1. Synthese von N, N &#39;-. (Alkan-1, n-diyl) diisonicotinamide <ol><li> Trocknen Sie einen einzigen Hals-oder Dreihalskolben in einem Ofen (100 ° C, 1 h), um sicherzustellen, dass alle Feuchtigkeit entfernt. </li><li> Hinzufügen festen Isonicotinsäure, oder dessen Derivat, in den Kolben mit einem magnetischen Rührstab. Wenn das Diaminoalkan Ligand (en) sind Feststoffe bei Raumtemperatur, dann 0,5 Mol (bezogen auf die Anzahl Mole des Isonicotinsäure) wird in den Kolben in dieser Stufe zugegeben. </li><li> Kappe der Hals (s) des Kolbens mit einer Gummimembran und Ersetzen der Luft im Kolben mit Stickstoff entweder durch einen kontinuierlichen Stickstoffstrom oder durch den Einsatz von Stickstoff gefüllten Ballons. </li><li> Verwenden Sie eine Injektionsnadel und eine Spritze zu wasserfreiem Dimethylformamid oder Dimethylsulfoxid (4 ml pro 500 mg Isonikotinsäure oder 2-Methyl-Isonikotinsäure) hinzufügen, um den Feststoff zu lösen. Wenn die Feststoffe nicht leicht zu lösen, dann erhitzt man die Lösung sanft. </li><li> In 7 Mol-Äquivalenten (zu der einBerg der Isonikotinsäure verwendet) Triethylamin (schwache Base) und 0,5 Mol-Äquivalenten der Diaminoalkan. Wenn die Lösung eine Flüssigkeit bei Raumtemperatur, dann fügen Sie 1,5 Moläquivalente. </li><li> In einem Mol-Äquivalent 1-Propylphosphonsäureanhydrid (Kopplungsmittel) unter ständigem Rühren, die die Reaktion auf über 5-12 h abzuschließen. </li></ol> 2. Reinigung der Liganden <ol><li> Für Bispyridin Liganden unter Verwendung Diaminoalkan Liganden mit 10 oder mehr Methylengruppen, warten Sie auf die Produkte aus der Lösung ausfällt als die Reaktion fortschreitet. </li><li> Für Bispyridin Liganden unter Verwendung Diaminooctan, fällt das Produkt durch Zugabe von ~ 40 ml Wasser. </li><li> Für Bispyridin unter Verwendung Diaminoalkane von zwei bis sechs Methylengruppen, fügen ~ 40 ml Wasser und erlaubt es, die Verbindungen über 1-3 Tage kristallisieren. </li><li> Sammeln jedes Bispyridin-Liganden durch Vakuum-Filtration und Rekristallisation von etwa 400-500 ml kochendem Wasser pro 200mg Ligand. Hinweis: Mehr Wasser für die längeren Bispyridin Liganden aufgrund ihrer stark reduzierten Wasserlöslichkeit erforderlich ist. </li><li> Mit NaOH und KOH (pH 9) zu der Lösung, um sicherzustellen, daß die Verbindungen frei von Basen nach Umkristallisation. </li></ol> 3. Synthese und Reinigung von den zweikernigen Platin-Komplexe <ol><li> Vollständig auflösen trans diamminodichloridoplatinum (II), Transplatin, in heißem (70-80 ° C) Wasser (150 ml pro 200 mg Transplatin) eine klare stark gelb gefärbte Lösung zu erzeugen. </li><li> Fügen Sie eine 0,5 Mol Äquivalent der Bispyridin Liganden und rühren Sie die Lösung bei der Temperatur, bis die Liganden löst sich (klare Lösung). Warten Sie, bis die Lösung nahezu farblos drehen, schalten Sie die Hitze, und bei Raumtemperatur für ein paar zusätzliche Stunden. </li><li> Das Lösemittel wird durch Rotationsverdampfung, die eine gelb gefärbte Pulver erhalten wird. </li><li> Zu reinigen, die Platin-Komplex (es) durch Auflösen in einer minimalen Menge von warmem Wasser (~ 50 &amp;# 186; C). Wenn restlichen gelb oder weiß gefärbt Feststoffe vorhanden sind, dann filtern diese aus. </li><li> Hinzufügen von Aceton zu der Lösung, bis ein weißer Niederschlag gebildet wird, der auf eine polymere Form der Metallkomplexe zu sein scheint und für bis zu 10% des Reaktionsproduktes. Die Zugabe von Aceton (~ zusätzliche 20-30 ml), bis kein Niederschlag mehr erscheint. Hinweis: Diese weiße Niederschlag ist eine Verunreinigung. </li><li> Entfernen Sie diesen Niederschlag durch Filtern der Inhalte durch Nylon-Filterpapier (0,2 um Porengröße) und Rotationsverdampfung des restlichen Lösung zur Trockene, die ein reines Produkt erhalten wird. Hinweis: Falls erforderlich, können dann zusätzliche Acetonpräzipitation Schritte, bis der Komplex ist reine durchgeführt werden. </li></ol>

