The calicheamicins

With the free hydroxyl groups in a suitably protected form, the introduction of the reactive allylic trisulfide triggering device can be addressed. When this advanced stage of the synthesis was reached, it was already known from the work of Magnus37 that the calicheamicin-type allylic methyl trisulfide can be formed upon... 

Cycloaromatization of the cyclic eneyneallene (68) produces the 1,5-didehydroin-dene biradical 69, that abstracts hydrogen atoms from the DNA strand in analogy to the calicheamicins (cf. Section 3.3). 

Disposition Metabolic studies indicate hydrolytic release of the calicheamicin derivative from gemtuzumab ozogamicin. Many metabolites of this derivative were found after in vitro incubation of gemtuzumab ozogamicin in human liver microsomes and cytosol, and in HL-60 promyelocytic leukemia cells. Metabolic studies characterizing the possible isozymes involved in the metabolic pathway of Mylotarg have not been performed. 

Further elaboration of models involved the design of water-soluble derivatives like diol 305, suitable for tests as DNA-affecting agents. It was rewarding to discover that the conversion 305 -> 306 can be carried out in water in the presence of DNA. As a result, a temperature- and time-dependent cleavage of double-stranded DNA was observed. Hence diol 305, the simplicity of its structure notwithstanding, can be properly considered as the synthetic mimic of the calicheamicin/esperamicin class of antibiotics. Most remarkably, it took less... 

Ahlert J, Shepard E, Lomovskaya N, Zazopoulos E, Staffa Bach-mann BO, Huang K, Fonstein L, Czisny A, Whitwam RE, Farnet CM, Thorson JS. The calicheamicin gene cluster and its iterative type 1 enediyne PKS. Science 2002 297 1173-1176. 

Halcomb, R L, Boyer, S H, Danishefsky, S J, Synthesis of the calicheamicin aryltetrasaccharide domain bearing a reducing terminus — coupling of fully synthetic aglycone and carbohydrate domains by the Schmidt reaction, Angew. Chem. Int. Ed. Engl, 31, 338-340, 1992. 

Nicolaou s total synthesis of the enediyne antibiotic, calicheamicin 71 [19], (Scheme 12.15 to Scheme 12.19) involves several new aspects in carbohydrate chemistry. The calicheamicin 71 oligosaccharide synthesis began with the construction of the D-ring intermediate from L-rhamnose. Thus, L-rhamnose 112 was converted into the glycosyl donor, trichloroacetimidate 118, through the... 

Roush, R W, Hunt, J A, Asymmetric allylboration of 2-iV,3-0-isopropylidene-A-Boc-L-serinal diastereoselective synthesis of the calicheamicin 7 aminosugar, J. Org. Chem., 60, 798-806, 1995. 

CD33 antigen, the entire complex is internalized into the cell where the calicheamicin is released and results in cellular toxicity due to double-strand DNA breaks. 

The family of enediynes includes the calicheamicins, esperamycins, dynemicin A, which is not glycosylated, the C-1027 chromophore and kedarcidin (O Fig. 18 and Fig. 19). The neocarzinostatin chromophore, which does not contain an (Z)-enediyne, is also included in this family of compounds because of a similar mode of action. 

The reactive cyclodecenediyne ring system found in the calicheamicins has recently been synthesized for the first time, together with a homologous series of larger (11- to 16-membered) rings containing the same enediyne unit. The synthesis of the first derivative (28) with DNA-cleaving properties by the same approach (equation 48) was reported soon afterwards. 

A dynemicin A analog resembling also the calicheamicin structure has been synthesized by Magnus et al. In this case the epoxide is not present and the role of safety catch is played by the carbonyl on the shortest bridge. The synthesis of 101 (Scheme 19.27) is achieved exploiting the reaction... 

Liu, C B.M. Smith, K. Ajito, H. Komatsu, L. Gomezpaloma, T.H. Li, E.A. Theodorakis, K.C. Nic-olaou, and P.K. Vogt (1996). Sequence selective carbohydrate DNA interaction dimeric and monomeric forms of the calicheamicin oligosaccharide interfere with transcription factor function. Proc. Natl. Acad. Sci. USA 93 940-944. 

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