Synthesis and Biological Activity of Epothilones

Klar, Ulrich; Skuballa, Werner; Buchmann, Bernd; Schwede, Wolfgang; Bunte, T.; Hoffmann, Jens; Lichtner, Rosemarie B.

doi:10.1021/bk-2001-0796.ch008

Cited by 20 publications

(29 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[19]). Important contributions to the understanding of the epothilone SAR have also come from the research groups at Novartis (Altmann and coworkers, now at the ETH in Zürich) [67,103] and Schering [104] as well as the collaborative efforts between Hçfle and co-workers at the GBF (for example, see refs. [105,106]) and the group at BMS (for example, see ref.…”

Section: Epothilone Analoguesmentioning

confidence: 99%

“…[109,129] Likewise, modifications designed to stabilize the purported bioactive conformation in this region, based on pharmacophore modeling, only led to inactive analogues. [67,104,130] More recently, however, a number of new epothilone analogues with modifications in the C9-C11 region have been described that are characterized by potent antiproliferative activity in vitro, some of which also show an improved in vivo pharmacological profile over Epo B and Epo D. These analogues are characterized by the presence of trans double bonds either between C10 and C11 or between C9 and C10. They have been obtained through both isolation from bacterial fermentation broths [10][11][12] and total chemical synthesis (spearheaded by the Danishefsky group).…”

Section: C9-c11 Modificationsmentioning

confidence: 99%

See 1 more Smart Citation

The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

et al. 2007

View full text Add to dashboard Cite

Epothilones have captured the attention of chemists, biologists, and drug researchers ever since they were found to inhibit human cancer cell growth through a “taxol‐like” mechanism over ten years ago. Today, at least seven epothilone‐derived agents have entered clinical trials. However, additional new and exciting analogues have emerged in recent years, suggesting that the potential of these natural products to serve as leads for new anticancer drugs is far from exhausted.

show abstract

Section: Epothilone Analoguesmentioning

confidence: 99%

Section: C9-c11 Modificationsmentioning

confidence: 99%

The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Total synthesis of EpoA to EpoD was accomplished in various laboratories including ours (5,7,(10)(11)(12)(13)(14). To get more insight into the differential effects of epoxide-and olefin-bearing epothilone analogs, we have synthesized the natural compounds EpoB͞ EpoD and the new compounds 6-propyl-EpoB (pEB) and 6-propyl-EpoD (pED) and characterized their effects on tumor cell growth inhibition.…”

mentioning

confidence: 99%

Subcellular distribution of epothilones in human tumor cells

Lichtner¹,

Rotgeri²,

Bunte³

et al. 2001

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

View full text Add to dashboard Cite

Epothilones are a new class of natural and potent antineoplastic agents that stabilize microtubules. Although 12,13-epoxide derivatives are potent antiproliferative agents, the activities of the corresponding 12,13-olefin analogs are significantly decreased. These data were confirmed for two new analogs, 6-propyl-EpoB (pEB) and 6-propyl-EpoD (pED), in comparison with the natural compounds EpoB͞EpoD, by using human A431, MCF7, and MDR1-overexpressing NCI͞Adr cells. By using tritiated pEB͞pED, compound uptake, release, and nuclear accumulation were investigated in A431 and NCI͞Adr cells. In these cells, epothilones can principally be recognized and exported by Verapamil-sensitive efflux pumps, which are not identical to MDR1. The degree of export depends on the structure, olefin vs. epoxide-analog, and also on the intracellular drug concentration. The accumulation of pED used at 3.5 or 70 nM, respectively, was increased in the presence of 10 M Verapamil in both cell lines 2-to 8-fold. In contrast, the intracellular levels of pEB were affected by Verapamil only at 3.5 nM pEB in NCI͞Adr (2-fold) and not in A431 cells. In addition, strong nuclear accumulation was observed for pEB (40 -50%) but not paclitaxel or pED (5-15%) in both cell lines. Our study suggests that differences in growth inhibitory efficacy between epoxide and olefin analogs may be based on different mechanisms of drug accumulation and subcellular distribution. Epothilones are a new class of natural products and potential antineoplastic agents. Although they have no structural similarities to taxanes, they exert cellular effects similarly to paclitaxel (Taxol). Thus, epothilones bind to tubulin and cause hyperstabilization of microtubules with subsequent mitotic arrest and apoptotic cell death (1-3). The molecular mechanisms by which epothilones and paclitaxel induce apoptosis remain to be elucidated.It has been demonstrated that epothilones are generally superior to paclitaxel in their ability to inhibit the proliferation of human cancer cell lines that are resistant to commonly used anticancer agents, including paclitaxel. The best understood mechanism of resistance to cytotoxic drugs, including antimicrotubule agents is drug export by multidrug-resistant pglycoprotein (MDR1) (4). Although taxanes are substrates for MDR1, epothilones are not, and thus MDR1-positive tumor cells remain sensitive to epothilones (1, 2, 5-9).The 12,13-epoxide moiety of epothilone A (EpoA) and B (EpoB) is dispensable for tubulin͞microtubule-related effects in vitro, because the corresponding olefin analogs (EpoC and EpoD), as inducers of tubulin polymerization, are equally potent to EpoA and EpoB (7,8,10). Formal removal of epoxide oxygen in EpoB, thus leading to EpoD, does cause a significant decrease (ϳ10-to 30-fold) in antiproliferative activity (9). Furthermore, exposure of tumor cells to EpoB for a 4-h period produces virtually the same growth inhibitory effect as a continuous 3-day exposure, whereas for EpoD, exposure times more than 4 h were required to produce ef...