<ol>
	<li>Wheate, N. J., Walker, S., Craig, G. E., Oun, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+status+of+platinum+anticancer+drugs+in+the+clinic+and+in+clinical+trials.">The status of platinum anticancer drugs in the clinic and in clinical trials.</a> Dalton Trans. 39, 8113-8127 (2010).</li><li>Kiernan, M. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+pain+with+platinum:+oxaliplatin+and+neuropathy.">The pain with platinum: oxaliplatin and neuropathy.</a> Eur. J. Cancer. 43, 2631-2633 (2007).</li><li>Markman, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+features+of+hypersensitivity+reactions+to+carboplatin.">Clinical features of hypersensitivity reactions to carboplatin.</a> J Clin. Oncol. 17, 1141-1145 (1999).</li><li>Ding, D., Allman, B. L., Salvi, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Review:+Ototoxic+characteristics+of+platinum+antitumor+drugs.">Review: Ototoxic characteristics of platinum antitumor drugs.</a> Anatomical Rec. 295, 1851-1867 (2012).</li><li>Galluzzi, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Molecular+mechanisms+of+cisplatin+resistance.">Molecular mechanisms of cisplatin resistance.</a> Oncogene. 31, 1869-1883 (2012).</li><li>Park, G. Y., Wilson, J. J., Song, Y., Lippard, S. 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P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Platinum+formulations+as+anticancer+drugs+clinical+and+pre-clinical+studies.">Platinum formulations as anticancer drugs clinical and pre-clinical studies.</a> Curr. Top. Med. Chem. 11, 2623-2631 (2011).</li><li>Wheate, N. J., Collins, J. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multi-nuclear+platinum+complexes+as+anti-cancer+drugs.">Multi-nuclear platinum complexes as anti-cancer drugs.</a> Coord. Chem. 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Cancer. 37, (2001).</li><li>Jodrell, D. I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Phase+II+studies+with+BBR3464,+a+novel+tri-nuclear+platinum+complex,+in+patients+with+gastric+or+gastro-oesophageal+adenocarcinoma.">Phase II studies with BBR3464, a novel tri-nuclear platinum complex, in patients with gastric or gastro-oesophageal adenocarcinoma.</a> Eur. J. Cancer. 40, 1872-1877 (2004).</li><li>William, W. N., Glisson, B. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Novel+strategies+for+the+treatment+of+small-cell+lung+carcinoma.">Novel strategies for the treatment of small-cell lung carcinoma.</a> Nat. Rev. Clin. Oncol. 8, 611-619 (2011).</li><li>Raynaud, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=cis-Amminedichloro(2-methylpyridine)+Platinum(II)+(AMD473),+a+novel+sterically+hindered+platinum+complex:+In+vivo+activity,+toxicology,+and+pharmacokinetics+in+mice.">cis-Amminedichloro(2-methylpyridine) Platinum(II) (AMD473), a novel sterically hindered platinum complex: In vivo activity, toxicology, and pharmacokinetics in mice.</a> Clin. Cancer Res. 3, 2063-2074 (1997).</li><li>Holford, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=biochemical+and+pharmacological+activity+of+the+novel+sterically+hindered+platinum+co-ordination+complex+cis-[amminedichloro(2-methylpyridine)]+platinum(II)+(AMD473).">biochemical and pharmacological activity of the novel sterically hindered platinum co-ordination complex cis-[amminedichloro(2-methylpyridine)] platinum(II) (AMD473).</a> Anti-Cancer Drug Des. 13, 1-18 (1998).</li><li>Munk, V. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Investigations+into+the+interactions+between+DNA+and+conformationally+constrained+pyridylamine+platinum(II)+analogues+of+AMD473.">Investigations into the interactions between DNA and conformationally constrained pyridylamine platinum(II) analogues of AMD473.</a> Inorg. Chem. 42, 3582-3590 (2003).</li><li>Wheate, N. J., Collins, J. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multi-nuclear+platinum+drugs:+A+new+paradigm+in+chemotherapy.">Multi-nuclear platinum drugs: A new paradigm in chemotherapy.</a> Curr. Med. Chem. - Anti-Cancer Agents. 5, 267-279 (2005).</li><li>Beale, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+phase+I+clinical+and+pharmacological+study+of+cis-diamminedichloro(2-methylpyridine)+platinumm+II+(AMD473).">A phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinumm II (AMD473).</a> British journal of cancer. 88, 1128-1134 (2003).</li><li>Sessa, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+and+pharmacological+phase+I+study+with+accelerated+titration+design+of+a+daily+times+five+schedule+of+BBR3464,+a+novel+cationic+triplatinum+complex.">Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex.</a> Ann. Oncol. 11, 977-983 (2000).</li><li>Brown, S. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Combining+aspects+of+the+platinum+anticancer+drugs+picoplatin+and+BBR3464+to+synthesize+a+new+family+of+sterically+hindered+dinuclear+complexes;+their+synthesis,+binding+kinetics+and+cytotoxicity.">Combining aspects of the platinum anticancer drugs picoplatin and BBR3464 to synthesize a new family of sterically hindered dinuclear complexes; their synthesis, binding kinetics and cytotoxicity.</a> Dalton Trans. 41, 11330-11339 (2012).</li><li>Still, B. M., Anil Kumar, P. G., Aldrich-Wright, J. R., Price, W. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=195Pt+NMR+-+Theory+and+application.">195Pt NMR - Theory and application.</a> Chem. Soc. Rev. 36, 665-686 (2007).</li><li>Wheate, N. J., Cullinane, C., Webster, L. K., Collins, J. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis,+cytotoxicity,+cell+uptake+and+DNA+interstrand+cross-linking+of+4,4'-dipyrazolylmethane-linked+multinuclear+platinum+anti-cancer+complexes.">Synthesis, cytotoxicity, cell uptake and DNA interstrand cross-linking of 4,4'-dipyrazolylmethane-linked multinuclear platinum anti-cancer complexes.</a> Anti-Cancer Drug Des. 16, 91-98 (2001).</li></ol>

