Bleomycin synthesis

Bleomycin A2 (32) is a complex molecule, and its synthesis involves many steps 7-10 To conform to space limitations, in this description of bleomycin synthesis coverage will be limited to key reactions exhibiting innovative chemistry or important stereochemical outcomes. 

Stereochemically controlled synthesis of this subunit, which contains five stereogenic centers, is important to an efficient bleomycin synthesis. (2S,3S,4i )-4-(/er/-Butoxycarbonyl-amino)-3-hydroxy-2-methylpentanoic acid (15) was obtained via a stereoselective syn aldol addition of a boron Z-enolate with (27 )-2-(tert-butoxycarbonylamino)propanal (Scheme 4). Similarly, the L-threonine subunit 18 was prepared by diastereoselective syn aldol addition of an N- acy I ox azo I i di n one stannous Z-enolate with acetaldehyde. The bithiazole unit 19 was prepared using a direct DCC-promoted condensation of 3-(methylsulfanyl)propylamine. Convergent access to tetrapeptide S was obtained by coupling of acid 15 and deprotected 18 to give dipeptide 20, followed by further coupling with the bithiazole 19 to ultimately give tetrapeptide S (21). 

Figure 16.7-7. Resolution of D,L-erythro-(vhydroxyhistidi ne as the enantiospecific step in bleomycine synthesis.

The stmcture of bleomycin shown in Figure 13 was reported in 1978 (250) total synthesis was reported in 1982 (251—253). The commercial fermentation and purification of bleomycin has been described (244) as has its nonribosomal synthesis using a large multien2yme complex (254). 

The antineoplastic antibiotics, unlike their anti-infection antibiotic relatives, do not have anti-infective (against infection) abilily. Their action is similar to the alkylating dragp. Antineoplastic antibiotics appear to interfere with DNA and RNA synthesis and therefore delay or inhibit cell division, including the reproducing ability of malignant cells. Examples of antineoplastic antibiotics include bleomycin (Blenoxane), doxorubicin (Adriamycin), and plicamycin (Mithracin). 

Cooperative work with Prof. Nobuo Tanaka (Professor Emeritus of the University of Tokyo) in 1969 showed the mechanism of action of bleomycin to involve DNA strand-scission. The difficult total synthesis of bleomycin was accomplished (1981) in cooperation with Takita and others, including Hamao s son, Yoji Umezawa. H. Umezawa was very satisfied with the success of this total synthesis, and his sustained enthusiasm for improved bleomycins led to peplomycin (1978 used clinically since 1981) and libro-mycin(1985). 

Total synthesis of bleomycin A2, T. Takita, Y. Umezawa, S. Saito, H. Morishima, H. Naganawa, H. Umezawa, T. Tsuchiya, T. Miyake, S. Ka-geyama, S. Umezawa, Y. Muraoka, M. Suzuki, M. Otsuka, M. Narita, S. Kobayashi, and M. Ohno, Tetrahedron Lett., 23 (1982) 521-524. 

Bleomycin is a complex of no less than 16 glycopeptide antibiotics made from the family Streptomyces verticilus, which have different R groups [88-94]. Bleomycines exhibit antitumor, antiviral, and antibacterial activity. When bound to DNA, they disturb the spiraling of both single and double strands of DNA. To a lesser degree, they inhibit RNA and protein synthesis. It is administered both intravenously and intramuscularly. 

In 1980, in collaboration with Professor Ohno, Faculty of Phanmaceutical Sciences, the University of Tol o, we were successful in the chemical synthesis of pyrimidoblamic acid (84). This was one of the most important parts of the total synthesis of bleomycin. Soon therecifter. Dr. Takita et (55) in my institute were successful in the synthesis of the entire peptide peu t of bleomycin A2 1981 and then in the total synthesis of bleomycin A2 in the same year (56,54). Before this, we chemically converted bleomycin A2 to bleomycin demethyl A2 and estcibllshed synthetic processes for preparing bleonycinic acid from bleomycin demethyl A2 and for preparing various bleomycins from bleonycinic acid (62). Thus, the structures of bleomycins shown in Fig. 4 were conclusively estcibllshed. After our synthesis, Hecht al.also reported on the synthesis of the deglycobleomycin demethyl A2 (3) and the synthesis of bleomycin demethyl A2 (1). 

The classic example of schedule dependency is cy-tarabine, a drug that specifically inhibits DNA synthesis and is cytotoxic only to cells in S-phase. Continuous infusion or frequent administration of cytarabine hydrochloride is superior to intermittent injection of the drug. Bleomycin is another drug for which continuous infusion may increase therapeutic efficacy. 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Screening of microbial products has led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both cause DNA strand scission and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin. 

Peptide antibiotics are not often the drags of first choice for systemic therapy of important human disease. However, the World Health Organization, which chooses drags especially for Third World use based on efficacy, safety, quality, price, and availability, includes as essential such peptide antibiotics as bleomycin, dactinomycin, and bacitracin (as an ointment containing neomycin), plus several /8-lactams. See also Antibiotics, Antibiotics -Lactams. Systemic use of peptide antibiotics is many times limited by nephroloxicity and other toxicities. Semisynthesis or complete chemical synthesis of analogues of peptide antibiotics has most often not resulted in improved drags. 

Stillman MJ, Shaw CF III, Suzuki KT (1992) Metallothioneins. Synthesis, structure, and properties of metallothioneins, phytochelatins and metal-thiolate complexes. VCH Publishers, New York Stratford IJ, Hoe S, Adams GE, Hardy C, Williamson C (1983) Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles. Int J Radiat Biol 43 31-43 Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin-induced DNA degradation. Chem Rev 87 1107-1136... 

The synthesis of 2 ,4-disubstituted 2,4 -bithiazoles by a series of two regioselective cross coupling reactions has been reported. This bithiazole unit has been found in a number of natural products such as the bleomycins and macrocyclic antibiotics such as cyclothiazomycin. 

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