Molecular Modeling, Total Synthesis, and Biological Evaluations of C9‐Deoxy Bryostatin 1

Keck, Gary E.; Poudel, Yam B.; Rudra, Arnab; Stephens, Jeffrey C.; Kedei, Noémi; Lewin, Nancy E.; Peach, Megan L.; Blumberg, Peter M.

doi:10.1002/ange.201001200

Cited by 15 publications

(11 citation statements)

References 30 publications

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“…The Toledo cell line is derived from a non‐Hodgkin's B cell lymphoma. It is among the most sensitive cell lines for growth inhibition by phorbol ester and, unlike leukemia cell lines such as U937, K562, or MV‐4–11, is similarly growth inhibited by bryostatin 1 . Merle 41 and Merle 23, like PMA and bryostatin 1, inhibited Toledo cell growth (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Deletion of the C26 Methyl Substituent from the Bryostatin Analogue Merle 23 Has Negligible Impact on Its Biological Profile and Potency

et al. 2018

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Important strides are being made in understanding the effects of structural features of bryostatin 1, a candidate therapeutic agent for cancer and dementia, in conferring its potency toward protein kinase C and the unique spectrum of biological responses that it induces. A critical pharmacophoric element in bryostatin 1 is the secondary hydroxy group at the C26 position, with a corresponding primary hydroxy group playing an analogous role in binding of phorbol esters to protein kinase C. Herein, we describe the synthesis of a bryostatin homologue in which the C26 hydroxy group is primary, as it is in the phorbol esters, and show that its biological activity is almost indistinguishable from that of the corresponding compound with a secondary hydroxy group.

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Section: Resultsmentioning

confidence: 99%

Deletion of the C26 Methyl Substituent from the Bryostatin Analogue Merle 23 Has Negligible Impact on Its Biological Profile and Potency

et al. 2018

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“…[2] All three previously reported total syntheses relied upon a Julia olefination to unite a southern and northern hemisphere followed by a macrolactonization to close the macrocycle. [3][4][5][6] However, due to the basic nature of the Julia olefination reaction, the two exo-cyclic a,b-unsaturated enoates had to be masked and revealed after macrocyclization, resulting in lengthy syntheses (> 40 steps in the longest linear chain and > 70 steps in total).…”

Section: Resultsmentioning

confidence: 99%

Total Syntheses of Bryostatins: Synthesis of Two Ring‐Expanded Bryostatin Analogues and the Development of a New‐Generation Strategy to Access the C7–C27 Fragment

Trost

Yang

Dong

2011

Chemistry A European J

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This paper reports the synthesis of novel ring-expanded bryostatin analogues. By carefully modifying the substrate, a selective and high-yielding Ru-catalyzed tandem enyne coupling/Michael addition was employed to construct the northern fragment. A ring-closing metathesis was utilized to form the 31-membered macrocycle of the analogue. These ring-expanded bryostatin analogues possess anticancer activity against several cancer cell lines. Given the difficulty of forming the C16-17 olefin in the late stage, we also describe our development of a new-generation strategy to access the C7-C27 fragment containing both the B- and C-ring subunits.

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“…Keck’s research program is focused on the total synthesis of natural products with biological activity, including bryostatin chemistry. He has reported in Angewandte Chemie on C9‐deoxy bryostatin 1,4a and in ChemBioChem on the resemblance between bryostatin 1 and phorbol esters 4b …”

Section: Awarded …︁mentioning

confidence: 99%

Arthur C. Cope Scholar Awards

2014

Angew Chem Int Ed

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Molecular Modeling, Total Synthesis, and Biological Evaluations of C9‐Deoxy Bryostatin 1

Cited by 15 publications

References 30 publications

Deletion of the C26 Methyl Substituent from the Bryostatin Analogue Merle 23 Has Negligible Impact on Its Biological Profile and Potency

Deletion of the C26 Methyl Substituent from the Bryostatin Analogue Merle 23 Has Negligible Impact on Its Biological Profile and Potency

Total Syntheses of Bryostatins: Synthesis of Two Ring‐Expanded Bryostatin Analogues and the Development of a New‐Generation Strategy to Access the C7–C27 Fragment

Arthur C. Cope Scholar Awards

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