All over the world, societies are facing rapidly aging populations combined with a growing number... more All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer’s disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood–brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood–brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These f...
Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitor... more Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.
Macedonian Journal of Chemistry and Chemical Engineering, 2013
This review article describes the synthesis and coordination chemistry of three types of thiophen... more This review article describes the synthesis and coordination chemistry of three types of thiophenol-based heterodonor ligands containing tertiary phosphine and/or arsine groups in combination with sulfur. Phenylthio(diphenyl)phosphine and -arsine ligands, EPh2(SPh) (E = P, As), incorporate an E–S bond in their structures. Upon reaction with different metal carbonyls, metal-mediated cleavage of the E–S bonds of these ligands has been observed, leading to a variety of sulfur- and phosphorus- or arsenic-containing metallacycles. The structurally isomeric phosphino- and arsinoarylthiols HSC6H4-2-EPh2 (ESH) combine a phosphine or arsine centre with a thiol functionality, which is usually deprotonated on coordination. These compounds have been shown to be very versatile ligands that form stable complexes with a wide range of transition metals. The heterotopic ligand 1-Ph2AsSC6H4-2-PPh2 (P,SAs) not only combines the properties of phenylthio(diphenyl)arsine and 2-diphenylphosphanylbenzeneth...
The role of autophagy in cancer is often complex, ranging from tumor‐promoting to ‐suppressing ef... more The role of autophagy in cancer is often complex, ranging from tumor‐promoting to ‐suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo‐[3‐(η6‐p‐cymene)‐1‐(quinolin‐8‐yl‐acetate)‐3,1,2‐RuC2B9H10] (4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor‐promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy‐prone glioblastomas.
3,1,2-Ruthenadicarbadodecaborane complexes bearing the [C2B9H11]2− (dicarbollide) ligand are robu... more 3,1,2-Ruthenadicarbadodecaborane complexes bearing the [C2B9H11]2− (dicarbollide) ligand are robust scaffolds, with exceptional thermal and chemical stability. Our previous work has shown that these complexes possess promising anti-tumor activities in vitro, and tend to form aggregates (or self-assemblies) in aqueous solutions. Here, we report on the synthesis and characterization of four ruthenium(II) complexes of the type [3-(η6-arene)-1,2-R2-3,1,2-RuC2B9H9], bearing either non-polar (R = Me (2–4)) or polar (R = CO2Me (7)) substituents at the cluster carbon atoms. The behavior in aqueous solution of complexes 2, 7 and the parent unsubstituted [3-(η6-p-cymene)-3,1,2-RuC2B9H11] (8) was investigated via UV-Vis spectroscopy, mass spectrometry and nanoparticle tracking analysis (NTA). All complexes showed spontaneous formation of self-assemblies (108–109 particles mL−1), at low micromolar concentration, with high polydispersity. For perspective applications in medicine, there is thus a...
The [(η6-arene)RuC2B9H11] complexes (arene = p-cymene (2), biphenyl (3) and 1-Me-4-COOEt-C6H4 (4)... more The [(η6-arene)RuC2B9H11] complexes (arene = p-cymene (2), biphenyl (3) and 1-Me-4-COOEt-C6H4 (4)) show cytotoxic activity and excellent selectivity towards specific tumour cells.
Dalton transactions (Cambridge, England : 2003), Jan 6, 2016
A series of Ru(II) arene complexes of mono- and bidentate N-donor ligands with carboxyl or ester ... more A series of Ru(II) arene complexes of mono- and bidentate N-donor ligands with carboxyl or ester groups and chlorido ancillary ligands were synthesised and structurally characterised. The complexes have a distorted tetrahedral piano-stool geometry. The binding interaction was studied with calf thymus DNA (CT-DNA) by absorption titration, viscosity measurement, thermal melting, circular dichroism, ethidium bromide displacement assay and DNA cleavage of plasmid DNA (pBR322), investigated by gel electrophoresis. The dichlorido complexes bind covalently to DNA in the dark, similar to cisplatin, while the monochlorido complexes bind covalently on irradiation, similar to cisplatin analogues. The compounds are selectively cytotoxic against several tumour cell lines and show specific nonlinear correlation between dose and activity. This phenomenon is closely related to their potential to act preferentially as inhibitors of cell division.
