A tandem hydroamination-alkynylation reaction to furnish tetrasubstituted propargylic amines is d... more A tandem hydroamination-alkynylation reaction to furnish tetrasubstituted propargylic amines is developed.
A tandem hydroamination–alkynylation was developed as a unique mode of accessing tetrasubstituted... more A tandem hydroamination–alkynylation was developed as a unique mode of accessing tetrasubstituted propargylic amines. The first equivalent of an alkyne acts as the electrophile in a Markovnikov hydroamination. The resultant ketimine intermediate is attacked by the second equivalent of alkyne in its nucleophilic copper acetylide form. Studies on the role of each component indicate that the overall reaction is first-order in copper, amine, and alkyne. In addition, a tandem hydroamination–hydrovinylation provides for an unprecedented onestep synthesis of a 1-amino-1,3-butadiene from phenylacetylene and morpholine.
Gold(III) complexes bearing bidentate ligands based on the 1,10-phenanthroline and 2,2'-bipyridin... more Gold(III) complexes bearing bidentate ligands based on the 1,10-phenanthroline and 2,2'-bipyridine scaffolds have shown promising anticancer activity against a variety of tumor cell lines. In particular, our laboratory has previously found that a pseudo five coordinate gold(III) complex possessing the 2,9-di-sec-butyl-1,10-phenanthroline ligand {[((di-sec-butyl)phen)AuCl3]} exhibits antitumor activity against a panel of five different lung and head-neck tumor cell lines. However, the [((di-sec-butyl)phen)AuCl3] complex was determined to be less active than the free 2,9-di-sec-butyl-1,10-phenanthroline ligand. In order to determine if this class of gold(III) complexes has a distinct mechanism of initiating tumor cell death or if these gold complexes simply release the polypyridyl ligand in the intracellular environment, structural analogues of the [((di-sec-butyl)phen)AuCl3] complex have been synthesized and structurally characterized. These structural congeners were prepared by using mono-alkyl and di-phenyl substituted 1,10-phenanthroline ligands, di-alkyl and di-phenyl substituted 4-methyl-1,10-phenanthroline ligands, and mono-alkyl 2,2'-bipyridine ligands. The redox stability of this library of distorted square pyramidal gold(III) complexes has been studied and the in vitro antitumor activity of gold(III) complexes and corresponding polypyridyl ligands has been determined. The [((di-n-butyl)phen)AuCl3] and [((mono-n-butyl)phen)AuCl3] complexes have been found to be significantly more potent at inhibiting the growth of A549 lung tumor cells than the clinically used drug cisplatin. More importantly, these two gold(III) complexes are significantly more active than their respective free ligands, providing evidence that this class of pseudo five coordinate gold(III) complexes has a mechanism of initiating tumor cell death that is independent of the free ligand.
Cisplatin [cis-diamminedichloroplatinum-(II)] has been used since 1978 to treat a number of diffe... more Cisplatin [cis-diamminedichloroplatinum-(II)] has been used since 1978 to treat a number of different cancer cell lines. However, its effectiveness has been limited due to both harmful side effects as well as the development of cisplatin resistant cancers. Thus, alternatives to cisplatin have become an important focus in anti-cancer research. Gold-(III), an isoelectronic species to platinum-(II), has been of focus to us because of its ability to form metal complexes with similar geometries to platinum-(II) complexes. Previously, 2-sec-butyl-1,10-phenanthroline (sec-butylphen) and its corresponding [(sec-butylphen)AuCl3] complex were synthesized and their anticancer properties subsequently characterized by means of in-vitro tumor cytotoxicity studies. These studies showed a significantly higher cytotoxicity for the sec-butylphen ligand and gold-(III) complex than cisplatin. In addition, when the IC50 values of the free ligand and gold-(III) complex were compared, it was revealed that the free ligand was more cytotoxic, suggesting that it is more active in tumor cell death. In order to determine if gold-(III) complexes have a distinct mechanism for killing cancer cells, structural analogues were synthesized: 2-methyl-9-sec-butyl-1,10-phenanthroline, 2,9-di-sec-butyl-1,10-phenanthroline, and 2,9-di-methyl-1,10-phenanthroline, as well as their corresponding gold-(III) complexes. Their structures were verified using 1H NMR, X-ray crystallography, and elemental analysis. SRB cytotoxicity studies revealed that both ligand and gold-(III) complexes displayed greater cytotoxicity than cisplatin. The data also indicated that the gold-(III) complex antitumor activity does not change as a function of ligand IC50, suggesting that the gold-(III) complexes have a distinct mechanism of tumor cell death. Current research in our laboratory is focused on mono-substituted analogues of 1,10-phenanthroline. 2-n-butyl-1,10-phenanthroline and its gold-(III) complex have been synthesized and their structures have been verified by means of 1H NMR and X-ray crystallography. Elemental analysis, as well as GSH and SRB studies are currently underway.
