Cyclic conjugated enediynes related to calicheamicins and esperamicins:  calculations, synthesis, and properties

Nicolaou, K. C.; Zuccarello, Guido; Ogawa, Yasushi; Schweiger, E. J.; Kumazawa, Toshihiro

doi:10.1021/ja00222a077

Cited by 303 publications

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“…[9] Photoreduction products such as dienynes, which are formed in the case of benzenoid enediynes, [4b] were not detected. We then irradiated the strained, ten-membered cyclic enediyne 7 [8,10] with a low-pressure mercury lamp (4 Â 20 W) at room temperature for 3 h. Tetrahydronaphthalene (8) was obtained, and an appreciable amount of 1,2-diethynylcyclohexene (9) [11] was formed in all solvents except iPrOH ( Table 2). Compound 9 underwent photolysis under the same reaction conditions, and it was consumed completely upon photolysis in iPrOH for 3 h to give 8 in 3 % yield.…”

Section: Dedicated To Professor Satoru Masamune On the Occasion Of Himentioning

confidence: 99%

“…The formation of 9 in over 50 % yield is highly remarkable because enediyne 9 should arise from the retro-Bergman reaction of the hypothetical diradical intermediate 10, and because 9 has never been isolated in the thermal reaction of 7. [10,12] Scheme 2. Photolysis of 7 in [D 8 ]iPrOH for 5 min (30 % conversion).…”

Section: Dedicated To Professor Satoru Masamune On the Occasion Of Himentioning

confidence: 99%

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Photochemical Cycloaromatization of Non-Benzenoid Enediynes

Kaneko

Takahashi

Hirama

1999

Angew. Chem. Int. Ed.

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Section: Dedicated To Professor Satoru Masamune On the Occasion Of Himentioning

confidence: 99%

Section: Dedicated To Professor Satoru Masamune On the Occasion Of Himentioning

confidence: 99%

Photochemical Cycloaromatization of Non-Benzenoid Enediynes

Kaneko

Takahashi

Hirama

1999

Angew. Chem. Int. Ed.

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“…In this mechanism (Scheme Im) (10) program in these laboratories (23,24). The parent series of 10-through 16-membered ring enediynes (20b-h) were conveniently prepared via the RambergBacklund reaction of the corresponding a-chlorosulfones 19b-h (Scheme IV).…”

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confidence: 99%

Chemistry and biology of natural and designed enediynes.

Nicolaou

Smith²,

Yue³

1993

Proc. Natl. Acad. Sci. U.S.A.

248

172

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“…Key to the reactivity of enediynes is the proximity (7,8) of the terminal -yne C 1 -C 6 carbon atoms, which interact along the reaction coordinate to form the cyclized diradical intermediate ( Fig. 1 B and C).…”

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confidence: 99%

“…For example, ab initio computations indicate that the parent (Z)-hex-3-ene-1,5-diyne possesses a C 1 -C 6 distance of 4.32 Å (9) and is quite stable at physiological temperature with an activation enthalpy (ΔH ‡ ) of 28.2 kcal/mol. Nicolaou et al (7,10) have provided an empirical rule indicating that a critical C 1 -C 6 distance of ∼3.20-3.31 Å is required for spontaneous Bergman cyclization reactivity at 36.5-37.5°C (i.e., physiological temperature). In addition to the C 1 -C 6 distance, other contributions to enediyne reactivity include ring strain effects (11,12) and the underpinning enediyne electronic structure (e.g., configuration interaction, pseudo-JahnTeller effects, etc.)…”

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Designed metalloenediyne warheads damage DNA and outpace DNA polymerase

Kirk¹

2017

Proc. Natl. Acad. Sci. U.S.A.

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Normal cells eventually undergo a highly regulated process of programmed cell death, or apoptosis, while abnormalities in this process may lead to uncontrolled cell proliferation and cancer. Cancer cells differ from normal cells with respect to their resistance to signals that control both cell growth and apoptosis. Furthermore, they divide more rapidly than normal cells, resulting in the development of cancerous tumors and metastasis. This has led to tremendous research efforts that aim to identify the various causes of cancer and aggressively treat this deadly disease. One strategy for combating cancer focuses on the inhibition of DNA polymerases, which function to synthesize DNA and are essential for DNA replication and damage repair. An orthogonal approach centers on the development of chemotherapeutic agents that can damage DNA in a manner that does not allow repair or replication by DNA polymerases. In PNAS, Zaleski and coworkers (1) use this latter approach and describe studies of new enediyne transition metal complexes (metalloenediynes) that function as cytotoxic metal-mediated diradical generators.Enediynes ( Fig. 1) are highly toxic bacterial natural product compounds that contain the 3-ene-1,5-diyne conjugated unit as part of a 9-to 10-member ring system (2). These compounds are susceptible to thermal-activated and photoactivated Bergman cycloaromatization reactions that result in the formation of 1,4-didehydrobenzene diradical derivatives. The diradicals generated from enediynes are highly reactive chemical "warheads" that can abstract hydrogen atoms from the DNA sugar backbone as a mechanistic component of their DNA cleaving reactivity. As such, they are among the most potent naturally occurring cytotoxic compounds that function as antitumor agents (2). Thus, many natural enediynes possess limited therapeutic utility due to their high toxicity. This has led to extensive research efforts focused on the design of new enediyne agents (3), the attachment of the enediyne warhead to drug delivery systems that specifically target DNA (2), and how to trigger a specific event or cascade of events that result in siteselective diradical formation (4). DNA double-strand breaks that are induced by enediyne activity can trigger a DNA damage protein response leading to cell cycle arrest. The activation of checkpoint pathways that regulate the mechanism of DNA repair can then lead to apoptotic cell death if the DNA lesion is not repairable (5).The cycloaromatization reaction that leads to diradical formation is similar to Woodward-Hoffmann [2+2] cycloadditions (6). Key to the reactivity of enediynes is the proximity (7, 8) of the terminal -yne C 1 -C 6 carbon atoms, which interact along the reaction coordinate to form the cyclized diradical intermediate ( Fig. 1 B and C). For example, ab initio computations indicate that the parent (Z)-hex-3-ene-1,5-diyne possesses a C 1 -C 6 distance of 4.32 Å (9) and is quite stable at physiological temperature with an activation enthalpy (ΔH ‡ ) of 28.2 kcal/mol. Nicolaou et a...

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Cyclic conjugated enediynes related to calicheamicins and esperamicins: calculations, synthesis, and properties

Cited by 303 publications

References 0 publications

Photochemical Cycloaromatization of Non-Benzenoid Enediynes

Photochemical Cycloaromatization of Non-Benzenoid Enediynes

Chemistry and biology of natural and designed enediynes.

Designed metalloenediyne warheads damage DNA and outpace DNA polymerase

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