Total Synthesis of (–)‐Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure–Activity Relationships of the Epothilones

Abstract

The cuprates were formed by addition of weighed tablets of Cul or CuCN to the precooled (1 70-210 K) solutions of the organolithium reagents. After complete dissolution of the copper salt (occasionally with slight warming). the freezing point was determined as above. In the case of the amidocuprate [tBu(iPr,N)Cu(CN)Li,], one equivalent of diisopropylamine was added prior to CuCN.

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

“…Recently, the total synthesis of epothilones A and B was accomplished in these laboratories. 10,17 These successes allowed for the synthesis of a variety of epothilone derivatives as well. We have studied the biologic effects of EA, EB, dEA and dEB on prostate cancer cell lines and found that they all inhibit growth potently ( Figure 2 and Table 1).…”

“…Thirdly, synthesis of epothilones is now possible. 10,17,18 This will allow the generation of multiple derivatives, some of which may have increased potency, bypass resistance mechanisms or have decreased toxicity. The similar binding and biologic effects of the very dissimilar taxane and epothilone structures suggests that synthesis of derivative drugs with altered properties will be possible.…”

“…11 ± 15 The reasons that prostate cancers are resistant to paclitaxel are unknown, although the high levels of P-glycoprotein and Bcl-2 expression observed in advanced tumors may play a role. 2,16 Recently, the total synthesis of epothilones A and B (EA, EB) and their desoxy counterparts (dEA, dEB) was accomplished in these laboratories 10,17 and others. 18 ± 20 We now report potent in vitro cytotoxicity effects of these synthetically derived epothilones on prostate cancer cells.…”

Highlights of Natural Products in Prostate Cancer Drug Discovery

“…The main difference resides in the fact that taxanes are substrates for P-glycoprotein and epothilones are not, and this a b i l i t y t o g e t h e r w i t h e a s e o f f o r m u l a t i o n h a v e b e e n c o n s i d e r e d a d v a n t a g e s f o r overcoming taxane resistance of tumor cells (Wartmann & Altmann, 2002, Cheng et al, 2008. Moreover, whereas the synthesis of paclitaxel relies on 10-deacetylbaccatin III which is available from the needles of various Taxus species , total synthesis of patupilone B has been accomplished (Su et al, 1997). The progress of epothilones in the PC setting has been extensively reviewed (Lee & Kelly, 2009, Lassi & Dawson, 2010, Cheng et al, 2008, Bystricky & Chau, 2011.…”

The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

“…The clinical successes of paclitaxel have spurred searches for other agents that inhibit the growth of tumors through similar tubulin-based mechanisms of action. More recently discovered compounds with a taxol-like mechanism of action include the discodermolides (4,5), eleutherobins (6), laulimalides (7), and epothilones (8)(9)(10)(11)(12)(13)(14). Despite their supposed common binding site on tubulin assemblies (15)(16)(17)(18), their chemical structures and͞or pharmacological profiles are drastically different.…”