Synthesis of Boroxifen, A <i>N</i><i>ido-</i>Carborane Analogue of Tamoxifen

Valliant, John F.; Schaffer, Paul; Stephenson, Karin A.; Britten, James F.

doi:10.1021/jo0158229

Cited by 67 publications

(43 citation statements)

References 36 publications

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“…Several unsuccessful attempts at incorporating a functionality such as a carboxylic acid, phenol, trichloromethyl, nitrile or phosphine, which can be subsequently functionalized with an organometallic cluster, onto the tamoxifen skeleton were also made. A partially successful strategy was found with the incorporation of an alkyne functionality following a similar procedure to that reported for the synthesis of a nido-carborane analogue of tamoxifen [16]. Deprotection of 8 or 10 with BBr 3 were not successful but treatment of 10 with Co 2 (CO) 8 , 1b, afforded 11 as an oil (Scheme 4).…”

Section: Studies On the Incorporation Of Clusters Into Tamoxifenmentioning

confidence: 99%

Organometallic cluster analogues of tamoxifen: Synthesis and biochemical assay

Chan¹,

Leong²,

Jaouen³

et al. 2006

Journal of Organometallic Chemistry

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Section: Studies On the Incorporation Of Clusters Into Tamoxifenmentioning

confidence: 99%

Organometallic cluster analogues of tamoxifen: Synthesis and biochemical assay

Chan¹,

Leong²,

Jaouen³

et al. 2006

Journal of Organometallic Chemistry

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“…Carboranes have also been reported to be a potential pharmacophore. It allows the bioisosteric replacement for phenyl rings, adamantine or steroid structures as rigid scaffolding in bioactive molecules and pharmacological agents [8,[13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Droplet electrochemical study of the pH dependent redox behavior of novel ferrocenyl-carborane derivatives and its application in specific cancer cell recognition

Shah

et al. 2015

Analytica Chimica Acta

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“…This same carborane derivative exhibited a 10-fold increase in potency in vivo as compared with an endogenous 33-membered pheromone biosynthesisactivating neuropeptide because of lack of vulnerability from aminopeptidase attack (12). Further success using carboranes has resulted in the discovery of powerful carboranyl analogues of the anti-estrogen tamoxifen (13) and the controversial drug thalidomide (14). In an effort to expand upon these successes, we have endeavored to identify further biological targets where the unique properties of carboranes may prove to be beneficial.…”

mentioning

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.

109

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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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Synthesis of Boroxifen, A Nido-Carborane Analogue of Tamoxifen

Cited by 67 publications

References 36 publications

Organometallic cluster analogues of tamoxifen: Synthesis and biochemical assay

Organometallic cluster analogues of tamoxifen: Synthesis and biochemical assay

Droplet electrochemical study of the pH dependent redox behavior of novel ferrocenyl-carborane derivatives and its application in specific cancer cell recognition

Synthesis and evaluation of transthyretin amyloidosis inhibitors containing carborane pharmacophores

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