone moieties, a short side chain with a carbonyl group, and an aminosugar bound to the C-7 of the four-ring system. DOX and DNR only differed in the side chain terminus (-CH2OH in DOX vs. -CH3 in DNR). Second generation anthracyclines, like epitubicin (EPI) and idatubicin (IDA), were obtained after minor chemical modifications of DOX or DNR, respectively (Fig- 1). 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

Although miany anthracycline euitibotics have been Isolated since the discovery and structvire determination of early anthracyclines in the decade of 1950, the screening for red- or yellow-pigment antitumor euitlblotlcs still leads to the finding of new... 

It is a cytotoxic anthracycline antibiotic isolated from Streptomyces pneuceticus. It is... 

Muindi JRF, Sinha BK, Gianni L, Myers CE (1984) Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. FEBS Lett 172 226-230 Mujica V, Nitzan A, Mao Y, Davis W, Kemp M, Roitberg A, Ratner MA (1999) Electron transfer in molecules and molecular wires geometry dependence, coherent transfer, and control. In Jortner J, Bixon M (eds) Electron transfer From isolated molecules to biomolecules. Part Two, Advances in Chemical Physics Series, Vol 107. Wiley, New York, pp 403-428 Mullenger L, Ormerod MG (1969) The radiosensitization of Micrococcus sodonensis by N-ethyl ma-leimide. Int J Radiat Biol 15 259-269... 

The anthracyclines are aminoglycosidic derivatives of tetracyclic compounds that contain an anthraquinone chromophore. Originally, dauno-mycin and adriamycin, its hydroxy analogue, were isolated from cultures of Streptomyces peucetiusd The main target of these drugs appears to be DNA, most likely by formation of an intercalation complex. The drugs also affect topoisomerase II, an enzyme which interacts with the DNA that has been modified by intercalation. ... 

Himalomycin A 263and B 264, two new anthracycline antibiotics, were isolated from the culture broth of the marine Streptomyces sp/ isolate B6921, and both exhibited strong antibacterial activity but no anti-algal activity against the tested micro-algae. 

Mithramycin ) is an (anthracycline group) antibiotic isolated from Streptomyces sp. It has cytotoxic properties and clinically may be used as an oral and parenteral anticancer agent, particularly for testicular cancer, plomestane (inn, usan] (MDL 18962) is a steroid with AROMATASE inhibitor (oestrogen synthetase inhibitor) activity. It is under investigation for some anticancer applications, e.g. for treatment of breast cancer. 

Serving as the key step for an anthracycline synthesis, addition of the epoxytetrone dienophile (452) to diene (451) gave a mixture of adducts (453) and (454) in ratios of 4 1 (CsHe, 5 C) up to 7 1 (acetone, 5 °C) (Scheme 107). The major isomer (453), isolated by crystallization (74% yield from 451), was then converted into (+)-4-deme oxydaunomycinone (641) (Scheme 142) via glycoside cleavage with 0.5N... 

Daunorubicin (1) and doxorubicin (2), the prototypes of anthracycline antibiotics, were isolated from various Streptomyces strains and early introduced into the clinic for cancer chemotherapy. Despite considerable... 

Yoshimoto, A., Matsuzawa, Y., Oki, T., Takeuchi, T., and Umezawa, H. (1981) New anthracycline metabolites from mutant strains of Streptomyces galilaeus MA144-M1. I. Isolation and characterization of various blocked mutants. J. Antibiot. 34, 951—958. 

Daunomycin (310) and doxorubicin (311) are anthracycline glycosides, isolated from Streptomyces peucetius [18]. These compounds are used in cancer chemotherapy due to their ability to bind DNA. Both compounds inhibit RT and production of murine leukemia virus [18]. 

Boucek and colleagues (1993) examined the effect of doxorubicin on the SR function in isolated intact and permeabilized rabbit cardiac tissue. In the latter study, it was noted that doxorubicin (10-120 pM) was able to cause contractions in a similar manner to caffeine by releasing Ca " from SR and seemed to have no impact on the function of the myofilaments. Evidence has also been presented to indicate that anthracyclines (daunorubicin 10-300 pM) can perturb Ca " handling by the SR in a free radical-independent manner in rabbit cardiac tissue however, the quinone moiety of the molecule appears to be a prerequisite for such an action (Shadle et al. 2000). It is possible that alterations in Ca " release from the SR by anthracyclines could contribute to the inotropic and lusitropic dysfunction observed in cardiac tissue with this class of drugs. 

Avery powerful oxidant, TMDO epoxidizes alkenes up to 10 times faster than the widely used dimethyldioxirane (DMDO), which in turn reacts 10 times faster than a peracid such as perbenzoic acid. The electron-deficient enone C=C bond in anthracycline 59 resists attack by DMDO, but reacts with TMDO to give epoxide 60 in 95% isolated yield. " Naphthalene (61) is transformed by TMDO into dioxide 62... 

The anthracycline antibiotics form a group of red aromatic microbial polyke-tides. Most have been isolated from bacteria of the order Streptomycetales, about one quarter was found in so-called rare actinomycetes [1-3]. Their diversity is based on structural differences in the aglycone and on a wide array of attached sugar residues. 

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