Probing the SAR of dEpoB via Chemical Synthesis:  A Total Synthesis Evaluation of C26-(1,3-dioxolanyl)-12,13-desoxyepothilone B

Chappell, Mark D.; Harris, Christina R.; Kuduk, Scott D.; Balog, Aaron; Wu, Zhicai; Zhang, Fei; Lee, Chul Bom; Stachel, Shawn J.; Chou, Ting‐Chao; Guan, Youxin

doi:10.1021/jo020180q

Cited by 26 publications

(7 citation statements)

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“…Thus, Danishefsky and coworkers have demonstrated C26-(1,3-dioxolanyl)-12,13-Epo D 7 (Fig. 4) to exhibit enhanced in vitro antiproliferative activity over Epo D [64]. However, in vivo this compound was found to be significantly less efficacious than Epo D. In contrast, C26-fluoro-Epo B 8 (Fig.…”

Section: Epothilone Analogs and Sar Studiesmentioning

confidence: 94%

Recent Developments in the Chemical Biology of Epothilones

Altmann

2005

CPD

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Epothilones A and B are naturally occurring microtubule-stabilizers, which inhibit the growth of human cancer cells in vitro at nM or even sub-nM concentrations. In contrast to paclitaxel (Taxol) epothilones are also active against different types of multidrug-resistant cancer cell lines in vitro and against multidrug-resistant tumors in vivo (epothilone B). Their attractive preclinical profile has made epothilones important lead structures in the search for improved cytotoxic anticancer drugs and epothilone B is currently undergoing phase II clinical trials. Numerous synthetic and semi-synthetic analogs have been prepared since the absolute stereochemistry of epothilone B was first disclosed in mid-1996 and their in vitro biological activity has been determined. Apart from generating a wealth of SAR information, these efforts have led to the identification of at least four compounds (in addition to epothilone B), which are currently at various stages of clinical evaluation in humans. This review is first intended to provide a summary of the basic features of the in vitro biological profile of epothilone B, with particular emphasis on recent developments in this area. A second part will outline the most relevant aspects of the epothilone SAR with regard to effects on tubulin polymerization, in vitro antiproliferative activity, and in vivo antitumor activity. This will include a brief discussion of research directed at the determination of the bioactive conformation of epothilones. In a final section, the preclinical profile of those epothilone analogs currently in clinical development will be discussed in greater detail.

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Section: Epothilone Analogs and Sar Studiesmentioning

confidence: 94%

Recent Developments in the Chemical Biology of Epothilones

Altmann

2005

CPD

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“…Among them, epothilone 490 69, a natural compound with high in vitro toxicity, and some of its analogs were synthesized by Danishefsky and its group [17][18][19][20][21][22]. Among them, epothilone 490 69, a natural compound with high in vitro toxicity, and some of its analogs were synthesized by Danishefsky and its group [17][18][19][20][21][22].…”

Section: Analogs Of Epothilonesmentioning

confidence: 99%

Synthetic Methodologies for the Preparation of Epothilones and Analogs

Luduvico¹,

Hyaric²,

Almeida³

et al. 2006

MROC

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Epothilones are natural products present in the myxobacterium Sorangium cellulossum strain 90. Due to their antitumoral activity, they are good candidates for the treatment of various forms of cancer, and epothilones B and D and some synthetic analogs are actually under advanced clinical trials. This review describes the synthesis of epothilones A and B and some of their analogs. synthetic methodologies reported in the literature to prepare epothilones A and B and some of their analogs. TOTAL SYNTHESIS OF EPOTHILONES The Danishefsky Group StrategiesThe first total synthesis of both epothilones A and B, including their respective deoxy precursors C and D, were carried out in the working group of S. J. Danishefsky [8-10].The main strategies used for the construction of the macrocycle include a macroaldolization reaction [9][10][11], an olefin metathesis approach [11,12], and a macrolactonization procedure [11]. Three key step reactions were employed: Suzuki-type coupling, aldol reaction and a stereoselective Noyori reduction [12] (Fig. 2). Metathesis (Approach I, Fig. 2) Initially, a strategy in which the C9-C10 bond would be formed during the macrocyclization reaction was chosen. The First Generation Ring-Closing OlefinTwo key intermediates 11 [11,12] and 18 [10,11] were synthesized as shown in scheme 1. Compound 11 was synthesized from β-benzyloxy(isobutyraldehyde) 7: a titanium cyclocondensation, followed by a reduction with lithium aluminum hydride provided glycal 8. Compound 9 was obtained by oxidative solvolytic fragmentation of a cycloproprane intermediate. After reductive deiodination of 9 and triphenylsilylation, cleavage of the pyran ring afforded dithioacetal 10. Protection of alcohol, followed by olefin formation and liberation of the aldehyde function led to intermediate 11. 50

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“…Following their own philosophies, either a limited number of selected analogs or large libraries were synthesized via combinatorial chemistry. 49,115,119,128,[132][133][134][135][136] C17-C18 Stille coupling allowed the introduction of a great variety of five-and six-membered heterocyclic side-chains, optionally carrying additional substituents. 130,131 Further, the C6 64 and C12 methyl groups were replaced by larger alkyl and modified alkyl groups.…”

Section: A Total Synthesismentioning

confidence: 99%