Biomimetic Total Syntheses of (+)-Cephalostatin 7, (+)-Cephalostatin 12, and (+)-Ritterazine K

Jeong, Jae Uk; Sutton, Scott C.; Kim, Seongkon; Fuchs, P. L.

doi:10.1021/ja00145a045

Cited by 67 publications

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“…The Fuchs group has also studied the biomimetic coupling of the northern and southern units [84], following the hypothesis that Nature might utilize the random 5) The reaction actually has a yield of 81%, but 15% corresponds to the C25 epimer of South 7 carried onward from the Sharpless dihydroxylation reaction.…”

Section: Alkaloids Derived From Terpene Precursorsmentioning

confidence: 99%

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

Gravel

2011

Biomimetic Organic Synthesis

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Section: Alkaloids Derived From Terpene Precursorsmentioning

confidence: 99%

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

Gravel

2011

Biomimetic Organic Synthesis

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“…[1] In the 1980s, reports emerged describing the first members of these unique dimeric bis -steroidal pyrazine spiroketals with potent anti-tumor activity. [2,3] Soon thereafter, synthetic campaigns were launched, successfully validating and refining the structural assignments, [4] as well as providing materials to assess structure activity relationships (SARs). [5] These synthetic efforts were key in providing initial validation of the unique cytostatic activity of this class of molecules [6] and demonstrating that the ritterazines and cephalostatins share a common MOA.…”

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confidence: 99%

Ritterostatin G_N1_N, a Cephalostatin–Ritterazine Bis‐steroidal Pyrazine Hybrid, Selectively Targets GRP78

et al. 2017

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Natural products discovered using agnostic approaches, unlike rationally designed or HTS obtained leads, offer the ability to reveal new biological pathways, and hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine-cephalostatin family of natural products displays robust and potent anti-tumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we use comparative cellular and molecular biological methods to uncover the ritterazine/cephalostatin mode of cytotoxic action (MOA) in human tumor cells. Our findings indicate that while ritterostatin GN1N, a cephalostatin-ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER) based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.

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“…By 1998, Fuchs and colleagues had completed the first total synthesis of 1 (in 65 synthetic steps) 4a and of two additional members of the cephalostatin family (7 and 12) and ritterazine K. 4b However, owing to the complexity of the targets only very small amounts of these substances were produced and in very low overall yields (2 mg of 1 , 10 −5 %, for instance), 4a not suitable to supply sufficient samples at reasonable cost for extended biological evaluation. However, the recent enantioselective total synthesis of cephalostatin 1 by Shair 3c does offer a potentially useful approach to scale-up and represents a splendid contribution.…”

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The Cephalostatins. 22. Synthesis of Bis-steroidal Pyrazine Pyrones

et al. 2012

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Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ-pyrone (in 16). The synthesis of pyrazine 12 from 5α-dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D–F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.

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Biomimetic Total Syntheses of (+)-Cephalostatin 7, (+)-Cephalostatin 12, and (+)-Ritterazine K

Cited by 67 publications

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Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

Ritterostatin G_N1_N, a Cephalostatin–Ritterazine Bis‐steroidal Pyrazine Hybrid, Selectively Targets GRP78

The Cephalostatins. 22. Synthesis of Bis-steroidal Pyrazine Pyrones

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Biomimetic Total Syntheses of (+)-Cephalostatin 7, (+)-Cephalostatin 12, and (+)-Ritterazine K

Cited by 67 publications

References 0 publications

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

Ritterostatin GN1N, a Cephalostatin–Ritterazine Bis‐steroidal Pyrazine Hybrid, Selectively Targets GRP78

The Cephalostatins. 22. Synthesis of Bis-steroidal Pyrazine Pyrones

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Ritterostatin G_N1_N, a Cephalostatin–Ritterazine Bis‐steroidal Pyrazine Hybrid, Selectively Targets GRP78