Antibiotics anthracyclines

Category Antibiotic, anthracycline Half-life 1.3-9 hours... 

Synonyms daunomycin DNR rubidomycin Trade names Cerubidine Daunoxome Indications Acute leukemias Category Antibiotic, anthracycline Half-life 14-20 hours... 

Synonyms 4-demethoxydaunorubicin 4-DMDR Trade names Idamycin (Pfizer) Zavedos Indications Acute myeloid leukemia Category Antibiotic, anthracycline Half-life 14-35 hours (oral)... 

Category Alkylating agent Antibiotic, anthracycline Half-life 23-78 minutes... 

Category Antibiotic, anthracycline Antineoplastic Half-life median terminal 75 hours Clinically important, potentially hazardous interactions with aldesleukin... 

Cytotoxic antibiotics Anthracyclines Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mito)Gintrone... 

Dihydioxytetiahydionapthacenedione derivatives, used as intermediates for the anthracycline antibiotics have been prepared by Friedel-Crafts reaction of tetralin derivatives with orthophthaloyl chlotide [88-95-9J in high yields (93). 

As exemplified in the present procedure, the reaction has been optimized and extended in scope it affords functionalized benzocyclobutenes as well as substituted isoquinolines in high yields. Benzocyclobutenes have been used as intermediates in the synthesis of many naturally occurring alkaloids, - steroids,polycyclic terpenoids,and anthracycline antibiotics. The traditional routes leading to the preparation of benzocyclobutenes have been... 

Synthetic studies on heteroanthracyclines, heteroanalogs of anthracycline antitumor antibiotics 97H(46)705. 

Similar results are obtained with the /htetralone derivatives 12, which are useful building blocks in the synthesis of anthracycline antibiotics. Furthermore, the usefulness of the diastereoselec-tive addition to ot-oxo acetals was impressively demonstrated in the synthesis of (-)-7-deoxy-daunomycinone, which uses the completely stereoselective addition of (trimethylsi-lylethynyl)magnesium chloride to the /i-tetraione acetal 12 (R =OMOM R2 = Br) as the key reaction31. 

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). 

A similar synthetic strategy was applied in the synthesis of menogaril 83, another important anthracycline antitumour antibiotic, and to the synthesis of the tricyclic core of olivin 87, the aglycon of the antitumour antibiotic olivomycin [61,62]. In both cases a tandem benzannulation/Friedel-Crafts cyclisation sequence yielded the tetracyclic and tricyclic carbon core, respectively (Scheme 42). 

Earlier model studies designed to explore the action of anthracycline antitumor antibiotics first noted a lability of QM adducts. QM1 was generated by oxidation of its precursor (QMP1) with silver oxide and shown to undergo reversible reaction... 

Angle, S. R. Rainer, J. D. Woytowicz, C. Synthesis and chemistry of quinone methide models for the anthracycline antitumor antibiotic. J. Org. Chem. 1997, 62, 5884-5892. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

Heparin has been reported to complex with a variety of basic species, including biogenic amines and drugs for reviews, see Refs. 10 and 391. For its possible relevance to the pharmacological properties of heparin and complexed species, mention is made here of complexes with histamine392,393 and anthracycline antibiotics.394 C.d. studies on the interaction of basic homopolypeptides with heparin and other glycosaminogly-cans have shown that heparin is able to induce an ordered, helical conformation in the polypeptide.395 397 Similar, and even more dramatic, effects were observed with mixed basic polypeptides, presumed to represent better models for the biologically relevant interactions with plasma proteins.368... 

The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). 

Daunorubicin -anthracycline antitumor antibiotic DNA intercalating agent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -vesicant if extravasated —cardiotoxicity (550 mg/M2) -Liposomal daunorubicin there is significantly less bone marrow suppression, nausea and vomiting, stomatitis, and cardiotoxicity... 

---