Scalable, Enantioselective Synthesis of Germacrenes and Related Sesquiterpenes Inspired by Terpene Cyclase Phase Logic

Foo, Klement; Usui, Ippei; Götz, Daniel C. G.; Werner, Erik W.; Holte, Dane; Baran, Phil S.

doi:10.1002/anie.201206904

Cited by 66 publications

(44 citation statements)

References 61 publications

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“…Thegeneration of structurally rich and diverse NP-based or -derived compound libraries is af ormidable challenge that may benefit from cutting-edge expertise in NP total or divergent total synthesis.E xamples of successful scalable syntheses of various natural products indicate the possibility of totally synthetic analogues of complex natural products being part of future compound collections for various screenings. [52,84] Methods to manipulate biosynthetic designs and deliver structurally modified complex natural products or their precursors for divergent synthesis strategies would help the scientific community engaged in discovery research to come out of the current productivity crisis. [85] Simple modifications of af unctional group can be extremely challenging on ac omplex molecule, such as an atural product.…”

Section: Discussionmentioning

confidence: 99%

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Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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Scaffold diversity is a crucial feature of compound collections that has a huge impact on their success in biological screenings. The synthesis of highly complex and diverse scaffolds, which could be based on natural products, for example, is an arduous task that requires expertise in various aspects of organic synthesis and structural analysis. This challenge has been addressed by a number of synthesis designs, which employ natural products as a source of scaffold diversity, transform suitably designed common intermediates into various molecular frameworks, or entail highly concise synthetic routes to a number of distinct and complex scaffolds. In this Minireview, we highlight recent synthetic developments towards the construction of diverse and complex scaffolds and the application of the resulting compound collections in drug and probe discovery.

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Section: Discussionmentioning

confidence: 99%

“…[52] In three simple steps,that is,acetylation, hydroboration, and oxidation of the formed diol, 11,13-dihydro-epi-parthenolide (84)w as obtained as am ixture of diastereomers. a-Bromination of lactone 84 followed by dehydrobromination gave rise to 7-epi-parthenolide (85).…”

Section: Methodsmentioning

confidence: 99%

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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“…This paper has outlined the first fundamental steps toward achieving this goal in a systematic fashion using a two-phase approach. 22 It appears that the wisdom of biosynthesis correlates to laboratory findings 23 in that the allylic positions of 1 (C-5, C-13, and C-10) are innately primed, matching the biosynthetic order, for early oxidation en route to Taxol. This realization, however, required extensive exploration using a panel of complementary allylic oxidation methods (see SI) culminating in the first total synthesis of 3 .…”

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confidence: 87%

Two-Phase Synthesis of (−)-Taxuyunnanine D

et al. 2014

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The first successful effort to replicate the beginning of the Taxol oxidase phase in the laboratory is reported, culminating in the total synthesis of taxuyunnanine D, itself a natural product. Through a combination of computational modeling, reagent screening, and oxidation sequence analysis, the first three of eight C–H oxidations (at the allylic sites corresponding to C-5, C-10, and C-13) required to reach Taxol from taxadiene were accomplished. This work lays a foundation for an eventual total synthesis of Taxol capable of delivering not only the natural product but also analogs inaccessible via bioengineering.

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“…Additionally, elaboration of 4 to its dimethylamine congener 5 provided an analogous prodrug to DMAPT ( LC-1 ). Given the continued interest in PTL , highlighted by its first total synthesis, 14 and the rekindled popularity of covalent drugs in general, 78, 79 C1-C10 modifications such as cyclopropanation may be useful for optimizing PTL and related germacranolides for therapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

“…9–13 In addition to its anti-leukemic activity, PTL has been explored as a potential therapeutic for a spectrum of indications. 14 …”

Section: Introductionmentioning

confidence: 99%

Synthesis and antileukemic activities of C1–C10-modified parthenolide analogues

Kempema

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Hexum

et al. 2015

Bioorganic & Medicinal Chemistry

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Parthenolide (PTL) is a sesquiterpene lactone natural product with anti-proliferative activity to cancer cells. Selective eradication of leukemic stem cells (LSCs) over healthy hematopoietic stem cells (HSCs) by PTL has been demonstrated in previous studies, which suggests PTL and related molecules may be useful for targeting LSCs. Eradication of LSCs is required for curative therapy. Chemical optimizations of PTL to improve potency and pharmacokinetic parameters have focused largely on the α-methylene-γ-butyrolactone, which is essential for activity. Conversely, we evaluated modifications to the C1-C10 olefin and benchmarked new inhibitors to PTL with respect to inhibitory potency across a panel of cancer cell lines, ability to target drug-resistant acute myeloid leukemia (AML) cells, efficacy for inhibiting clonal growth of AML cells, toxicity to healthy bone marrow cells, and efficiency for promoting intracellular reactive oxygen species (ROS) levels. Cyclopropane 4 was found to possess less toxicity to healthy bone marrow cells, enhanced potency for the induction of cellular ROS, and similar broad-spectrum anti-proliferative activity to cancer cells in comparison to PTL.

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Scalable, Enantioselective Synthesis of Germacrenes and Related Sesquiterpenes Inspired by Terpene Cyclase Phase Logic

Cited by 66 publications

References 61 publications

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

Two-Phase Synthesis of (−)-Taxuyunnanine D

Synthesis and antileukemic activities of C1–C10-modified parthenolide analogues

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