Regioselective synthesis of 3,4-diaryl-5-unsubstituted isoxazoles, analogues of natural cytostatic combretastatin A4

Чернышева, Н. Б.; Maksimenko, Anna S.; Andreyanov, Fedor A.; Кислый, В. П.; Strelenko, Yuri A.; Khrustalev, Victor N.; Semenova, Marina N.; Семенов, В. В.

doi:10.1016/j.ejmech.2018.01.070

Cited by 29 publications

(24 citation statements)

References 35 publications

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“…Dehydration of 5‐carboxamido‐isoxazoline N‐oxides 5 to afford isoxazole‐5‐carboxamides 6 proceeded via a complex reaction mechanism including deprotonation, subsequent electrocyclic ring opening, and cyclization of ketoamide 7 , as described previously for isoxazoline‐5‐carboxylates (Scheme ) . The intermediate ketoamides similar to 7 (Scheme ) were identified in the reaction mixtures . In the present study it was found that oximes 8 could be formed only by hydrolysis of intermediate ketoamide 7 with malonic acid monoamide formation.…”

Section: Resultssupporting

confidence: 78%

“…In our previous work 3,4‐diaryl isoxazoles were identified as antimitotics with microtubule destabilizing mode of action . Therefore, the targeted 3,4‐diaryl‐isoxazole‐5‐carboxamides 6c–f , h , i were evaluated for antimitotic microtubule destabilizing activity using a phenotypic sea urchin embryo assay , .…”

Section: Resultsmentioning

confidence: 99%

“…4,5‐Diarylisoxazole scaffold can be found in a wide variety of non steroidal anti‐inflammatory drugs (NSAIDs),, inhibitors of platelet aggregation, tubulin polymerization inhibitors,, estrogen receptor modulators, antiviral, anti‐diabetic, anti‐convulsant, and other agents . Polyoxygenated 4,5‐diarylisoxazoles with 3‐carboxamide groups (Figure , A) were reported to inhibit heat shock protein Hsp90, a chaperone that assists folding of various proteins including those implicated in malignancy.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous work, starting 3,4‐diaryl‐isoxazoline N‐oxide‐5‐carboxylic esters were synthesized in high yields . Unfortunately, their subsequent rearrangement was not selective, giving decarboxylated 3,4‐diaryl‐5H‐isoxazoles as the main products with only negligible amount of the required 3,4‐diarylisoxazole‐5‐carboxylic acids . Considering the literature evidence, the present study was aimed to develop an efficient, inexpensive, and scalable protocol for regioselective synthesis of 3,4‐diaryl‐isoxazole‐ 5‐carboxamides from available materials under mild conditions.…”

Section: Introductionmentioning

confidence: 99%

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Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

et al. 2019

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A simple scalable procedure for the synthesis of 3,4‐diaryl‐isoxazole‐5‐carboxamides 6 under mild conditions from readily available material was developed. The targeted compounds 6, structural analogues of heat shock protein inhibitors, were obtained by the rearrangement of intermediate 3,4‐diaryl‐5‐carboxamido‐isoxazoline N‐oxides 5. In contrast to carboxamido‐isoxazoline oxides 5, base‐catalyzed recyclization of 3,4‐diaryl‐5‐(ethoxycarbonyl)isoxazoline N‐oxides 9c unexpectedly yielded 5‐hydroxy‐1,2‐oxazin‐6‐ones 17c instead of ethyl 3,4‐diaryl‐isoxazole‐5‐carboxylates 10. Crystal and molecular structure of 4‐(2,5‐dimethoxy‐3,4‐methylenedioxyphenyl)‐5‐hydroxy‐3‐phenyl‐6H‐1,2‐oxazin‐6‐one 17c was established by single‐crystal X‐ray diffraction study. In a phenotypic sea urchin embryo assay, carboxamide 6f showed moderate antimitotic antitubulin activity compared to 5‐unsubstituted 3,4‐diarylisoxazoles 15, which featured strong microtubule destabilizing effect.

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Section: Resultssupporting

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

et al. 2019

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“…The known methods for the synthesis of 4‐(het)arylisoxazoles include palladium‐catalyzed C–C couplings,, , various heterocyclizations and recyclizations, diazotative deamination of the corresponding 5‐aminoisoxazoles, and formal [3+2] cycloaddition of alkynes, electron‐deficient enamines or their synthetic equivalents with halogenoximes , . The latter approach can be considered as the most convenient since generally, the target products are obtained in good yields with high regioselectivity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines

et al. 2018

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An approach to 4‐hetarylisoxazole‐derived amines and other related 3,4‐disubstituted isoxazoles which relies on [3+2] cycloaddition of amino acid‐derived halogenoximes and push‐pull enamines is described. The target products are obtained at gram scale in up to 81 % overall yield. The efficiency of the method is affected by the electronic properties of the enamine component at the key step.

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Novel substituted 5‐methyl‐4‐acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells

Sadovnikov

Vasilenko

Gracheva

et al. 2022

Archiv der Pharmazie

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A series of novel antimitotic agents was designed using the replacement of heterocyclic cores in two tubulin‐targeting lead molecules with the acylated 4‐aminoisoxazole moiety. Target compounds were synthesized via heterocyclization of β‐aryl‐substituted vinylketones by tert‐butyl nitrite in the presence of water as a key step. 4‐Methyl‐N‐[5‐methyl‐3‐(3,4,5‐trimethoxyphenyl)isoxazol‐4‐yl]benzamide (1aa) was found to stimulate partial depolymerization of microtubules of human lung carcinoma A549 cells at a high concentration of 100 µM and to totally inhibit cell growth (IC50 = 0.99 µM) and cell viability (IC50 = 0.271 µM) in the nanomolar to submicromolar concentration range. These data provide evidence of the multitarget profile of the cytotoxic action of compound 1aa. The SAR study demonstrated that the 3,4,5‐trimethoxyphenyl residue is the key structural parameter determining the efficiency both towards tubulin and other molecular targets. The cytotoxicity of 3‐methyl‐N‐[5‐methyl‐3‐(3,4,5‐trimethoxyphenyl)isoxazol‐4‐yl]benzamide (1ab) to the androgen‐sensitive human prostate adenocarcinoma cancer cell line LNCaP (IC50 = 0.301 µM) was approximately one order of magnitude higher than that to the conditionally normal cells lines WI‐26 VA4 (IC50 = 2.26 µM) and human umbilical vein endothelial cells (IC50 = 5.58 µM) and significantly higher than that to primary fibroblasts (IC50 > 75 µM).

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Regioselective synthesis of 3,4-diaryl-5-unsubstituted isoxazoles, analogues of natural cytostatic combretastatin A4

Cited by 29 publications

References 35 publications

Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines

Novel substituted 5‐methyl‐4‐acylaminoisoxazoles as antimitotic agents: Evaluation of selectivity to LNCaP cancer cells

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