Total Synthesis of (–)‐Epothilone A

Balog, Aaron; Meng, Dongfang; Kamenecka, Ted; Bertinato, Peter; Su, Dai‐Shi; Sorensen, Erik J.; Danishefsky, Samuel J.

doi:10.1002/anie.199628011

Cited by 221 publications

(81 citation statements)

References 14 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Sepp‐Lorenzino

Balog

et al. 1999

Prostate Cancer Prostatic Dis

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Epothilones are a new class of natural products that bind to tubulin and prevent the depolymerization of microtubules, although they have no structural similarity to paclitaxel. Taxanes are only marginally effective in the treatment of disseminated prostate cancer, although they may have useful activity when administered in combination with estramustine. Unlike paclitaxel, epothilones are not substrates for P-glycoprotein and are active in multidrug resistant cells. Epothilones A and B (EA, EB) have recently been synthesized in toto. In this report, we examine the effects of synthetic epothilones and their desoxy derivatives, as well as paclitaxel, on prostate cancer cell lines. EB was the most active of these compounds in tissue culture (IC 50 : 50 ± 75 pM), four to ten-fold more potent than paclitaxel. EA and the desoxyderivatives of EA and EB (dEA, dEB) were also active, but less potent than EB. Each of these compounds causes mitotic block followed by apoptotic cell death. The relative potencies for cell cycle arrest and cytotoxicity directly correlate with the ability of the drugs to bind microtubules, stabilize mitotic spindles and induce the formation of interphase microtubule bundles. Therefore, synthetic epothilones are potent inhibitors of prostate cancer cell lines and work in a fashion similar to paclitaxel. Recently, we showed that farnesyl transferase inhibitors sensitize tumor cells to paclitaxelinduced mitotic arrest. We now have extended these observations to show that paclitaxel and the epothilones synergize with FTI to arrest the growth of prostate cancer cells. Moreover, this occurs in DU145, a cell line that is not particularly sensitive to the FTI. The combination of FTI and epothilone represent a new potential clinical strategy for the treatment of advanced prostatic cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sepp‐Lorenzino

Balog

et al. 1999

Prostate Cancer Prostatic Dis

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“…By far the most intriguing property of the epothilones at the in vitro level is their lack of cross resistance to MDR cell lines when compared with major antitumor agents, including paclitaxel, vinblastine, adriamycin, camptothecin, and etoposide, all of which are currently used in clinical settings (6)(7)(8)(9). The epothilones are also more watersoluble (6,(10)(11)(12)) and more readily available through chemical synthesis (6,(13)(14)(15)(16)(17)(18)(19)(20) than is paclitaxel. The solubility advantage could allow for less cumbersome administration and increased bioavailability of the chemotherapy agent than paclitaxel.…”

mentioning

confidence: 99%

Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel

Chou

Zhang

Harris

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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160

103

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The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in their ability to retain activity against multidrug-resistant ( Paclitaxel (Taxol**), Fig. 1, is currently used as the front-line therapeutic agent in a variety of solid forms of cancer including ovarian, breast, colon, lung, and liver neoplasms (1). Acquired resistance to paclitaxel and other commonly used cancer chemotherapy agents may be mediated by a number of mechanisms, including overexpression of the energy-dependent drug-transport protein P-glycoprotein (ref. 2, and references therein). Broad-spectrum resistance to structurally and mechanistically diverse anticancer agents constitutes the multidrugresistance (MDR) phenotype. A search for paclitaxel analogues with improved performance in vitro and in vivo has met with limited success (3, 4), although certain MDR reversal agents appear promising when coadministered with the anticancer agent (5).Although the 16-membered ring structure of the epothilones bears little structural resemblance to paclitaxel, the two agents share a common cellular mechanism of action (6-8). Both the epothilones and paclitaxel exert their biological effects by stabilizing microtubule assemblies, thus leading to the arrest of cell division and eventual cell death. By far the most intriguing property of the epothilones at the in vitro level is their lack of cross resistance to MDR cell lines when compared with major antitumor agents, including paclitaxel, vinblastine, adriamycin, camptothecin, and etoposide, all of which are currently used in clinical settings (6-9). The epothilones are also more watersoluble (6, 10-12) and more readily available through chemical synthesis (6,(13)(14)(15)(16)(17)(18)(19)(20) than is paclitaxel. The solubility advantage could allow for less cumbersome administration and increased bioavailability of the chemotherapy agent than paclitaxel. The synthetic advantage would be useful in generating epothilone congeners more advantageous than the natural product.We recently reported that Z-12,13-desoxyepothilone (dEpoB; Fig. 1), a synthetic intermediate en route to epothilone B, † † demonstrated promising activity both in vitro and in murine models harboring tumor xenografts (6, 21). In the previous report, we also showed that dEpoB was Ͼ35,000-fold more potent than paclitaxel in inhibiting cell growth of DC-3F͞ADX in vitro. During the earlier in vivo pharmacologic evaluations of the epothilones, both dEpoB and paclitaxel were administered with dimethyl sulfoxide (DMSO) as a solvent by using i.p. injection (6,22). However, i.v. administration is more appropriate for paclitaxel than for dEpoB, resulting in higher efficacy and lower toxicity. Because the primary focus of this research was to compare dEpoB and paclitaxel, we adjusted the administ...

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“…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.…”

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confidence: 99%

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

Chou

O’Connor

Tong

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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108

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We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth inhibition (IC50) for a variety of anticancer agents were measured in CCRF-CEM͞VBL1000 cells (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, 8 yr). This continued exposure led to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug, respectively. The therapeutic effect of dEpoB and paclitaxel was also compared in vivo in a mouse model by using various tumor xenografts. dEpoB is much more effective in reducing tumor sizes in all MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious antitumor agents with both a broad chemotherapeutic spectrum and wide safety margins.

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Total Synthesis of (–)‐Epothilone A

Cited by 221 publications

References 14 publications

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

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

Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel

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

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