Preparation, characterization and the anticancer activity of a novel series of triaminemonochloroplatinum(II) cations linked to anthraquinone intercalators
“…An interesting structure−activity relationship, which arose from this work, was that higher activity was observed when the Pt moiety was attached at the 4-position ( 35 ) versus at the 2-position ( 34 ). This relationship was also observed by Gibson and colleagues in a series of complexes with anthraquinone, where the attachment of the Pt moiety at the 1-position ( 36 ) resulted in the complex having greater activity than the analogue where the attachment was at the 2-position ( 37 ) …”
Section: 6 Complexes With Biologically Active Carrier
Ligandssupporting
confidence: 62%
“…This relationship was also observed by Gibson and colleagues in a series of complexes with anthraquinone, where the attachment of the Pt moiety at the 1-position (36) resulted in the complex having greater activity than the analogue where the attachment was at the 2-position (37). 220 Other examples of Pt complexes with bioactive carrier groups include the attachment of a Pt moiety to doxorubicin 221,222 and to oestrogen analogues that bind to oestrogen receptors. [223][224][225] Lippard and colleagues reported Pt complexes with 9-aminoacridine and chloroquine, 226 ethidium bromide, 227 and acridine orange.…”
Section: Complexes With Biologically Active Carriermentioning
Industrial Research Fellow, investigating the coordination of technetium and rhenium to peptides and the synthesis of low molecular weight radiopharmaceuticals. His research interests centered on the applications of technetium and rhenium radiopharmaceuticals to oncology and neurology. In 1998, he joined the platinum development team at AnorMed, Inc., as a Senior Developmental Scientist. His current research interests include the design and synthesis of new Pt antitumor agents and the design of efficient processes for large-scale manufacture of Pt compounds. Christen Giandomenico received his Ph.D. degree in Chemistry from Columbia University and has held Post-doctoral positions at the University of Chicago and the Stanford Research Institute. In 1985 he joined Johnson-Matthey where he was a co-inventor of JM216, the first orally active platinum anticancer drug. He is a named inventor on six patents and is the author of 19 scientific articles. In 1996 he helped found AnorMED, a company dedicated to the discovery and development of metal-based therapeutics. He is currently Director of Chemical Development at AnorMED.
“…An interesting structure−activity relationship, which arose from this work, was that higher activity was observed when the Pt moiety was attached at the 4-position ( 35 ) versus at the 2-position ( 34 ). This relationship was also observed by Gibson and colleagues in a series of complexes with anthraquinone, where the attachment of the Pt moiety at the 1-position ( 36 ) resulted in the complex having greater activity than the analogue where the attachment was at the 2-position ( 37 ) …”
Section: 6 Complexes With Biologically Active Carrier
Ligandssupporting
confidence: 62%
“…This relationship was also observed by Gibson and colleagues in a series of complexes with anthraquinone, where the attachment of the Pt moiety at the 1-position (36) resulted in the complex having greater activity than the analogue where the attachment was at the 2-position (37). 220 Other examples of Pt complexes with bioactive carrier groups include the attachment of a Pt moiety to doxorubicin 221,222 and to oestrogen analogues that bind to oestrogen receptors. [223][224][225] Lippard and colleagues reported Pt complexes with 9-aminoacridine and chloroquine, 226 ethidium bromide, 227 and acridine orange.…”
Section: Complexes With Biologically Active Carriermentioning
Industrial Research Fellow, investigating the coordination of technetium and rhenium to peptides and the synthesis of low molecular weight radiopharmaceuticals. His research interests centered on the applications of technetium and rhenium radiopharmaceuticals to oncology and neurology. In 1998, he joined the platinum development team at AnorMed, Inc., as a Senior Developmental Scientist. His current research interests include the design and synthesis of new Pt antitumor agents and the design of efficient processes for large-scale manufacture of Pt compounds. Christen Giandomenico received his Ph.D. degree in Chemistry from Columbia University and has held Post-doctoral positions at the University of Chicago and the Stanford Research Institute. In 1985 he joined Johnson-Matthey where he was a co-inventor of JM216, the first orally active platinum anticancer drug. He is a named inventor on six patents and is the author of 19 scientific articles. In 1996 he helped found AnorMED, a company dedicated to the discovery and development of metal-based therapeutics. He is currently Director of Chemical Development at AnorMED.