A building set for chiral phosphorus. The principle of stereotopic face differentiation is succes... more A building set for chiral phosphorus. The principle of stereotopic face differentiation is successfully applied to a PC bond. A divergent ligand synthesis is feasible after reduction of the chiral auxiliary.
1,2-Bis(N,N-dimethyl-aminochlorophosphanyl)-1,2-dicarba-closo-dodecaborane(12) reacts with lithia... more 1,2-Bis(N,N-dimethyl-aminochlorophosphanyl)-1,2-dicarba-closo-dodecaborane(12) reacts with lithiated phenylacetylene to give a carbaboranyl-based phosphane, while alkynylchlorophosphanes and dilithiated carbaborane give bis(alkynylphosphanyl)carbaboranes.
The generally difficult conjugation of two relevant pharmacophores, indole and carbaborane, has b... more The generally difficult conjugation of two relevant pharmacophores, indole and carbaborane, has been readily achieved by sequential deboronation and substitution yielding a water-soluble carbaboranyl indole.
... environment (max. deviation of N, P from mean planes of trapezoids: 0.240.36 Å). The bidenta... more ... environment (max. deviation of N, P from mean planes of trapezoids: 0.240.36 Å). The bidentate phosphinoamido ligands span the m edges of the distorted dodecahedron to give the mmmm [37b] stereoisomer. This appears ...
All over the world, societies are facing rapidly aging populations combined with a growing number... more All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer’s disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood–brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood–brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These f...
Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitor... more Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.
Macedonian Journal of Chemistry and Chemical Engineering, 2013
This review article describes the synthesis and coordination chemistry of three types of thiophen... more This review article describes the synthesis and coordination chemistry of three types of thiophenol-based heterodonor ligands containing tertiary phosphine and/or arsine groups in combination with sulfur. Phenylthio(diphenyl)phosphine and -arsine ligands, EPh2(SPh) (E = P, As), incorporate an E–S bond in their structures. Upon reaction with different metal carbonyls, metal-mediated cleavage of the E–S bonds of these ligands has been observed, leading to a variety of sulfur- and phosphorus- or arsenic-containing metallacycles. The structurally isomeric phosphino- and arsinoarylthiols HSC6H4-2-EPh2 (ESH) combine a phosphine or arsine centre with a thiol functionality, which is usually deprotonated on coordination. These compounds have been shown to be very versatile ligands that form stable complexes with a wide range of transition metals. The heterotopic ligand 1-Ph2AsSC6H4-2-PPh2 (P,SAs) not only combines the properties of phenylthio(diphenyl)arsine and 2-diphenylphosphanylbenzeneth...
The role of autophagy in cancer is often complex, ranging from tumor‐promoting to ‐suppressing ef... more The role of autophagy in cancer is often complex, ranging from tumor‐promoting to ‐suppressing effects. In this study, two novel hybrid molecules were designed, containing a ruthenacarborane fragment conjugated with a known modulator of autophagy, namely a quinoline derivative. The complex closo‐[3‐(η6‐p‐cymene)‐1‐(quinolin‐8‐yl‐acetate)‐3,1,2‐RuC2B9H10] (4) showed a dual mode of action against the LN229 (human glioblastoma) cell line, where it inhibited tumor‐promoting autophagy, and strongly inhibited cell proliferation, de facto blocking cellular division. These results, together with the tendency to spontaneously form nanoparticles in aqueous solution, make complex 4 a very promising drug candidate for further studies in vivo, for the treatment of autophagy‐prone glioblastomas.
