Of anthracyclines

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. 

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. 

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. 

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... 

Further investigation of the original QM1 also demonstrated that simple thiols could react reversibly although regeneration of QM1 was very slow.25 In contrast, a later model of anthracycline was shown to form stable adducts with a thiol despite the lability of corresponding adducts formed by oxygen and nitrogen nucleophiles.26... 

Clinicians should play a role in chemotherapy safety, patient education, and monitoring patient response to therapy. For example, cumulative doses of anthracyclines should be monitored along with signs and symptoms of heart failure. Clinicians also should monitor concurrent medications along with chemotherapy for drug interactions. 

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

Dimethylsulfoxide (DMSO) is the antidote of choice for anthracycline and mitomycin C extravasations. It readily penetrates tissues and increases diffusion in the tissue area. In addition, DMSO is a free-radical scavenger that functions to block this principal mechanism of anthracycline- and mitomycin C-mediated tissue injury. DMSO generally is well tolerated but may cause some mild burning and redness. Dexrazoxane is a free-radical scavenger typically used for cardio-protection from anthracyclines. Promising results have been seen with large-volume extravasations and in a mouse model.38... 

Fogli et al. developed and validated an HPLC method with fluorescence detection for simultaneous routine TDM of anthracyclines and their metabolites.27 They coupled a Waters LC Module I Plus system equipped with a WISP 416 autosampler with a Model 474 scanning fluorescence spectrophotometer. The stationary phase was a Supelcosil LC-CN column (250 x 4.6 mm, 5 /um particle size) with a /iBondapak-CN guard column. The mobile phase consisted of 50mM monobasic sodium phosphate buffer and acetonitrile (65 35 v/v), adjusted to pH 4.0 with phosphoric acid. The flow rate was 1 mL/min. The fluorescence detection was set at excitation wavelengths of 233, 254, and 480 nm and at an emission wavelength of 560 nm. 

Stock solutions of anthracyclines (1 mg/mL) were prepared in double distilled water and stored at 4°C in the dark. Standard working solutions were prepared by diluting stock solutions with double distilled water or 0.1 M phosphoric acid. Aliquots of blank human plasma (0.5 mL) were spiked with working solutions of anthracyclines, mixed with 0.5 mL of 0.2M dibasic sodium phosphate buffer (pH 8.4), extracted with 4 mL of chloroform 1-heptane (9 1 v/v) by shaking for 15 min and centrifuged at 4000 rpm for 10 min. The lower organic layer was re-extracted with 0.25 mL of 0.1M phosphoric acid. The upper aqueous layer was collected and assayed. The injection volume was 50 fiL. Retention times for daunorubicinol, daunorubicin, idarubicinol, idarubicin, doxorubicinol, doxorubicin, epirubicinol, and epirubicin were 6,7, 9.1, 8.0, 11.3, 5.1,6.4, 5.5, and 7.0 min, respectively. 

Tomioka et al.74 reported an interesting example of applying chiral diamine (—)-102 in the synthesis of the chromophore part of anthracycline antibiotics (Scheme 4-34). 

Figure 2.7 Purification of a mixture of anthracycline antibiotics using heart cut recycle liquid chromatography to yield the most active fraction. Conditions column, JAIGEL-310 eluent, chloroform-methanol-25% NH4OH (200 5 1) flow rate, 4 ml min-1 detection refractivity index.

Beer PD, Bayly SR (2005) Anion Sensing by Metal-Based Receptors. 255 125-162 Beretta GL, Zunino F (2008) Molecular Mechanisms of Anthracycline Activity. 283 1-19 Bergamini G, see Balzani V (2007) 280 1-36 Bergamini G, see Campagna S (2007) 280 117-214... 

Escalante L, Ramos I, Imriskova I, Langley E, Sanchez S. (1999) Glucose repression of anthracycline formation in Streptomyces peucetius var. caesius. Appl Microbiol Biotechnol 52 572-578. 

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