“…The following synthetic procedure was adapted from those outlined by Katzhendler et al 12 and Alderden. 16 Propane-1,3diamine (21 mL, 0.25 mol) was added to a solution of 1chloroanthraquinone (7 g, 0.025 mol) in dry acetonitrile (200 mL, dried over molecular sieves 4A ˚) and refluxed for 20 h in the absence of light.…”
Section: Experimental Synthesis Of (Propyl-3-amine)-1-azaanthracene-9...mentioning
confidence: 99%
“…In order to increase the rate and extent of localisation of the platinum in the vicinity of its target, DNA, thereby decreasing the number of side reactions on route to the target, and to increase the rate of reaction with the nucleobases, a number of investigators have prepared and investigated platinum complexes with DNA intercalators attached. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] Although a number of these complexes do bind to DNA more rapidly and have demonstrated activity similar to or better than that of cisplatin, none has yet proven sufficiently active to warrant clinical trial. This is a disappointing result given the potential advantages of such compounds and led us to investigate the reasons for their lower than expected activity.…”
The binding of a platinum intercalator complex [Pt(1C3)(dien)](2+) (1C3 = 1-[(3-aminopropyl)amino]-anthracene-9,10-dione, dien = 3-azapentane-1,5-diamine) to DNA and to the self-complementary oligonucleotide 5'-d(TGGCCA)-3' has been investigated by UV-visible spectrophotometry and 2D NMR spectroscopy, respectively. The uncomplexed anthraquinone, 1C3, has an apparent DNA binding constant of 1.4 x 10(4), similar to that of ethidium bromide. Addition of the coordinatively saturated {Pt(dien)} moiety increases the binding constant to 3.7 x 10(5) M(-1), showing the effect of the increased positive charge introduced by this moiety. Multiple binding modes are evident from the lack of isosbestic points in the titration spectra and the non-linear nature of the half-reciprocal plot used to calculate the binding constant. [Pt(1C3)(dien)](2+) forms a 2 : 1 adduct with 5'-d(TGGCCA)-3' and is shown by 2D NMR to intercalate primarily in the TG:CA base pairs at the ends of the oligonucleotide with the side chain and {Pt(dien)} situated in the minor groove.
“…1 Studies of Pt compounds with biologically active carrier groups have yielded interesting results, such as improved activity in cisplatin resistant cell lines 2 and interesting structure-activity relationships (SAR). 3 Despite these different structure-activity relationships, still lacking are platinum compounds suitable as synthons in the synthesis of the conjugates. Although conjugates between platinum and oligodeoxynucleotides have been reported before, 4 there have been no prior reports of a physiologically active platinum center in the conjugates as we will report in the present study.…”
Three classes of hydroxy-tethered platinum(II) complexes have been synthesized from K(2)PtCl(4) and appropriate amino alcohols. A sequence of selective oxidation and hydrolysis has been developed to prepare hydroxy-tethered platinum(IV) complexes. A novel procedure for the synthesis of amminetrichloroplatinate(II) anion has been generated and used to synthesize a number of monohydroxy-tethered nonchelating platinum complexes. These tethered platinum complexes, including hydroxy-tethered, phosphoramidite-tethered, and monodeoxyribonucleotide-tethered platinum(II) and -(IV) complexes, have been examined in vitro for antitumor activity in both leukemia and ovarian cancer cell lines. Activity of some of these complexes was similar to cis-platin, and most of them showed much better potency than carboplatin. We observed an interesting structure-activity correlation for platinum(II) complexes for both PA-1 and SK-OV-3 ovarian cancer cell lines. However, platinum(IV) complexes showed much more diversified response among cancer cell lines studied. We observed enhanced selectivity among different cancer cell lines for some agents. The most promising is the monodeoxyribonucleotide-tethered platinum(IV) complex, which is the first analogue of the conjugates between a platinum fragment and monodeoxyribonucleotides, showing antitumor activity and selectivity among the cell lines. Finally, the p53 status of the cells appears to contribute to the effectiveness of these agents in that cells harboring wild-type p53 appear to be more sensitive to these agents.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
