Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics

Nicolaou, K. C.; Zuccarello, Guido; Riemer, Claus; Estevez, VA; Dai, Wei

doi:10.1021/ja00045a005

Cited by 160 publications

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“…It was correctly predicted from the calculated cd distance of 3.20 A that this molecule would be sufficiently stable for isolation and handling at ambient temperatures but would undergo the Bergman reaction at physiological temperature at a sufficient rate to cause DNA cleavage. Thus enediyne 22 caused significant cleavage of phage 4X174 double-stranded supercoiled DNA in the absence of any additives at concentrations as low as 10 ,uM at 37°C, with the extent of cleavage being dependent upon concentration, incubation time, and temperature (24,27). As a control, it was demonstrated that the corresponding Bergman cyclized product 24 (Scheme V) caused no DNA cleavage (24,27).…”

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confidence: 94%

“…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%

“…The diol 22 (Scheme V) was designed in order to endow the molecule with some degree of water solubility and also to provide for the option of attachment to delivery systems (24,27). It was correctly predicted from the calculated cd distance of 3.20 A that this molecule would be sufficiently stable for isolation and handling at ambient temperatures but would undergo the Bergman reaction at physiological temperature at a sufficient rate to cause DNA cleavage.…”

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confidence: 99%

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Chemistry and biology of natural and designed enediynes.

Nicolaou

Smith²,

Yue³

1993

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

250

172

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confidence: 94%

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confidence: 99%

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confidence: 99%

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Chemistry and biology of natural and designed enediynes.

Nicolaou

Smith²,

Yue³

1993

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

250

172

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“…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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confidence: 99%

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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“…Compounds 5a-5c and their corresponding Pd/C-catalyzed hydrogenation products were transformed into dibromides 7a-7c and 6a-6c, respectively, by bromination using PPh 3 /CBr 4 . 29 Alkylation of the corresponding azaaromatic free bases, including 2-picoline, 3-picoline, 4-picoline, and nicotine, using the above obtained dibromide 6a, 6b, 6c, 7a, 7b, or 7c, afforded the corresponding bis-azaaromatic quaternary ammonium compound 3a, 3b, 3c, 4a, 4b, or 4c, respectively (Table 1). Among these analogues, the 1,2-isomers in both the 3 and 4 series (3a and 4a, respectively) and 1,3-isomers in series 4 (i.e., 4b) represent 'angular' conformations of bPiDDB, whereas the 1,3-isomers in series 3 (i.e., 3b, see Fig.…”

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Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

Zheng

Zhang

Pivavarchyk

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure-activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release. KeywordsNicotinic acetylcholine receptor; Quaternary ammonium; Dopamine release; Nicotine addiction Tobacco contains one of the most widely abused psychoactive substances in the world, that is, (S)-nicotine (1; Fig. 1), which is believed to be primarily responsible for tobacco dependence. 1,2 Like many abused drugs, nicotine addiction has been linked to the release of the neurotransmitter, dopamine (DA). [3][4][5] Nicotine-evoked DA release, which is thought to be responsible for reward, leading to addiction, is believed to result from activation of presynaptic neuronal nicotinic acetylcholine receptors (nAChRs). [6][7][8][9][10][11][12] Nicotine stimulates all known nAChR subtypes 13 and upon activation, these receptors modulate the release of various neurotransmitters. [14][15][16] The subunit composition of nAChR subtypes responsible for mediating nicotine-evoked DA release has not been elucidated conclusively. 17 In this regard, subtype-selective nAChR antagonists, which inhibit nicotine-evoked DA release, may have potential as novel treatments for nicotine addiction. [18][19][20][21] Previous work in our laboratories has led to the discovery of N, N′-dodecane-1,12-diyl-bis-3picolinium dibromide (bPiDDB; 2; Fig. 1), which potently inhibited nAChR subtype(s) mediating nicotine-evoked [ 3 H]DA release from superfused rat striatal slices in vitro (IC 50 = 5 nM), and did not interact at the ligand binding site of either α4β2 * or α7 * nAChRs. 22,23 In vivo microdialysis studies demonstrated that pretreatment with bPiDDB dose-dependently reduced the increase in extracellular DA in rat nucleus accumbens produced by acute or repeated nicotine treatment. 24 nature and polarity of the molecule, bPiDDB is brain bioavailable, due to its facilitated transport via the blood-brain barrier choline transporter. 25 Moreover, behavioral studies in rats showed that bPiDDB dose-dependently decreased intravenous nicotine selfadministration, but not sucrose-maintained responding, suggesting a specific inhibition of nicotine reward. 26 Taken together, bPiDDB and its analogues represent lead compounds for the development of a new class of therapeutic agents for the treatment of tobacco dependence.bPiDDB (2) contains two 3-picolinium head groups connected via an N-N-12-methylene linker unit; thus, it is a highly flexible, di-cationic molecule. A better understan...

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Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics

Cited by 160 publications

References 0 publications

Chemistry and biology of natural and designed enediynes.

Chemistry and biology of natural and designed enediynes.

Designed metalloenediyne warheads damage DNA and outpace DNA polymerase

Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

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