Die Autoren haben nichts zu offenbaren.

In dieser Arbeit haben zweikernigen Platin-Komplexe als potentielle Antikrebsmittel synthetisiert. Dabei wurden Bispyridin Brückenliganden über eine Amid-Kupplungsreaktion mit Isonikotinsäure und variabler Länge Diaminoalkane synthetisiert. Zuvor die Synthese Bispyridin-Liganden und deren Methyl-Analoga mit 2 bis 8 Methylengruppen und ihre jeweiligen Platin-Komplexe berichtet worden. In dieser Arbeit wurde die Synthese und Reinigungsverfahren überarbeitet so dass es schneller und billiger und haben dies durch Synth...

Platin-Antikrebsmittel weiterhin eine der am weitesten verbreiteten Familie der Mittel bei der Behandlung von menschlichen Krebs 1. Trotz ihres Erfolgs sind, werden sie in ihrer Anwendung durch schwere Dosis-limitierenden Nebenwirkungen 4.2 beschränkt. Die begrenzten Dosen, die an Patienten verabreicht werden können, bedeutet auch, dass Tumoren können Widerstand 5 zu entwickeln. Als solche neue Medikamente weiterhin entwickelt, um die Nebenwirkungsprofil zu verbessern und zu überwinden erworbenen Resistenz, wie phenanthriplatin 6 und 7 phosphaplatin werden. In den späten 1990er Jahren wurde ein dreikernigen Platin-Medikament entwickelt, BBR3464 (Schema 1) 8, das ist bis zu 1.000 x zytotoxischer in vitro als der führende Platin-Medikament Cisplatin. BBR3464 ist auch in der Lage, erworbene Resistenz in einem Panel von menschlichen Krebszelllinien 9 zu überwinden. Leider ist die erhöhte Aktivität der BBR3464 um 50 abgestimmt - bis 100 - fach höhere Toxizität, dieschränkt seine Verwendung 10-12. Es ist auch leicht im Körper abgebaut, was bedeutet, wenig von der Droge erreicht Krebszellkerne intakt 9. Picoplatin ist ein mononuklearen Platin-basierten Medikament, das eine 2-Methyl-Pyridin-Liganden (Schema 1) 13 enthält. Die Methylgruppe des Arzneimittels schützt sie vor dem Angriff von biologischen Nukleophilen; insbesondere Cystein und Methionin enthält Peptiden / Proteinen 14-16. Als solches ist das Medikament sehr stabil und hat eine wesentlich höhere Konzentration, verglichen mit sowohl BBR3464 und Cisplatin 17 Krebszellkerne erreicht. Seine reduzierte Reaktivität bedeutet auch eine höhere picoplatin maximal verträgliche Dosis verglichen mit BBR3464 und Cisplatin 10,18,19. Dieses Projekt daher versucht, die Eigenschaften von BBR3464 picoplatin und kombinieren, um neue Medikamente, die in der Lage, erworbene Resistenz, die eine verbesserte biologische Stabilität und weniger schwere Neben effe anzuzeigen überwinden produzierenCTS (z. B. Fig. 1). Dabei wurde eine Reihe von zweikernigen Platinkomplexe mit Bispyridin Brückenliganden 20 hergestellt. Die Liganden werden mit Amidkupplungsreaktionen mit Isonicotinsäure, oder dessen Derivate, wie 2-Methyl-isonicotinsäure variabler Länge Diaminoalkane gemacht. Umsetzung von einem Mol-Äquivalent des Liganden mit zwei Moläquivalenten Transplatin ergibt die gewünschte Platin-Komplexe (Schema 1).

