Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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5-Year Impact Factor – 2.135
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2012, vol. 21, nr 5, September-October, p. 563–571

Publication type: original article

Language: English

The Synthesis of 3,5,6,7-Tetrasubstituted Isoxazolo[4,5-B]Pyridines and an Evaluation of Their In Vitro Antiproliferative Activity

Synteza 3,5,6,7-tetrapodstawionych izoksazolo[4,5-b]pirydyn i badanie ich aktywności antyproliferacyjnej

Krystyna Poręba1,A,B,C,D,E,F, Joanna Wietrzyk2,A,B,C,D,F

1 Department of Drug Technology, Wroclaw Medical University, Wrocław, Poland

2 Laboratory of Tumor Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland

Abstract

Background. Derivatives of isoxazolopyridines exhibit diverse biological activity. One method of synthesizing isoxazolo[4,5-b]pyridines is Friedländer condensation.
Objectives. To establish the conditions necessary for conventional and microwave synthesis of new 3,5,6,7-tetrasubstituted isoxazolo[4,5-b]pyridines and their antiproliferative activity.
Material and Methods. The substrates in the synthesis of new isoxazolo[4,5-b]pyridines were 4‑amino-5-benzoylisoxazole3-carboxamide and selected carbonyl compounds containing a reactive α-methylene group. Reactions were carried out using classical methods in the presence of catalysts ZnCl2 or In (OTf)3, and in a microwave reactor in the presence of ZnCl2 under solvent-free conditions. Selected compounds were tested in vitro on eight tumor cell lines to assess their antiproliferative activity. Results and Discussion. A series of new derivatives of 3,5,6,7-tetrasubstituted isoxazolo [4,5-b]pyridines was obtained from Friedländer condensation of 4-amino-5-benzoyloisoxazolo-3-carboxamide with selected carbonyl compounds with an active methylene group. The compounds were obtained by conventional and microwave methods, in the presence of catalysts ZnCl2 or In (OTf)3. The structures of the products were determined on the basis of elemental analysis and infrared (IR), Nuclear Magnetic Resonance (1H NMR) and Mass Spectrometry (MS) data. Selected compounds were tested in vitro on eight tumor cell lines in the direction of antiproliferative activity.
Conclusion. Only the use of conventional heating in a thermostated oil bath in the presence of catalysts ZnCl2, or In (OTF)3 or microwave irradiation in the presence ZnCl2 in the solvent-free conditions allowed good yields of the new derivatives of poly-substituted isoxazolo[4,5-b]pyridines to be obtained. Among the compounds tested in vitro only 6-benzoyl-5, 7-difenyloisoxazolo[4,5-b]pyridine showed antyproliferative activity at a concentration of 3.9 μg/ml.

Streszczenie

Wprowadzenie. Pochodne układu izoksazolopirydyny wykazują różnorodną aktywność biologiczną. Jedną z metod syntezy pochodnych izoksazolo[4,5-b]pirydyny jest kondensacja Friedländera.
Cel pracy. Opracowanie warunków syntezy konwencjonalnej i mikrofalowej nowych pochodnych izoksazolo[4,5- -b]pirydyny o aktywności antyproliferacyjnej.
Materiał i metody. Substratami w syntezie nowych pochodnych izoksazolopirydyny były: amid kwasu 4-amino-5- -benzoiloizoksazolo-3-karboksylowego i wybrane związki karbonylowe mające aktywną grupę metylenową. Reakcje były prowadzone metodami klasycznymi wobec ZnCl2 lub In(OTf)3 jako katalizatorów oraz w reaktorze mikrofalowym w obecności ZnCl2 w warunkach bez rozpuszczalnika. Wybrane związki były testowane in vitro na ośmiu liniach nowotworowych w kierunku aktywności antyproliferacyjnej.
Wyniki. W wyniku reakcji kondensacji Friedländera amidu kwasu 4-amino-5-benzoiloizoksazolo-3-karboksylowego z wybranymi związkami karbonylowymi posiadającymi aktywną grupę metylenową otrzymano serię nowych 3,5,6,7-tetrapodstawionych pochodnych izoksazolo[4,5-b]pirydyny. Związki były otrzymane 2 metodami: konwencjonalną w obecności katalizatorów ZnCl2 lub In(OTf)3 oraz mikrofalową wobec ZnCl2. Strukturę otrzymanych nowych pochodnych określono na podstawie analizy elementarnej i widm spektralnych IR, 1H NMR i MS. Wybrane związki były testowane in vitro w kierunku aktywności antyproliferacyjnej.
Wnioski. Tylko zastosowanie konwencjonalnego ogrzewania na termostatowanej łaźni olejowej w obecności katalizatorów: ZnCl2 lub In(OTf)3 lub pod wpływem promieniowania mikrofalowego wobec ZnCl2 w warunkach bez rozpuszczalnika pozwoliło otrzymać nowe polipodstawione pochodne izoksazolo[4,5-b]pirydyny z dobrymi wydajnościami. Spośród testowanych in vitro związków tylko 6-benzoilo-5,7-difenyloizoksazolo[4,5-b]pirydyna wykazała aktywność antyproliferacyjną w stężeniu 3,9 μg/ml.

Key words

isoxazolopyridines, microwave synthesis, antitproliferative activity

Słowa kluczowe

izoksazolopirydyny, synteza mikrofalowa, aktywność antyproliferacyjna

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