show abstract

“…One of the obvious modifications suggested by this model is the incorporation of variably positioned meta-substituted phenyl rings in the C(9)ÀC(12) segment of epothilones, which should lead to a stabilization of the bioactive conformation. Thus, compounds such as 8 or 9 arose as attractive target structures for our analog program, and the similarity between the preferred conformation of Epo B and those of compounds 8/9 is illustrated in the Figure. Analog 9 has been independently identified by the Schering AG group as an interesting compound to investigate, and its synthesis and biological assessment have recently been published [29]. Surprisingly, this analog was found to exhibit −reduced× biological activity [29] (more specific data are not available in [29]; cf.…”

mentioning

confidence: 99%

“…Thus, compounds such as 8 or 9 arose as attractive target structures for our analog program, and the similarity between the preferred conformation of Epo B and those of compounds 8/9 is illustrated in the Figure. Analog 9 has been independently identified by the Schering AG group as an interesting compound to investigate, and its synthesis and biological assessment have recently been published [29]. Surprisingly, this analog was found to exhibit −reduced× biological activity [29] (more specific data are not available in [29]; cf. also [30]), indicating that either the above conformational premises may be incorrect or, alternatively, that the incorporation of the bulky m-phenylene moiety is incompatible with the topology of the tubulin binding site.…”

mentioning

confidence: 99%

Total Synthesis and Biological Evaluation of a C(10)/C(12)‐Phenylene‐Bridged Analog of Epothilone D

End

Furet

Campenhout

et al. 2004

Chemistry & Biodiversity

View full text Add to dashboard Cite

The total synthesis of compound 8, a conformationally constrained analog of epothilone D (2), has been achieved through a convergent strategy based on three key fragments comprising C(1)-C(6) (26), C(7)-C(12) (16), and C(13)-O(16) (19) of the macrocyclic framework. Construction of the C(12)-C(13) bond involved Pd(0)-mediated B-alkyl Suzuki coupling between aryl bromide 16 and olefin 19, and proceeded in excellent yield, while formation of the C(6)-C(7) bond through aldol reaction was somewhat less efficient. Surprisingly, macrolactonization was rather low-yielding and gave protected 8 only in 39% yield. Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B, the compound was devoid of any significant antiproliferative activity.

show abstract

Synthesis and Biological Activity of Epothilones

Cited by 20 publications

References 0 publications

The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

The Chemistry and Biology of Epothilones—The Wheel Keeps Turning

Subcellular distribution of epothilones in human tumor cells

Total Synthesis and Biological Evaluation of a C(10)/C(12)‐Phenylene‐Bridged Analog of Epothilone D

Contact Info

Product

Resources

About