<table border="0" cellpadding="0" cellspacing="0" width="782">
	<tbody>
		<tr height="24">
			<td height="24" style="height:24px;width:297px;">D2O</td>
			<td style="width:175px;">Aldrich</td>
			<td align="right" style="width:159px;">151882</td>
			<td style="width:152px;">99.9% D</td>
		</tr>
		<tr height="24">
			<td height="24" style="height:24px;width:297px;">DMSO-d6</td>
			<td style="width:175px;">Aldrich</td>
			<td align="right" style="width:159px;">156914</td>
			<td style="width:152px;">99.96% D</td>
		</tr>
		<tr height="60">
			<td height="60" style="height:60px;width:297px;">1,8-diaminooctane</td>
			<td style="width:175px;">Aldrich</td>
			<td style="width:159px;">D22401</td>
			<td align="right" style="width:152px;">98%</td>
		</tr>
		<tr height="60">
			<td height="60" style="height:60px;width:297px;">1,10-diaminodecane</td>
			<td style="width:175px;">Aldrich</td>
			<td style="width:159px;">D14204</td>
			<td align="right" style="width:152px;">98%</td>
		</tr>
		<tr height="80">
			<td height="80" style="height:80px;width:297px;">1,12-diaminododecane</td>
			<td style="width:175px;">Aldrich</td>
			<td style="width:159px;">D1,640-1</td>
			<td align="right" style="width:152px;">98%</td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:297px;">Isonicotinic acid</td>
			<td style="width:175px;">Aldrich</td>
			<td style="width:159px;">I17508</td>
			<td align="right" style="width:152px;">99%</td>
		</tr>
		<tr height="120">
			<td height="120" style="height:120px;width:297px;">1-Propylphosphonic anhydride solution</td>
			<td style="width:175px;">Aldrich</td>
			<td align="right" style="width:159px;">431303</td>
			<td style="width:152px;">50 wt% in ethyl acetate</td>
		</tr>
		<tr height="100">
			<td height="100" style="height:100px;width:297px;">Trans-diaminodichloridoplatinum(II)</td>
			<td style="width:175px;">Aldrich</td>
			<td style="width:159px;">P1525</td>
			<td style="width:152px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Dimethylsulfoxide</td>
			<td style="width:175px;">Sigma-Aldrich</td>
			<td style="width:159px;">Z76855</td>
			<td style="width:152px;">&#62;99.9%, anhydrous</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">N,N&#8217;-dimethylformamide</td>
			<td style="width:175px;">Sigma-Aldrich</td>
			<td align="right" style="width:159px;">227056</td>
			<td style="width:152px;">99.8%, anhydrous</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Triethylamine</td>
			<td style="width:175px;">Sigma-Aldrich</td>
			<td style="width:159px;">T0886</td>
			<td style="width:152px;">&#62;99%</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Nylon filter membranes</td>
			<td style="width:175px;">Whatman</td>
			<td style="width:159px;">7402-004</td>
			<td style="width:152px;">Pore size, 0.2 &#181;m</td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Equipment</td>
			<td style="width:175px;"></td>
			<td style="width:159px;"></td>
			<td style="width:152px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Magnetic stirring hotplate</td>
			<td style="width:175px;"></td>
			<td style="width:159px;"></td>
			<td style="width:152px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Magnetic stirring bar&#160;</td>
			<td style="width:175px;"></td>
			<td style="width:159px;"></td>
			<td style="width:152px;"></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Round bottom or three neck flask</td>
			<td style="width:175px;"></td>
			<td style="width:159px;"></td>
			<td style="width:152px;"></td>
		</tr>
		<tr height="40">
			<td height="40" style="height:40px;width:297px;">Rubber septums of sufficient size for chosen round bottom or three neck flask</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">5 mL hypodermic syringes</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Hypodermic needles</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Rubber party ballons</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Rubber bands</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="24">
			<td height="24" style="height:24px;width:297px;">A source of N2 gas</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Rotary evaporator</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Drying oven</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">NMR tubes</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">NMR spectrometer</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">500 mL beakers</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:297px;">Glass or plastic pipettes</td>
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amide coupling reaction for the synthesis of bispyridine-based ligands and their complexation to platinum as dinuclear anticancer agents

