Antitumor natural products

The presence of 9-diazofluorene groups in kinamycin antitumor natural products would lead one to think of an active role for the diazo group. The hypothesis may be substantiated by the fact that one of the precursors in kinamycin biosynthesis, kinafluorenone 10 [44], which lacks the diazo moiety, shows no antibiotic activity against B. subtilis ATCC 6633, known to be very sensitive to the kinamycins. However, prekinamycin (9) [49], which is similar to kinafluorenone but retains the diazo group, shows activity to-... 

The isolation of diazobenzo[fr ]fluorenes as stable antitumor natural products raises several questions about their mode of action. The inability to cleave DNA by diazotization of 9-aminofluorene may imply that if the diazo functionality is involved in the mode of interaction of kinamycins with DNA, its conversion to diazonium and the ensuing reduction may seem to be of negligible importance. An additional possibility, which will be discussed later, is that 9-diazofluorene may not be the ideal model for these natural products. In exploring DNA cleavage as a possible route to the kinamycins role as a stable antitumor agent, which may supplement their speculative and as yet unconfirmed role as alkylating molecules [67], this early model seemed to suggest that the well-established activation of diazonium may not be relevant. 

Parco et al. described a copper-catalyzed amidation of vinyl iodide 115 to give 116 (Scheme 20).28e Enhanced conversions were attained using copper(i) thiophenecarboxylate (GuTG) in a polar aprotic solvent such as NMP. The total synthesis of the antitumor natural product, lobatamide G, has been accomplished by using this reaction.28f Buchwald et al. developed a general and efficient copper-catalyzed method using N,N -dimethyl ethylenediamine L8. The double-bond geometry of the alkenyl halides was retained under the reaction conditions. 

Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H, Uesugi M, Ishihama Y, Iwata M, Mizui Y. (2007) Sphcing factor SF3b as a target of the antitumor natural product pladienohde. Nat Chem Biol 3 570-575. 

The class of 3-silyl-substituted reagents provides, upon addition with aldehydes, allylic silanes that offer many options for further derivatization. Oxidative processes are described in previous sections (see the sections on Preparation of 1,2-Diols and 1,4-Diols). If the appropriate silicon substituents are chosen, formal [3+2] cycloadditions with aldehydes can be promoted under Lewis acid catalysis. For example, the mismatched addition of the Z-3-propyl-3-benzhydryldimethyl allylsilane 183 to an a-benzyloxy aldehyde proceeds with low diastereofacial selectivity in favor of product 184 however, after protection of the secondary alcohol, an efficient [3+2] annulation provides the polysubsubstituted furan 185 in good yield and acceptable stereoselectivity (Scheme 24). ° The latter is brought forward to a tricyclic unit found in the antitumor natural product angelmicin B. 

The discovery of Taxol is a fruit of a National Cancer Institute (NCI)-sponsored project on identification of antitumor agents from natural resources. Bioassay-guided fractionation led to the isolation of this unique compound from Taxus bre-vifolia (pacific yew). Wani et al. also identified another famous antitumor natural product camptothecin. Unlike camptothecin, which was abandoned in the phase of clinical trial because of its severe toxicity, Taxol was almost discarded at the preliminary phase because it only exhibited moderate in vitro activity toward P388, a murine leukemia cell line that was used in the standard evaluation system by NCI researchers at that time. However, it was rescued by a subsequent finding of its strong and selective antitumor activities toward several solid tumors, and more... 

The antitumor natural product epothilone A was synthesized in the laboratory of J.S. Panek. They utilized the B-aikyi Suzuki cross-coupling between an sp -hybridized alkylborane and a (Z)-iodoalkene for the construction of the main fragment. The alkylborane was prepared by hydroborating the terminal alkene with 9-BBN and the (Z)-iodoalkene was added along with the palladium catalyst and the base. 

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