Bleomycin analog

Figure 15.9 Solid-phase synthesis of bleomycin analogs by Thomas et al. [30],...

Section II,A From recent two-dimensional NMR studies on bleomycin analogs, a revisited structural model for specificity, binding, and double-strand cleavage was proposed (367). An investigation of the reaction of Fe "-BLM with iodosylbenzene by ES-MS showed that neither hypervalent iron nor activated oxygen was involved but that hjq)ervalent iodide I(III) was the oxidant (368). 

Salgo and Pryor [111] studied the effect of Trolox C (a water-soluble analog of vitamin E) on peroxynitrite-mediated DNA damage in rat thymocytes. They proposed that peroxynitrite mediated the formation of TBAR products, which caused the DNA-protein crosslinks. The latter were inhibited by the posttreatment of cells with Trolox. However, Trolox produced no effects on hydrogen peroxide- or bleomycin-induced DNA damage in human lymphocytes [108],... 

Bleomycin (BLM) was first isolated as a copper complex from a culture of Streptomyces verticillus. Since then numerous analogs have been prepared by modifying the conditions of fermentation. Bleomycins (114, bleomycin A2) are used clinically in combination cancer chemotherapy for the treatment of head and neck cancer, certain lymphomas, and testicular cancer (555). 

There are fewer reports on other parenteral routes of administration of emulsions such as intramuscular, subcutaneous, and intraperitoneal. V Mer-in-oil and w/o/w emulsions of bleomycin, mytomycin C, and 5-Luorouracil have been administered by these routes, apparently resulting in increased regional lymphatic uptake, hence the term lymphotropic emulsions (Davis et al., 1987). Gasco et al. (1990) developed a w/o emulsion of an LHRH analog measurements of testosterone levels after intramuscular administration to rats suggested that the formulation led to prolonged release of the drug. 

Analogs of the metal-chelating center of bleomycin, which is a glycopeptide antibiotic, have been synthesized and the stmctmes of their copper(II) complexes have been determined. These complexes show similar bonding as bleomycin. The copper is in a highly distorted enviromnent approaching square pyramidal, with 3N coordination that includes coordination by an imidazole nitrogen. 

Drugs, such as bleomycin, aclacinomycin and deoxyspergualin, were discovered by the Umezawa group at the Institute of Microbial Chemistry in Japan and developed in collaboration with the NCI a number of the agents currently in advanced precUnical development at the NCI, such as UCN-01, and quinocarmycin and spicamycin analogs (Fig. 4), are the result of collaborations between Japanese companies, such as Kyowa Hakko Kogyo, Fujisawa Pharmaceutical Co. Ltd, and IQrin Brewery Ltd, and the NCI. ... 

During Studies dealing with the action of bleomycin on DNA, four analogous degradation products were described, two of which are 31 and 32. ... 

Camptothecin analogs Irinotecan Topotecan Epipodophyllotoxins Etoposide Teniposide Antitumor antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Mitoxantrone Valrubicin Microtubule agents Docetaxel Paclitaxel Vinblastine Vincristine Vinorelbine Enzymes Asparaginase Pegasparaginase Metals... 

Morphological Studies In analogy to other cytostatic drugs such as alkylating agents, bleomycin, or DDP, the treatment with the metallocene dichlorides of titanium and vanadium induces the formation of giant cells with one or several nuclei as well as the appearance of abnormal mitotic figures (43) ... 

---