Cisplatin, [cis-diamminedichloroplatinum-(II)], has been used since 1978 to treat a number of dif... more Cisplatin, [cis-diamminedichloroplatinum-(II)], has been used since 1978 to treat a number of different cancer cell lines; however, its effectiveness has been limited due to both harmful side effects and the development of cisplatin resistant cancers. Gold-(III) is an isoelectronic and isostructural species to platinum-(II), suggesting it has potential as an anticancer agent. In particular, gold-(III) complexes bearing bidentate ligands based on 1,10-phenanthroline and 2,2′-bipyridine have exhibited significant anticancer activity against a variety of tumor cell lines. Previously, our lab found that a pseudo five-coordinate gold-(III) complex bearing the 2,9-di-sec-butyl-1,10-phenanthroline ligand,[(di-sec-butylphen)AuCl3], exhibited anticancer activity against five different lung and head-neck tumor cell lines; however, the complex was found to be less active than the free 2,9-di-sec-butyl-1,10-phenanthroline ligand. In order to determine if our class of gold-(III) complexes have a distinct mechanism of tumor cell death or if they simply release the ligand into the intracellular environment, a library of structural analogues of the original complex were synthesized using mono-alkyl and di-phenyl substituted 1,10-phenanthroline ligands, di-alkyl and di-phenyl substituted 4-methyl-1,10-phenanthroline ligands, and mono-alkyl 2,2′-bipyridine ligands. The redox stability of these distorted square pyramidal gold-(III) complexes was studied and the in vitro antitumor activity of the gold-(III) complexes and corresponding free ligands were determined. The [(di-n-butylphen)AuCl3] and [(mono-n-butylphen)AuCl3] complexes were found to not only be more effective than cisplatin at inhibiting the growth of A549 lung tumor cells, but also more active than their respective free ligands, providing evidence that this class of gold-(III) complexes has a mechanism of tumor cell death that is independent of the free ligand. Currently, our laboratory is investigating the activity of platinum-(II) complexes with the same set of ligands based on 1,10-phenanthroline and 2,2′-bipyridine in an effort to compare their activity with our gold-(III) complexes. Structural analysis, as well as GSH and SRB studies, is currently underway.
A tandem hydroamination-alkynylation reaction to furnish tetrasubstituted propargylic amines is d... more A tandem hydroamination-alkynylation reaction to furnish tetrasubstituted propargylic amines is developed.
A tandem hydroamination–alkynylation was developed as a unique mode of accessing tetrasubstituted... more A tandem hydroamination–alkynylation was developed as a unique mode of accessing tetrasubstituted propargylic amines. The first equivalent of an alkyne acts as the electrophile in a Markovnikov hydroamination. The resultant ketimine intermediate is attacked by the second equivalent of alkyne in its nucleophilic copper acetylide form. Studies on the role of each component indicate that the overall reaction is first-order in copper, amine, and alkyne. In addition, a tandem hydroamination–hydrovinylation provides for an unprecedented onestep synthesis of a 1-amino-1,3-butadiene from phenylacetylene and morpholine.
Gold(III) complexes bearing bidentate ligands based on the 1,10-phenanthroline and 2,2'-bipyridin... more Gold(III) complexes bearing bidentate ligands based on the 1,10-phenanthroline and 2,2'-bipyridine scaffolds have shown promising anticancer activity against a variety of tumor cell lines. In particular, our laboratory has previously found that a pseudo five coordinate gold(III) complex possessing the 2,9-di-sec-butyl-1,10-phenanthroline ligand {[((di-sec-butyl)phen)AuCl3]} exhibits antitumor activity against a panel of five different lung and head-neck tumor cell lines. However, the [((di-sec-butyl)phen)AuCl3] complex was determined to be less active than the free 2,9-di-sec-butyl-1,10-phenanthroline ligand. In order to determine if this class of gold(III) complexes has a distinct mechanism of initiating tumor cell death or if these gold complexes simply release the polypyridyl ligand in the intracellular environment, structural analogues of the [((di-sec-butyl)phen)AuCl3] complex have been synthesized and structurally characterized. These structural congeners were prepared by using mono-alkyl and di-phenyl substituted 1,10-phenanthroline ligands, di-alkyl and di-phenyl substituted 4-methyl-1,10-phenanthroline ligands, and mono-alkyl 2,2'-bipyridine ligands. The redox stability of this library of distorted square pyramidal gold(III) complexes has been studied and the in vitro antitumor activity of gold(III) complexes and corresponding polypyridyl ligands has been determined. The [((di-n-butyl)phen)AuCl3] and [((mono-n-butyl)phen)AuCl3] complexes have been found to be significantly more potent at inhibiting the growth of A549 lung tumor cells than the clinically used drug cisplatin. More importantly, these two gold(III) complexes are significantly more active than their respective free ligands, providing evidence that this class of pseudo five coordinate gold(III) complexes has a mechanism of initiating tumor cell death that is independent of the free ligand.