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. Isonicotinic acid, or its derivatives, are coupled to variable length diaminoalkane chains under an inert atmosphere in anhydrous DMF or DMSO with the use of a weak base, triethylamine, and a coupling agent, 1-propylphosphonic anhydride. The products precipitate from solution upon formation or can be precipitated by the addition of water. If desired, the ligands can be further purified by recrystallization from hot water. Dinuclear platinum complex synthesis using the bispyridine ligands is done in hot water using transplatin. The most informative of the chemical characterization techniques to determine the structure and gross purity of both the bispyridine ligands and the final platinum complexes is 1H NMR with particular analysis of the aromatic region of the spectra (7-9 ppm). The platinum complexes have potential application as anticancer agents and the synthesis method can be modified to produce trinuclear and other multinuclear complexes with different hydrogen bonding functionality in the bridging ligand.

Die Bispyridin-Liganden und ihre jeweiligen Zweikernplatinkomplexe werden durch 1 H-, 13 C-und 195 Pt-NMR (Tabelle 1 und 2) und Elektrospray-Ionisations-Massenspektroskopie charakterisiert. Genaue Schmelzpunkte können unter Verwendung der Differentialscanningkalorimetrie und Reinheit wird am besten durch Elementaranalyse für C, H und N-Anteil bestimmt werden. Von den meisten Einsatz ist 1 H-NMR, wie es ist schnell und einfach zu bedienen, so...

Watch this Scientific Journal Video about Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents at JoVE.com

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Dieses Protokoll beschreibt die Verwendung von Amid-Kupplungen von Isonicotinsäure und Diaminoalkane zu Brückenliganden, die zur Verwendung in der Synthese von mehrkernigen Platinkomplexe, welche Aspekte der Antikrebs-Arzneimittel und BBR3464 picoplatin kombinieren bilden.

Amid-Kupplung für die Synthese von Bispyridin basierten Liganden und ihre Komplexierung Platinum als zweikernige Antikrebsmittel

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. ...

amide-coupling-reaction-for-synthesis-bispyridine-based-ligands-their

Research

JoVE Journal

Chemistry

13.8K Aufrufe.  The University of Sydney.  Dieses Protokoll beschreibt die Verwendung von Amid-Kupplungen von Isonicotinsäure und Diaminoalkane zu Brückenliganden, die zur Verwendung in der Synthese von mehrkernigen Platinkomplexe, welche Aspekte der Antikrebs-Arzneimittel und BBR3464 picoplatin kombinieren bilden. 

Serie: Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Anticancer Metal Complexes: Synthesis and Cytotoxicity Evaluation by the MTT Assay

Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; therefore their preparation should be conducted under an inert atmosphere. Evaluation of the anticancer activity of these complexes can be achieved by the MTT assay.
The MTT assay is a colorimetric viability assay based on enzymatic reduction of the MTT molecule to formazan when it is exposed to viable cells. The outcome of the reduction is a color change of the MTT molecule. Absorbance measurements relative to a control determine the percentage of remaining viable cancer cells following their treatment with varying concentrations of a tested compound, which is translated to the compound anticancer activity and its IC50 values. The MTT assay is widely common in cytotoxicity studies due to its accuracy, rapidity, and relative simplicity.
Herein we present a detailed protocol for the synthesis of air sensitive metal based drugs and cell viability measurements, including preparation of the cell plates, incubation of the compounds with the cells, viability measurements using the MTT assay, and determination of IC50 values.

