Total Synthesis of Epothilone A through Stereospecific Epoxidation of the p-Methoxybenzyl Ether of Epothilone C

Abstract

Nano‐peapods: Magnetically responsive photonic nanochains have been produced by inducing chain alignment of uniform magnetic particles during their silica coating process and then allowing additional deposited silica to wrap entire structures. The optical diffraction of these nanochains can be switched on and off by applying magnetic fields.

Recent Developments in the Chemical Biology of Epothilones

“…No such effect was observed upon simultaneous treatment with these agents or if Apo-2L/TRAIL treatment preceded treatment with BMS-247550 (20) [106]. It has also been reported that ectopic overexpression of Smac/DIABLO in human acute leukemia Jurkat T-cells or co-treatment with the N-terminal tetra-or heptapetide of this protein significantly enhance the apoptosis-inducing effects of BMS-247550 (20) in this cell line [107]. It is worth noting that Bhalla and coworkers strongly emphasize that their studies in A2780-1A9 cells would indicate that "apoptosis of A2780-1A9 cells follows [BMS-247550 (20)-induced] mitotic arrest, which is not associated with a marked increase in the levels of survivin" (cf., however, the recent work by Horwitz and coworkers [34,35]).…”

“…Similar differences have been observed for lactam-based analogs of Epo C and D, both of which are significantly less potent against P-gp-overexpressing human cancer cell lines than drug-sensitive lines [104]. Like other types of microtubule inhibitors BMS-247550 (20) was found by Bhalla and coworkers to induce G2/M arrest and apoptosis in human cancer cell lines [105]. As for Epo B [36] (vide supra), apoptosis induction in MDA-MB-468 human breast carcinoma cells appears to be related to a conformational change in the Bax protein and its subsequent translocation to the mitochondrial membrane [105].…”

“…As for Epo B [36] (vide supra), apoptosis induction in MDA-MB-468 human breast carcinoma cells appears to be related to a conformational change in the Bax protein and its subsequent translocation to the mitochondrial membrane [105]. While it is unclear at this point how BMS-247550 (20) can trigger changes in Bax conformation, it is suggested that this could, at least in part, be a consequence of increased association of Bax with the Bax-binding protein Bif-1 [105]. In line with a Bax-dependent mechanism of cell death, BMS-247550-mediated apoptosis, but not G2/M arrest, is significantly delayed in the presence of increased levels of the antiapoptotic protein Bcl-2.…”

“…This is paralleled by a delay in Bax conformational change. Co-treatment of Bcl-2-overexpressing cells with a Bcl-2 antagonist (e. g. Bak-BH3 peptide) leads to resensitization of the cells to the effect of BMS-247550 (20), if the Bcl-2 inhibitor is added 12 h after 20, but not upon concurrent treatment with both agents [105]. Interestingly, BMS-247550-induced cell death, at least in MDA-MB 468 breast carcinoma cells, appears to be caspasedependent [105], contrary to what has been reported for Epo B in other cell lines [37,39,40].…”

“…[16][17][18][19]; for more recent work cf. [20]) since the first disclosure of their absolute stereochemistry in 1996 [10]. Perhaps more importantly, the methodology developed in the course of those studies could be exploited for the synthesis of a host of analogs (reviewed in [16,17,[21][22][23]; more recent work will be referred to in the context of specific modifications), which has allowed the empirical elucidation of the most important structural parameters required for biological activity.…”