Cisplatin [cis-diamminedichloroplatinum-(II)] has been used since 1978 to treat a number of diffe... more Cisplatin [cis-diamminedichloroplatinum-(II)] has been used since 1978 to treat a number of different cancer cell lines. However, its effectiveness has been limited due to both harmful side effects as well as the development of cisplatin resistant cancers. Thus, alternatives to cisplatin have become an important focus in anti-cancer research. Gold-(III), an isoelectronic species to platinum-(II), has been of focus to us because of its ability to form metal complexes with similar geometries to platinum-(II) complexes. Previously, 2-sec-butyl-1,10-phenanthroline (sec-butylphen) and its corresponding [(sec-butylphen)AuCl3] complex were synthesized and their anticancer properties subsequently characterized by means of in-vitro tumor cytotoxicity studies. These studies showed a significantly higher cytotoxicity for the sec-butylphen ligand and gold-(III) complex than cisplatin. In addition, when the IC50 values of the free ligand and gold-(III) complex were compared, it was revealed that the free ligand was more cytotoxic, suggesting that it is more active in tumor cell death. In order to determine if gold-(III) complexes have a distinct mechanism for killing cancer cells, structural analogues were synthesized: 2-methyl-9-sec-butyl-1,10-phenanthroline, 2,9-di-sec-butyl-1,10-phenanthroline, and 2,9-di-methyl-1,10-phenanthroline, as well as their corresponding gold-(III) complexes. Their structures were verified using 1H NMR, X-ray crystallography, and elemental analysis. SRB cytotoxicity studies revealed that both ligand and gold-(III) complexes displayed greater cytotoxicity than cisplatin. The data also indicated that the gold-(III) complex antitumor activity does not change as a function of ligand IC50, suggesting that the gold-(III) complexes have a distinct mechanism of tumor cell death. Current research in our laboratory is focused on mono-substituted analogues of 1,10-phenanthroline. 2-n-butyl-1,10-phenanthroline and its gold-(III) complex have been synthesized and their structures have been verified by means of 1H NMR and X-ray crystallography. Elemental analysis, as well as GSH and SRB studies are currently underway.
Cisplatin, [cis-diamminedichloroplatinum-(II)], has been used since 1978 to treat a number of dif... more Cisplatin, [cis-diamminedichloroplatinum-(II)], has been used since 1978 to treat a number of different cancer cell lines; however, its effectiveness has been limited due to both harmful side effects and the development of cisplatin resistant cancers. Gold-(III) is an isoelectronic and isostructural species to platinum-(II), suggesting it has potential as an anticancer agent. In particular, gold-(III) complexes bearing bidentate ligands based on 1,10-phenanthroline and 2,2′-bipyridine have exhibited significant anticancer activity against a variety of tumor cell lines. Previously, our lab found that a pseudo five-coordinate gold-(III) complex bearing the 2,9-di-sec-butyl-1,10-phenanthroline ligand,[(di-sec-butylphen)AuCl3], exhibited anticancer activity against five different lung and head-neck tumor cell lines; however, the complex was found to be less active than the free 2,9-di-sec-butyl-1,10-phenanthroline ligand. In order to determine if our class of gold-(III) complexes have a distinct mechanism of tumor cell death or if they simply release the ligand into the intracellular environment, a library of structural analogues of the original complex were synthesized using mono-alkyl and di-phenyl substituted 1,10-phenanthroline ligands, di-alkyl and di-phenyl substituted 4-methyl-1,10-phenanthroline ligands, and mono-alkyl 2,2′-bipyridine ligands. The redox stability of these distorted square pyramidal gold-(III) complexes was studied and the in vitro antitumor activity of the gold-(III) complexes and corresponding free ligands were determined. The [(di-n-butylphen)AuCl3] and [(mono-n-butylphen)AuCl3] complexes were found to not only be more effective than cisplatin at inhibiting the growth of A549 lung tumor cells, but also more active than their respective free ligands, providing evidence that this class of gold-(III) complexes has a mechanism of tumor cell death that is independent of the free ligand. Currently, our laboratory is investigating the activity of platinum-(II) complexes with the same set of ligands based on 1,10-phenanthroline and 2,2′-bipyridine in an effort to compare their activity with our gold-(III) complexes. Structural analysis, as well as GSH and SRB studies, is currently underway.
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