A method for synthesis of air-sensitive titanium and vanadium anticancer agents is described, along with the evaluation of their cytotoxic activity towards human cancer cell line by the MTT Assay.

Anti-Krebs-Metall-Komplexe: Synthese und Zytotoxizität Bewertung durch die MTT-Assay

Titanium (IV) and vanadium (V) complexes are highly potent anticancer agents. A challenge in their synthesis refers to their hydrolytic instability; ...

Forschung

Chemie

Split-and-pool Synthesis and Characterization of Peptide Tertiary Amide Library

Peptidomimetics are great sources of protein ligands. The oligomeric nature of these compounds enables us to access large synthetic libraries on solid phase by using combinatorial chemistry. One of the most well studied classes of peptidomimetics is peptoids. Peptoids are easy to synthesize and have been shown to be proteolysis-resistant and cell-permeable. Over the past decade, many useful protein ligands have been identified through screening of peptoid libraries. However, most of the ligands identified from peptoid libraries do not display high affinity, with rare exceptions. This may be due, in part, to the lack of chiral centers and conformational constraints in peptoid molecules. Recently, we described a new synthetic route to access peptide tertiary amides (PTAs). PTAs are a superfamily of peptidomimetics that include but are not limited to peptides, peptoids and N-methylated peptides. With side chains on both &#945;-carbon and main chain nitrogen atoms, the conformation of these molecules are greatly constrained by sterical hindrance and allylic 1,3 strain. (Figure 1) Our study suggests that these PTA molecules are highly structured in solution and can be used to identify protein ligands. We believe that these molecules can be a future source of high-affinity protein ligands. Here we describe the synthetic method combining the power of both split-and-pool and sub-monomer strategies to synthesize a sample one-bead one-compound (OBOC) library of PTAs.

Peptide tertiary amides (PTAs) are a superfamily of peptidomimetics that include but are not limited to peptides, peptoids and N-methylated peptides. Here we describe a synthetic method which combines&#160;both split-and-pool and sub-monomer strategies to synthesize a one-bead one-compound library of PTAs.

Split-and-Pool-Synthese und Charakterisierung von Peptid-Amid-Tertiär-Bibliothek

Peptidomimetics are great sources of protein ligands. The oligomeric nature of these compounds enables us to access large synthetic libraries on solid ...

Synthesis of Non-uniformly Pr-doped SrTiO3 Ceramics and Their Thermoelectric Properties

We demonstrate a novel synthesis strategy for the preparation of Pr-doped SrTiO3 ceramics via a combination of solid state reaction and spark plasma sintering techniques. Polycrystalline ceramics possessing a unique morphology can be achieved by optimizing the process parameters, particularly spark plasma sintering heating rate. The phase and morphology of the synthesized ceramics were investigated in detail using X-ray diffraction, scanning electron microcopy and energy-dispersive X-ray spectroscopy. It was observed that the grains of these bulk Pr-doped SrTiO3 ceramics were enhanced with Pr-rich grain boundaries. Electronic and thermal transport properties were also investigated as a function of temperature and doping concentration. Such a microstructure was found to give rise to improved thermoelectric properties. Specifically, it resulted in a significant improvement in carrier mobility and the thermoelectric power factor. Simultaneously, it also led to a marked reduction in the thermal conductivity. As a result, a significant improvement (> 30%) in the thermoelectric figure of merit was achieved for the whole temperature range over all previously reported maximum values for SrTiO3-based ceramics. This synthesis demonstrates the steps for the preparation of bulk polycrystalline ceramics of non-uniformly Pr-doped SrTiO3.

Synthesis of Non-uniformly Pr-doped SrTiO3 Ceramics and Their Thermoelectric Properties

A protocol for the synthesis and processing of polycrystalline SrTiO3 ceramics doped non-uniformly with Pr is presented along with the investigation of their thermoelectric properties.

Synthese von nicht-einheitlich Pr-dotierten SrTiO<sub&gt; 3</sub&gt; Keramik und ihre thermoelektrischen Eigenschaften

We demonstrate a novel synthesis strategy for the preparation of Pr-doped SrTiO3 ceramics via a combination of solid state reaction and spark plasma ...

