Anthracyclines

Anthracyclines.—Diels-Alder reactions continue to be a dominant feature in many approaches to the anthracycline antibiotics. The rather unreactive dienophile (194) takes part in such reactions with o-quinodimethanes to provide 

Cycloadditions between naphthoquinones and a 1,2-dimethylidenecyclo-hexane derivative have been used to prepare pentacyclic compounds, e.g. (196), while a related cycloaddition between isobenzofurans and benzoquinone monoacetal derivatives occurs regioselectively leading to anthracycline derivatives such as (197).  

A study of the regioselectivity of Diels-AIder reactions between electron-rich dienes and methoxy- or methyl-substituted quinones has provided data that will be of use in designing syntheses in this area.  

In an extension of earlier work, intermediates for the synthesis of 6-deoxyan-thracyclines have been prepared from naphthoquinones using the novel diene 

An approach to an anthracycline, 8,10-dideoxycarminomycinone (204), which does not involve a Diels-Alder reaction, is by base-induced addition of the nitro-acetal (202) to the anthraquinone (201) resulting in the regioselective formation of (203), which is then converted to (204) using relatively standard methodology. Also of considerable interest in this area are several different total syntheses of aklavinone (205). 

Metallation of anthracyclines releases protons, and using a of 10.0 for the first phenolic group, Martin calculated log values (for M + H2L M(HL) + H , where H2L refers to the neutral ligand) of 11.0 and 7.3 for Fe and Cu , respectively [81]. Metal ion binding must take into account possible formation of hydroxo and polymeric metal complexes at basic pH, and such events make analysis difficult, e.g. a polymeric 1 1 complex CuL forms at high pH [84]. With variation of pH and molar ratio, various complexes are formed between the ligand and these metals. The 2 1 Cu(HL)2 adduct predominates at 5 pH 8 [84, 86], with a reported log P = 16.66 [84], which seems high in comparison to the value of 7.3 reported [81]. Resonance Raman spectroscopy has been particularly useful in analysis of these systems and studies on the Cu(II)— adriamycin—DNA adduct indicated that an intercalated adduct could be formed [87]. 

Palladium(II) and platinum(II) complexes of adriamycin have also been reported recently [90, 91]. 

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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. 

If the enone is part of a decalone system, i.e., a / - and an y-substituent are present, on reaction with lithiated areneacetonitriles in THF the exclusive formation of (Tv-substituted decalones is observedl26. The diastereoselectivity at the exocyclic stereogenic center is, however, poor. Applications in the synthesis of anthracyclines are given in the literature127,12S. 

Dacarbazine is the most active compound used for treating metastatic melanoma. It is also combined with anthracyclines and other cytostatics in the treatment of different sarcomas and Hodgkin s disease. Dacarbazine may cause severe nausea and vomiting. Myelosuppres-sion results in leukopenia and thrombocytopenia. Alopecia and transient abnormalities in renal and hepatic function also occur. 

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). 

Topo II inhibition remains the most per suasive mechanism to explain the antitumor activity of anthracyclines accordingly, limited clinical studies showed that tumor... 

Anthracyclins. Figure 2 Mechanisms of anthracycline-induced apoptosis of tumor cells. ROS, reactive oxygen species topo II, topoisomerase II cyt c, cytochrome c. 

On pharmacodynamic grounds, tumor resistance may be caused by such diverse mechanisms as the mutation or redundancy of topo II, the overexpression and preferred nuclear localization of proteasome a-type subunits (leading to a anomalous degradation of topo II), genetic deletion or loss-of-function mutations of p53, overexpression of ROS-detoxifying enzymes, overexpression of Bcl-2 (leading to a diminished cyt c release), etc. However, none of these factors would universally predict the development of anthracycline-resistance in a given tumor or another. 

Cardiotoxicity may develop at lower than expected cumulative doses of anthracyclines in patients with risk factors like hypertension, preexisting arrhythmias or valvular disease, advanced age, prior irradiation of the mediastinum. 

Anthracyclins. Table 1 Strategies for reducing anthracycline cardiotoxicity... 

Substituting EPI for DOX Lower formation of ROS or secondary alcohol metabolite Same as those of DOX combination with drugs that stimulate anthracycline conversion to secondary alcohol metabolite or diminish the cardiac defenses against ROS... 

Liposomal encapsulation of DOX or DNR Preferred anthracycline delivery to the tumor Breast cancer, ovarian cancer, AIDS-related Kaposi s sarcoma, multiple myeloma (pegylated liposomal DOX). Breast cancer (uncoated liposomal DOX). AIDS-related Kaposi s sarcoma, acute mye-loblastic leukemia, multiple myeloma, non-Hodgkin s lymphomas (uncoated liposomal DNR)... 

Coadministration of dexrazoxane Chelation of iron in the heart, correction of iron dysregulation or mitigation of free radical formation Approved for use in patients who continue DOX above 300 mg/m2 or require another anthracycline after a prior exposure to 300 mg of DOX/m2... 

Substituting slow infusions for 5-10 min boluses Diminished anthracycline Cmax and cardiac uptake At the investigator s discretion (doubtful usefulness in pediatric settings)... 

DOX, as EPI seems to form fewer amounts of ROS and secondary alcohol metabolite, (ii) encapsulation of anthracyclines in uncoated or pegylated liposomes that ensure a good drug delivery to the tumor but not to the heart, (iii) conjugation of anthracyclines with chemical moieties that are selectively recognized by the tumor cells, (iv) coadministration of dexrazoxane, an iron chelator that diminishes the disturbances of iron metabolism and free radical formation in the heart, and (v) administration of anthracyclines by slow infusion rather than 5-10 min bolus (Table 1). Pharmacological interventions with antioxidants have also been considered, but the available clinical studies do not attest to an efficacy of this strategy. 

Minotti G, Menna P, Salvatorelli E et al (2004) Anthracyclines molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56 185-229... 

Lipshultz SE (2006) Exposure to anthracyclines during childhood causes cardiac injury. Semin Oncol 33(3 Suppl 8) S8-S14... 

Cytarabine is used in the chemotherapy of acute myelogenous leukemia, usually in combination with anthracyclines, thioguanine, or both. It is less useful in acute lymphoblastic leukemia and lymphomas and has marginal activity against other tumors. Myelosuppres-sion is a major toxicity, as is severe bone marrow hypoplasia nausea and mucositis may also occur. 

In general, the mechanisms of action are not cell cycle specific, although some members of the class show greatest activity at certain phases of the cell cycle, such as S-phase (anthracyclins, mitoxantrone), Gl- and early S-phases (mitomycin C) and G2- and M-phases (bleomycins). 

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). 

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