Synthetic studies toward (+)-cortistatin A

Wang, Zhang; Dai, Mingji; Park, Peter K.

doi:10.1016/j.tet.2011.10.026

Cited by 18 publications

(6 citation statements)

References 67 publications

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“…Further carbamate studies were outside of our interest because they mandated two pot processes. However, our early findings agreed with observations regarding carbamate DoM additions to aldehydes popularized by Snieckus, and subsequent acidification employed by Danishefsky and co-workers …”

Section: Ortho-aliphatic Phenols From O-qmssupporting

confidence: 92%

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The Domestication of ortho-Quinone Methides

et al. 2014

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ConspectusAn ortho-quinone methide (o-QM) is a highly reactive chemical motif harnessed by nature for a variety of purposes. Given its extraordinary reactivity and biological importance, it is surprising how few applications within organic synthesis exist. We speculate that their widespread use has been slowed by the complications that surround the preparation of their precursors, the harsh generation methods, and the omission of this stratagem from computer databases due to its ephemeral nature.About a decade ago, we discovered a mild anionic triggering procedure to generate transitory o-QMs at low temperature from readily available salicylaldehydes, particularly OBoc derivatives. This novel reaction cascade included both the o-QM formation and the subsequent consumption reaction. The overall transformation was initiated by the addition of the organometallic reagent, usually a Grignard reagent, which resulted in the formation of a benzyloxy alkoxide. Boc migration from the neighboring phenol produced a magnesium phenoxide that we supposed underwent β-elimination of the transferred Boc residue to form an o-QM for immediate further reactions. Moreover, the cascade proved controllable through careful manipulation of metallic and temperature levers so that it could be paused, stopped, or restarted at various intermediates and stages. This new level of domestication enabled us to deploy o-QMs for the first time in a range of applications including diastereocontrolled reactions.This sequence ultimately could be performed in either multipot or single pot processes. The subsequent reaction of the fleeting o-QM intermediates included the 1,4-conjugate additions that led to unbranched or branched ortho-alkyl substituted phenols and Diels–Alder reactions that provided 4-unsubstituted or 4-substituted benzopyrans and chroman ketals. The latter cycloadducts were obtained for the first time with outstanding diastereocontrol. In addition, the steric effects of the newly created stereocenters in subsequent reactions of chroman ketals and acetals were studied and proved predictable. Through the use of a chiral auxiliary, Diels–Alder products were deployed in numerous enantioselective reactions including several complex natural products syntheses. In this Account, we summarize our efforts, which we hope have contributed to the synthetic renaissance for this venerable species.

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Section: Ortho-aliphatic Phenols From O-qmssupporting

confidence: 92%

“…However, our early findings agreed with observations regarding carbamate DoM additions to aldehydes popularized by Snieckus, 30 and subsequent acidification employed by Danishefsky and co-workers. 31 …”

Section: Ortho -Aliphatic Phenols From O mentioning

confidence: 99%

The Domestication of ortho-Quinone Methides

et al. 2014

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“…CA has been reported to display antiproliferative properties toward HUVECs and antileukemic activity in CA-sensitive AML cell lines by selectively inhibiting CDK8 activity (7 – 9). Importantly, the characteristics necessary for the antiretroviral activity of dCA do not seem to overlap features needed for HUVECs’ antiangiogenic activity, which requires at least one OH or NMe 2 in ring A, a certain A-B-C skeleton angle, no oxidation of C 16 and C 17 in ring D, and an intact stereochemistry of ring E-F (30).…”

Section: Resultsmentioning

confidence: 99%

Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat

Mediouni

Chinthalapudi

Ekka

et al. 2019

mBio

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Tat activates virus production, and limited Tat transactivation correlates with HIV-1 latency. The Tat inhibitor dCA locks HIV in persistent latency. This drug class enables block-and-lock functional cure approaches, aimed at reducing residual viremia during therapy and limiting viral rebound. dCA may also have additional therapeutic benefits since Tat is also neurotoxic. Unfortunately, Tat inhibitors are not clinically available. We generated chemical derivatives and rationalized binding to an active and specific Tat conformer. dCA features required for Tat inhibition are distinct from features needed for inhibition of cyclin-dependent kinase 8 (CDK8), the only other known target of dCA. Furthermore, knockdown of CDK8 did not impact dCA’s activity on HIV-1 transcription. Binding of dCA to Tat’s basic domain altered the local protein environment and rendered Tat more resistant to proteolytic digestion. dCA locks a transient conformer of Tat, blocking functions dependent on its basic domain, namely its ability to amplify viral transcription. Our results define dCA’s mode of action, support structure-based-design strategies targeting Tat, and provide valuable information for drug development around the dCA pharmacophore.

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“…33 is the representative active analogue obtained by synthesis. Recently, although the total synthesis of (+)-cortistatin A was not accomplished, 654 the work sets the stage for several approaches for the preparation of novel analogues.…”

Section: Polyoxygenated Marine Steroidsmentioning

confidence: 99%

Anticancer steroids: linking natural and semi-synthetic compounds

et al. 2013

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Steroids, a widespread class of natural organic compounds occurring in animals, plants and fungi, have shown great therapeutic value for a broad array of pathologies. The present overview is focused on the anticancer activity of steroids, which is very representative of a rich structural molecular diversity and ability to interact with various biological targets and pathways. This review encompasses the most relevant discoveries on steroid anticancer drugs and leads through the last decade and comprises 668 references.

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Synthetic studies toward (+)-cortistatin A

Cited by 18 publications

References 67 publications

The Domestication of ortho-Quinone Methides

The Domestication of ortho-Quinone Methides

Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat

Anticancer steroids: linking natural and semi-synthetic compounds

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