Synthesis and Reaction Chemistry of Nanosize Monosodium Titanate

This paper describes the synthesis and peroxide-modification of nanosize monosodium titanate (nMST), along with an ion-exchange reaction to load the material with Au(III) ions. The synthesis method was derived from a sol-gel process used to produce micron-sized monosodium titanate (MST), with several key modifications, including altering reagent concentrations, omitting a particle seed step, and introducing a non-ionic surfactant to facilitate control of particle formation and growth. The resultant nMST material exhibits spherical-shaped particle morphology with a monodisperse distribution of particle diameters in the range from 100 to 150&#160;nm. The nMST material was found to have a Brunauer-Emmett-Teller (BET) surface area of 285 m2g-1, which is more than an order of magnitude higher than the micron-sized MST. The isoelectric point of the nMST measured 3.34 pH units, which is a pH unit lower than that measured for the micron-size MST. The nMST material was found to serve as an effective ion exchanger under weakly acidic conditions for the preparation of an Au(III)-exchange nanotitanate. In addition, the formation of the corresponding peroxotitanate was demonstrated by reaction of the nMST with hydrogen peroxide.

The surfactant mediated sol-gel synthesis of nanosized monosodium titanate is described, along with preparation of the corresponding peroxide modified material. An ion-exchange reaction with Au(III) is also presented.

Synthese und Reaktionschemie von nanoskaligen Mononatrium Titanat

This paper describes the synthesis and peroxide-modification of nanosize monosodium titanate (nMST), along with an ion-exchange reaction to load the ...

HKUST-1 as a Heterogeneous Catalyst for the Synthesis of Vanillin

Vanillin (4-hydoxy-3-methoxybenzaldehyde) is the main component of the extract of vanilla bean. The natural vanilla scent is a mixture of approximately 200 different odorant compounds in addition to vanillin. The natural extraction of vanillin (from the orchid Vanilla planifolia, Vanilla tahitiensis and Vanilla pompon) represents only 1% of the worldwide production and since this process is expensive and very long, the rest of the production of vanillin is synthesized. Many biotechnological approaches can be used for the synthesis of vanillin from lignin, phenolic stilbenes, isoeugenol, eugenol, guaicol, etc., with the disadvantage of harming the environment since these processes use strong oxidizing agents and toxic solvents. Thus, eco-friendly alternatives on the production of vanillin are very desirable and thus, under current investigation. Porous coordination polymers (PCPs) are a new class of highly crystalline materials that recently have been used for catalysis. HKUST-1 (Cu3(BTC)2(H2O)3, BTC = 1,3,5-benzene-tricarboxylate) is a very well known PCP which has been extensively studied as a heterogeneous catalyst. Here, we report a synthetic strategy for the production of vanillin by the oxidation of trans-ferulic acid using HKUST-1 as a catalyst.

The conversion of trans-ferulic acid to vanillin was achieved by heterogeneous catalysis. HKUST-1 was employed in this synthesis and the essential step in the catalytic process was the generation of unsaturated metal sites. Thus, when the catalyst was activated under vacuum, full vanillin conversion (yield of 95%) was obtained.

HKUST-1 als heterogener Katalysator für die Synthese von Vanillin

Vanillin (4-hydoxy-3-methoxybenzaldehyde) is the main component of the extract of vanilla bean. The natural vanilla scent is a mixture of approximately ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation.
We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

This protocol details the important steps required for the bioconjugation of a cysteine containing protein to a maleimide, including reagent purification, reaction conditions, bioconjugate purification and bioconjugate characterization.

Synthese von Protein Biokonjugate<em&gt; über</em&gt; Cystein-maleimid Chemie

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

Synthesis of Cyclic Polymers and Characterization of Their Diffusive Motion in the Melt State at the Single Molecule Level

We demonstrate a method for the synthesis of cyclic polymers and a protocol for characterizing their diffusive motion in a melt state at the single molecule level. An electrostatic self-assembly and covalent fixation (ESA-CF) process is used for the synthesis of the cyclic poly(tetrahydrofuran) (poly(THF)). The diffusive motion of individual cyclic polymer chains in a melt state is visualized using single molecule fluorescence imaging by incorporating a fluorophore unit in the cyclic chains. The diffusive motion of the chains is quantitatively characterized by means of a combination of mean-squared displacement (MSD) analysis and a cumulative distribution function (CDF) analysis. The cyclic polymer exhibits multiple-mode diffusion which is distinct from its linear counterpart. The results demonstrate that the diffusional heterogeneity of polymers that is often hidden behind ensemble averaging can be revealed by the efficient synthesis of the cyclic polymers using the ESA-CF process and the quantitative analysis of the diffusive motion at the single molecule level using the MSD and CDF analyses.