3,1,2-Ruthenadicarbadodecaborane complexes bearing the [C2B9H11]2− (dicarbollide) ligand are robu... more 3,1,2-Ruthenadicarbadodecaborane complexes bearing the [C2B9H11]2− (dicarbollide) ligand are robust scaffolds, with exceptional thermal and chemical stability. Our previous work has shown that these complexes possess promising anti-tumor activities in vitro, and tend to form aggregates (or self-assemblies) in aqueous solutions. Here, we report on the synthesis and characterization of four ruthenium(II) complexes of the type [3-(η6-arene)-1,2-R2-3,1,2-RuC2B9H9], bearing either non-polar (R = Me (2–4)) or polar (R = CO2Me (7)) substituents at the cluster carbon atoms. The behavior in aqueous solution of complexes 2, 7 and the parent unsubstituted [3-(η6-p-cymene)-3,1,2-RuC2B9H11] (8) was investigated via UV-Vis spectroscopy, mass spectrometry and nanoparticle tracking analysis (NTA). All complexes showed spontaneous formation of self-assemblies (108–109 particles mL−1), at low micromolar concentration, with high polydispersity. For perspective applications in medicine, there is thus a...
The [(η6-arene)RuC2B9H11] complexes (arene = p-cymene (2), biphenyl (3) and 1-Me-4-COOEt-C6H4 (4)... more The [(η6-arene)RuC2B9H11] complexes (arene = p-cymene (2), biphenyl (3) and 1-Me-4-COOEt-C6H4 (4)) show cytotoxic activity and excellent selectivity towards specific tumour cells.
Dalton transactions (Cambridge, England : 2003), Jan 6, 2016
A series of Ru(II) arene complexes of mono- and bidentate N-donor ligands with carboxyl or ester ... more A series of Ru(II) arene complexes of mono- and bidentate N-donor ligands with carboxyl or ester groups and chlorido ancillary ligands were synthesised and structurally characterised. The complexes have a distorted tetrahedral piano-stool geometry. The binding interaction was studied with calf thymus DNA (CT-DNA) by absorption titration, viscosity measurement, thermal melting, circular dichroism, ethidium bromide displacement assay and DNA cleavage of plasmid DNA (pBR322), investigated by gel electrophoresis. The dichlorido complexes bind covalently to DNA in the dark, similar to cisplatin, while the monochlorido complexes bind covalently on irradiation, similar to cisplatin analogues. The compounds are selectively cytotoxic against several tumour cell lines and show specific nonlinear correlation between dose and activity. This phenomenon is closely related to their potential to act preferentially as inhibitors of cell division.
A building set for chiral phosphorus. The principle of stereotopic face differentiation is succes... more A building set for chiral phosphorus. The principle of stereotopic face differentiation is successfully applied to a PC bond. A divergent ligand synthesis is feasible after reduction of the chiral auxiliary.
1,2-Bis(N,N-dimethyl-aminochlorophosphanyl)-1,2-dicarba-closo-dodecaborane(12) reacts with lithia... more 1,2-Bis(N,N-dimethyl-aminochlorophosphanyl)-1,2-dicarba-closo-dodecaborane(12) reacts with lithiated phenylacetylene to give a carbaboranyl-based phosphane, while alkynylchlorophosphanes and dilithiated carbaborane give bis(alkynylphosphanyl)carbaboranes.
The generally difficult conjugation of two relevant pharmacophores, indole and carbaborane, has b... more The generally difficult conjugation of two relevant pharmacophores, indole and carbaborane, has been readily achieved by sequential deboronation and substitution yielding a water-soluble carbaboranyl indole.
... environment (max. deviation of N, P from mean planes of trapezoids: 0.240.36 Å). The bidenta... more ... environment (max. deviation of N, P from mean planes of trapezoids: 0.240.36 Å). The bidentate phosphinoamido ligands span the m edges of the distorted dodecahedron to give the mmmm [37b] stereoisomer. This appears ...
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Papers by Evamarie Hey-Hawkins