Bleomycin derivatives

There are a number of more complex isothiazole structures, including naphthyl isothiazoles, steroidal isothiazoles <81JHC1485>, and isothiazoles incorporated into large molecules, such as bleomycin derivatives <87JA938>, but these will not be discussed. 

Table 4.9. STRUCTURE-ACTIVITY RELATIONSHIPS OF BLEOMYCIN DERIVATIVES...

Complex of glycopeptide antibiotics related to Bleomycins. Derived from Streptomyces verticillus. Active against gram-positive and -negative bacteria and tumours, inhibitor of nucleic acid synth. A complex mixt. of amines Phleomycins A, C, D, D2, E, F, G and H derived by directed biosynth. or semisynth. See also Bleomycins. X , 245 (e 23600) 296 (e 19600) (HjO) (Derep). 244 (e 24500) 298 (e 8300) 615 (e 100) (MeO (Berdy). 

Oligosaccharides also occur widely as components (via glycosidic bonds) of antibiotics derived from various sources. Figure 7.20 shows the structures of a few representative carbohydrate-containing antibiotics. Some of these antibiotics also show antitumor activity. One of the most important of this type is bleomycin A2, which is used clinically against certain tumors. 

The irradiation a 1 1 Cu-peplomycin complex, an antibiotic of the bleomycin family (Fig. 15), leads to a product of an isomerization of a thiazole ring. In this case, the compound converted from a 2,4 -bithiazole to a 4,4 -bithiazole derivative. When a 5 1 Cu - peplomycin complex was used, the product was a 3-isothiazolyl-4-thiazole derivative (86JA7089 87JA938). 

Okuma T, Terasaki Y, Kaikita K, et al. C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metallo-proteinases. J Pathol 2004 204(5) 594-604. 

LCLs derived from targeted populations have been utilized to evaluate genetic susceptibility to radiation sensitivity (9), sensitivity to mitomycin C in patients with Wilms tumor (10), and camptothecin-induced apoptosis (11). These cell lines have been useful for studying bleomycin-induced chromatid breaks and oxidant-induced apoptosis (12)... 

The bleomycins (Fig. 12.6) are a family of glycopeptide-derived antibiotics which are used in the treatment of various tumors. They bind iron in the blood and form an active hypervalent oxo-iron species. The two-dimensional structure is well known but no crystal structures of bleomycin or its metal complexes have been reported. The MM2 force field was modified and extended by modeling of the crystal structures of the cobalt complexes of two bleomycin analogues in order to develop a force field for... 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer (see Chapter 62). In fact, most major anticancer drugs are derived from plants or microorganisms. Important examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, paclitaxel... 

Bleomycins (BLMs) (Figure 3a) are a family of glycopeptide-derived antibiotics that have the ability to bind and degrade deoxyribonucleic acid (DNA), which... 

---