A protocol for the synthesis and characterization of diffusive motion of cyclic polymers at the single molecule level is presented.

Synthese cyclischer Polymere und Charakterisierung ihrer Diffusionsbewegung im geschmolzenen Zustand auf der Einzelmolekülebene

We demonstrate a method for the synthesis of cyclic polymers and a protocol for characterizing their diffusive motion in a melt state at the single ...

Preparation and In Vitro Characterization of Dendrimer-based Contrast Agents for Magnetic Resonance Imaging

Paramagnetic complexes of gadolinium(III) with acyclic or macrocyclic chelates are the most commonly used contrast agents (CAs) for magnetic resonance imaging (MRI). Their purpose is to enhance the relaxation rate of water protons in tissue, thus increasing the MR image contrast and the specificity of the MRI measurements. Current clinically approved contrast agents are low molecular weight molecules that are rapidly cleared from the body. The use of dendrimers as carriers of paramagnetic chelators can play an important role in the future development of more efficient MRI contrast agents. Specifically, the increase in local concentration of the paramagnetic species results in a higher signal contrast. Furthermore, this CA provides a longer tissue retention time due to its high molecular weight and size. Here, we demonstrate a convenient procedure for the preparation of macromolecular MRI contrast agents based on poly(amidoamine) (PAMAM) dendrimers with monomacrocyclic DOTA-type chelators (DOTA &#8211; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate). The chelating unit was appended by exploiting the reactivity of the isothiocyanate (NCS) group towards the amine surface groups of the PAMAM dendrimer to form thiourea bridges. Dendrimeric products were purified and analyzed by means of nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. Finally, high resolution MR images were recorded and the signal contrasts obtained from the prepared dendrimeric and the commercially available monomeric agents were compared.

Preparation and In Vitro Characterization of Dendrimer-based Contrast Agents for Magnetic Resonance Imaging

This protocol describes the preparation and characterization of a dendrimeric magnetic resonance imaging (MRI) contrast agent that carries cyclen-based macrocyclic chelates coordinating paramagnetic gadolinium ions. In a series of MRI experiments in vitro, this agent produced an amplified MRI signal when compared to the commercially available monomeric analogue.

Vorbereitung und<em&gt; In Vitro</em&gt; Charakterisierung der für Magnetresonanz-Kontrastmittel Dendrimer-basierten

Paramagnetic complexes of gadolinium(III) with acyclic or macrocyclic chelates are the most commonly used contrast agents (CAs) for magnetic resonance ...

Synthesis of Platinum-nickel Nanowires and Optimization for Oxygen Reduction Performance

Platinum-nickel (Pt-Ni) nanowires were developed as fuel cell electrocatalysts, and were optimized for the performance and durability in the oxygen reduction reaction. Spontaneous galvanic displacement was used to deposit Pt layers onto Ni nanowire substrates. The synthesis approach produced catalysts with high specific activities and high Pt surface areas. Hydrogen annealing improved Pt and Ni mixing and specific activity. Acid leaching was used to preferentially remove Ni near the nanowire surface, and oxygen annealing was used to stabilize near-surface Ni, improving durability and minimizing Ni dissolution. These protocols detail the optimization of each post-synthesis processing step, including hydrogen annealing to 250 &#176;C, exposure to 0.1 M nitric acid, and oxygen annealing to 175 &#176;C. Through these steps, Pt-Ni nanowires produced increased activities more than an order of magnitude than Pt nanoparticles, while offering significant durability improvements. The presented protocols are based on Pt-Ni systems in the development of fuel cell catalysts. These techniques have also been used for a variety of metal combinations, and can be applied to develop catalysts for a number of electrochemical processes.

&#160; The protocol describes the synthesis and electrochemical testing of platinum-nickel nanowires. Nanowires were synthesized by the galvanic displacement of a nickel nanowire template. Post-synthesis processing, including hydrogen annealing, acid leaching, and oxygen annealing were used to optimize nanowire performance and durability in the oxygen reduction reaction.

Synthese von Platin-Nickel Nanodrähte und Optimierung für Sauerstoff Leistung

Platinum-nickel (Pt-Ni) nanowires were developed as fuel cell electrocatalysts, and were optimized for the performance and durability in the oxygen ...

Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

Vorbereitung der stabile bicyclische Aziridinium Ionen und ihre Ring-Öffnung für die Synthese von Azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...