Calicheamicin antibiotics

Gemtuzumab zoqamicin -monoclonal antibody against CD33 with calicheamicin (antitumor antibiotic) -fevers and chills -hypotension -grade IV neutropenia and thrombocytopenia -LFT elevations ... 

Gemtuzumab ozogamicin (30 Mylotarg ) Calicheamicin (31) Enediyne-type antibiotic NP-derived Microbial Anticancer DNA-cleaving 319-331... 

It is noteworthy that Jones and Darby, who pioneered the enediyne rearrangement, now known as the Bergman rearrangement, and Nicolaou, who achieved the first total synthesis of the enediyne antibiotic calicheamicin 7 / were under the joint supervision of Profs. Franz Sondheimer and Peter Garratt. It might seem that all researchers in the enediyne field have been influenced by Sondheimer and Garratt. 

A. General description Gemtuzumab ozogamicin is composed of a recombinant humanized IgG4, kappa antibody conjugated with a cytotoxic antitumor antibiotic, calicheamicin. The anti-CD33 antibody is produced by mammalian cell suspension... 

Dedon PC, Goldberg IH (1992) Free-radical mechanisms involved in the formation of sequence-de-pendent bistranded DNA lesions by the antitumor antibiotics bleomycin, neocarzinostatin, and calicheamicin. Chem Res Toxicol 5 311 -332... 

A final example of metabolic pathway engineering is based on polyketide and nonribosomal peptide biosynthesis. Polyketides and nonribosomal peptides are complex natural products with numerous chiral centers, which are of substantial economic benefit as pharmaceuticals. These natural products function as antibiotics [erythromycin A (65), vancomycin (66)], antifungals (rapamycin, amphotericin B), antiparasitics [avermectin Ala (67)], antitumor agents [epothiolone A (68), calicheamicin yj, and immunosuppressants [FK506 (69), cyclosporin A], Because this exponentially growing and intensely researched field has developed, the reader is directed to review articles for additional details.347-359 Also with the potential economic benefit to develop the next blockbuster pharmaceutical, a number of patents and patent applications have been published.360-366... 

In another recent development in aromatic synthesis, the Bergman cydization [7] is beginning to be exploited for preparative purposes. This process has been studied for many years because of its importance with regard to the biological action of several marine antitumor antibiotics such as calicheamicin [58] and because of its interesting reaction mechanism [8]. Now, more and more synthetic applications are beginning to be reported in the literature [59]. 

In the synthesis of the core structure of the diynene antitumor antibiotics esperamicins and calicheamicins by Danishefsky et al. [108], an acetylene-aldehyde coupling reaction was used to achieve the cyclization. As shown in Scheme 60, reaction of a toluene solution of acetylene aldehyde 182 with potassium hexame-thyldisilazide at —78 °C for 20 min afforded a 52% yield of a 10 1 ratio of 183 and 184. 

The stability of carbocations flanked by n-coordinated organic moieties is dramatically enhanced so that they react easily with nucleophiles [125]. Magnus et al. [126] applied this principle to the synthesis of the core structure (208) of the diynene antibiotics esperamicim and calicheamicins. As shown in Scheme 68, diynene 205 was converted to enol silyl ether which was treated with Co2(CO)g to give dicobalt hexacarbonyl adduct 206. Exposure of 206 to 3 equiv of TiCU and 1 equiv of DABCO at —43 to —35 °C gave macrocycle 207 in 50% yield. 

For almost 15 years, neocarcinostatin stood alone as an antibiotic with a unique pattern of DNA-damaging action. However, owing to an intensive search for other natural compounds with similar activity, several other antibiotics containing the enediyne fragment were found. Thus in 1987, almost simultaneously, esperamicin Aj 292 ° and calicheamicin y 293 ° were... 

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... 

Kuck N, Fantini A, Wildey MJ, Thomas J, Greenstein M. Calicheamicins, a novel family of antitumor antibiotics taxon- 131. omy, fermentation and biological properties. J. Antibiot. (Tokyo) 1989 42 558-563. 132. 

Gemtuzumab ozogamicin (Mylotarg) consists of a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic enediyne antibiotic calicheamicin. It has been used to treat a subset of patients with acute myeloid leukemia in association with topotecan -I- cytarabine. Its most common adverse effects are myelosuppression, increased hepatic enzyme activity, infections, fever and chills, bleeding, nausea and vomiting, and dyspnea. 

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... 

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