2‐Carbaborane‐3‐phenyl‐1H‐indoles—Synthesis via McMurry Reaction and Cyclooxygenase (COX) Inhibition Activity

Abstract

Cyclooxygenase-2 (COX-2) inhibitors have been in the focus of medicinal chemistry for years and many compounds exhibiting high selectivity and affinity were developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX-2-selective 2,3-disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2-carbaborane-3-phenyl-1H-indoles could be synthesized by McMurry cyclization of the corresponding amides. While the meta-carbaboranyl-substituted derivatives (3a-c) lacked COX inhibition activity, the ortho-carbaboranyl analog (3d) was active but showed a selectivity shift towards COX-1.

nido‐Dicarbaborate Induces Potent and Selective Inhibition of Cyclooxygenase‐2

“…[6] The pronounced isomer-dependent COX inhibitory potency of carbaborane-containing, indole-based inhibitors has not been described for any other class of inhibitors to date. Whereas the introduction of ortho -carbaborane yields active inhibitors, the use of meta - or para -carbaborane results in suppression of the COX inhibitory potency.…”

“…[6c] However, the amide bond in indomethacin is rather labile and becomes more prone to hydrolysis on introduction of the carbaborane in 1 , due to the high electron deficiency of the cluster. In turn, the electron-withdrawing effect of the carbonyl group adjacent to the carbaborane also increases the lability of the cluster, [11] which results in rapid deboronation of 1 in polar solvents such as methanol (see Supporting Information).…”

IUPAC 2013 Distinguished Women in Chemistry or Chemical Engineering / New Members of the Royal Swedish Academy of Sciences

“…Hey‐Hawkins and her research group are interested in phosphorus‐functionalized and phosphorus‐rich compounds, carbaborane chemistry, and mono‐ and multinuclear transition‐metal complexes for applications such as homogeneous catalysis, and biological and medicinal chemistry. She has reported in Chemistry—A European Journal on the asymmetric phospha‐Diels–Alder reaction,2a and in ChemMedChem on the synthesis and inhibition activity of carbaboranyl‐functionalized indoles 2b. Hey‐Hawkins is on the editorial or advisory boards of ChemPlusChem and the Zeitschrift für Anorganische und Allgemeine Chemie…”

IUPAC 2013 Distinguished Women in Chemistry or Chemical Engineering / Neue Mitglieder der königlichen schwedischen Akademie der Wissenschaften

“…Hey‐Hawkins und ihre Forschungsgruppe befassen sich mit phosphorfunktionalisierten und phosphorreichen Verbindungen, der Carbaboranchemie sowie ein‐ und mehrkernigen Übergangsmetallkomplexen in der homogenen Katalyse, der biologischen und der medizinischen Chemie. In Chemistry—A European Journal erschien eine Arbeit von ihr über die asymmetrische Phospha‐Diels‐Alder‐Reaktion2a und in ChemMedChem eine über die Synthese und Inhibierungswirkung carbaboranylfunktionalisierter Indole 2b. Hey‐Hawkins gehört den Editorial und Advisory Boards von ChemPlusChem bzw.…”