Mithramycin, synthesis

Mithramycin shows a completely P-linked chain of D-conflgurated saccharides. This requires a totally different approach for the synthesis which is also done by application of the DBE method. The previously obtained disaccharide 180 is P-glycosylated with the monosaccharide precursor 176 to give the trisaccharide 185. After reductive debromination (Bu3SnH), an acid deformylation deblocked the C-3" position which is oxidized with pyridinium dichromate. Nucleophilic attack at the carbonyl group by methyl lithium affords a 1 1.2 mixture of 186 and 187 none of which is the desired compound [93]. Obviously, the methyl branch is formed exclusively in the axial way. 

Plicamycin [plick a MYE sin] (mithramycin) also exerts its cytotoxicity through restriction of DNA-directed RNA synthesis. Resistance is due to P-glycoprotein efflux. Plicamycin has a relative toxic specificity for osteoclasts preventing their resorption, and lowers plasma calcium concentration in hypercalcemic patients—especially those with bone tumors. Toxicities include hemorrhage as well as effects on the bone marrow, liver, and kidneys. 

Mithramycin inhibits RNA and protein synthesis by adhering to DNA. Mithramycin appears to effect bone resorption by stimulating osteoclast activity and results in hypocalcemia and hypophosphatemia. 

Antibiotics with Antineoplastic Activity - A number of tumor -inhibitory antibiotics form stable complexes with DNA thereby interfering with synthesis of RNA. Three of these antibiotics, actinomycin, mithramycin and daunomycin (which is probably identical to rubidomycin) possess... 

Mithramycin (Mithracin ) is a weakly acidic complex glycoside of the tetrahydroan-thracene chromomycine. It is obtained from Streptomyces plicatus. Its ability to inhibit nucleic acid synthesis appears to be primarily on RNA even though binding to DNA has also been demonstrated. Intercalation does not appear to be part of the process. It was proposed that binding of this antibiotic to the DNA template may simply prevent the polymerase enzyme from reading it. The result is inhibition of RNA synthesis. 

Mithramycin, which has a tetrahydroanthracene nucleus with two chains of pyranose rings attached, is obtained from several species of Streptomyces. It inhibits synthesis of RNA while that of DNA continues. It can cause hypo-calcaemia and, in general, is not very selective, but has proved useful in treating testicular tumours (HiWetaL, 1972). 

A further test of the hypothesis was made in synchronized cells. The model predicts that if R production is prevented before G1 [3], the constitutive rate of enzyme synthesis should continue for some hours beyond G1 [3]. That this prediction is confirmed is also illustrated in Figure 7. Actinomycin D (or daunamycin or mithramycin) added to preinduced, synchronized cells early in G1 allows the constitutive synthesis of TAT to continue beyond G1 [3], as shown by the failure of the inducer requirement to develop at that time. Thus, during G2, M, and early Gl, when transcription of structural and regulatory genes is presumably repressed, control at the translational level does not take place. However, as the cells enter the phase of the cycle where transcription control is lifted, i.e., late Gl and S, translational regulation by R becomes important. TAT can be induced by the steroids only during this translation control period consistent with the idea that somehow the inducers interfere with the function of R, the labile inhibitor of translation. 

Inhibitors of RNA Synthesis - An excellent review of the antibiotics that are specific inhibitors of DNA-controlled synthesis of RNA, a number of which are excellent anticancer agents (e.g. actinomycin, chromomycin A3 and daunomycin), has appeared.The structure of mithramycin has been established, and the total synthesis of actinomycins Cl, C2,... 

In connection with studies of the total synthesis of olivomycin A a review has appeared on the synthesis of the dideoxysugar components from acyclic precursors. In related work model reactions were carried out for the disaccharide coupling of the anthracycline antibiotic mithramycin (see Scheme 9). ... 

Sugar triflates have been employed as intermediate in various multistep syntheses. As shown in Scheme 10, the conversion of methyl 4-(9-benzoyl-2,6-dideoxy-/3-D-flrflhmo-pyranoside (66) to its /yjco-isomer (67) (required for model studies relating to the synthesis of mithramycin, see Chapter 3) involved a 4->3 benzoyl migration and a triflate displacement with neighbouring group participation. The triple triflate displacement (with inversions at Me... 

A series of avermectin analogues have been prepared with spacer arms between the disaccharide and the aglycone. Some of the products showed considerable bioactivity. This disaccharide (107) and epimers at C-4 and C-3 were made for use in the synthesis of mithramycin and related antitumour agents, and the AB disaccharide of olivomycin A, 2,6-dideoxy-3-0-(2,6-dideo qr-tf-D-fyxo-hexosyl)-Z)-it)ao-hexose was produced using the highly selective synthesis of 2-deoxyhexoses from 4-deoxy-2,3-0-isopropylidene-D-threose (Chapter 12). ... 

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