Rapid Cage Degradation of 1-Formyl- and 1-Alkyloxycarbonyl-Substituted 1,2-Dicarba-<i>closo</i>-dodecaboranes by Water or Methanol in Polar Organic Solvents

Schaeck, John; Kahl, Stephen B.

doi:10.1021/ic980995a

Cited by 50 publications

(38 citation statements)

References 6 publications

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“…Therefore, the lower the % ff, the more efficacious the inhibitor. A recent report has indicated that o-carborane, when possessing an electron-withdrawing group, such as carbonyl, ␣ to a cage carbon, is prone to nucleophilic attack and degradation to the corresponding anionic B 9 nido-carborane cage in the presence of wet polar organic compounds (46). Consequently, 1 H and 13 C NMR studies were performed on the methyl ester of 1 in both DMSO and acetone.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Julius

Farha²,

Chiang

et al. 2007

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

110

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Carboranes represent a potentially rich but underutilized class of inorganic and catabolism-inert pharmacophores. The regioselectivity and ease of derivatization of carboranes allows for facile syntheses of a wide variety of novel structures. The steric bulk, rigidity, and ease of B-and C-derivatization and lack ofinteractions associated with hydrophobic carboranes may be exploited to enhance the selectivity of previously identified bioactive molecules. Transthyretin (TTR) is a thyroxine-transport protein found in the blood that has been implicated in a variety of amyloid related diseases. Previous investigations have identified a variety of nonsteroidal antiinflammatory drugs (NSAIDs) and structurally related derivatives that imbue kinetic stabilization to TTR, thus inhibiting its dissociative fragmentation and subsequent aggregation to form putative toxic amyloid fibrils. However, the cyclooxygenase (COX) activity associated with these pharmaceuticals may limit their potential as long-term therapeutic agents for TTR amyloid diseases. Here, we report the synthesis and evaluation of carborane-containing analogs of the promising NSAID pharmaceuticals previously identified. The replacement of a phenyl ring in the NSAIDs with a carborane moiety greatly decreases their COX activity with the retention of similar efficacy as an inhibitor of TTR dissociation. The most promising of these compounds, 1-carboxylic acid-7-[3-fluorophenyl]-1,7-dicarba-closo-dodecaborane, showed effectively no COX-1 or COX-2 inhibition at a concentration more than an order of magnitude larger than the concentration at which TTR dissociation is nearly completely inhibited. This specificity is indicative of the potential for the exploitation of the unique properties of carboranes as potent and selective pharmacophores.amyloid ͉ cyclooxygenase ͉ nonsteroidal antiinflammatory drug ͉ fibril T he dicarba-closo-dodecaboranes (carboranes) are icosahedral carbon-containing boron clusters with extraordinary characteristic properties (such as resistance to catabolism, kinetic inertness to reagents, strong hydrophobicity, and wellestablished chemistry) that afford the opportunity for their exploitation as novel hydrophobic pharmacophores. The three isomeric dicarbon carboranes, closo-1,2-C 2 B 10 H 12 , closo-1,7-C 2 B 10 H 12 , and closo-1,12-C 2 B 10 H 12 , commonly known as ortho-, meta-, and para-carborane, respectively, share approximately the same volume as a rotated phenyl ring. This, as well as their structural integrity, ease of substitution, and delocalized bonding, suggests their description as three-dimensional analogs of aromatic hydrocarbons (1), allowing their facile substitution for phenyl rings as rigid scaffolding in pharmacological agents. This rigid scaffolding can be easily and selectively derivatized through deprotonation of the slightly acidic C-H vertices by a strong base (alkyllithium reagents, Grignard reagents, etc.) affording a strongly nucleophilic carboranyl anion capable of reaction with a wide range of electrophiles, inclu...

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Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Julius

Farha²,

Chiang

et al. 2007

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

110

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“…However, carbaboranes tend to undergo deboronation of the cluster (decapping) under such conditions, and their lability is noticeably enhanced by carbonyl groups. 4 The carboxylic acid congeners of the carbaboranyl ketone, salborin and asborin (1-acetoxy-1,2-dicarba-closo-dodecaboranyl-2-carboxylic acid), were shown to be already decapped under neutral conditions in aqueous solution. 5 Furthermore, also the exo-polyhedral C-C bond of carbonyl-substituted carbaboranes is prone to cleavage under alkaline conditions.…”

Section: Resultsmentioning

confidence: 99%

“…The compound was synthesised according to the literature. 4 1 H NMR (CDCl 3 ): δ = 1.30-3.50 (10H, br, C 2 B 10 H 10 ),…”

Section: Generalmentioning

confidence: 99%

Reduction of hydroxy-functionalised carbaboranyl carboxylic acids and ketones by organolithium reagents

et al. 2015

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While the reaction of carbaboranyl carboxylic acids and ketones with organolithium reagents generally leads to cleavage of the exo-polyhedral C-C bond, introduction of a hydroxyl group at the second carbon atom of the cluster enables the reduction of the carbonyl compounds to tertiary alcohols. The proposed mechanism involving the formation of dimeric contact ion pairs was supported by X-ray crystallography and theoretical calculations.

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“…During this step, the o-carborane cages, owing to their sensitivity to even moderately strong nucleophiles -including the templating agent Mg II (n-OPr) 2 in n-PrOH -may undergo significant chemical and structural changes, affording complex mixtures of anionic (nido) species. It is well known, indeed, that treatment of o-carboranes with different nucleophiles, including alkaline-metal alkoxides, represents a useful synthetic tool for inducing the closo→nido conversion of the carborane cage [57][58][59][60][61][62].…”

Section: Lipophilic Carboranyl-porphyrazines: Synthesis and Spectroscmentioning

confidence: 99%

Carboranylporphyrazines for anti-cancer therapies: synthesis and physicochemical properties

Pietrangeli

Ristori

Rosa

et al. 2010

J. Porphyrins Phthalocyanines

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Rapid Cage Degradation of 1-Formyl- and 1-Alkyloxycarbonyl-Substituted 1,2-Dicarba-closo-dodecaboranes by Water or Methanol in Polar Organic Solvents

Abstract: The previously unreported rapid degradation of certain closo-carboranes cages to nido-carborane cages by water or methanol in highly polar aprotic solvents is discussed.

Cited by 50 publications

References 6 publications

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

Reduction of hydroxy-functionalised carbaboranyl carboxylic acids and ketones by organolithium reagents

Carboranylporphyrazines for anti-cancer therapies: synthesis and physicochemical properties

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