A convenient synthesis of cis-restricted combretastatin analogues with pyrazole and isoxazole cores

Tsyganov, Dmitry V.; Semenova, Marina N.; Konyushkin, L. D.; Ushkarov, Vladimir I.; Raihstat, Mikhail M.; Семенов, В. В.

doi:10.1016/j.mencom.2019.03.015

Cited by 17 publications

(2 citation statements)

References 17 publications

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“…53 Possible reasons of the discrepancy will be discussed in details elsewhere. 74 Diarylisoxazoles with 3,4,5-trimethoxyphenyl substituent for the ring A (3a, 3b, 3k, and 3l) were highly potent showing EC values of 1−5 nM in the sea urchin embryo assay. These molecules exhibited strong cytotoxicity against human cancer cell lines including HeLa (cervical carcinoma), HepG2 (liver carcinoma), and OVCAR-3 (ovarian carcinoma) in the nanomolar IC 50 range (Table 4).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents

et al. 2018

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A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure–activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure–activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents

et al. 2018

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“…2) ． 20) この合成ではまず複数の官能基を持つカルコンに［bis (trifluoroacetoxy) iodo］ benzene (PhI (OCOCF 3 ) 2 )を用い転位反応を行い，得られたβ-ケトアセタールに三フッ化ホウ素とジメチルスルフィドを用いベンジル基の除去とイソフラボン骨格の構築を一挙に行った．その後，数段階を経て ( ±) -プテロカルピンを合成した．このようにイソフラボン骨格の構築は確立されていたが，それ以外の複素環の合成はわずかに限られていた．21,22) 上述近畿大学薬学部(〒577-8502 大阪府東大阪市小若江 3-4-1) e-mail: anakamura@phar.kindai.ac.jp 本総説は，2021 年度日本薬学会関西支部奨励賞(化学系薬学…”

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Development of Synthetic Methods for Heterocyclic Compounds Using the Oxidative Rearrangement of Chalcones and Application to Total Synthesis

Nakamura

2023

YAKUGAKU ZASSHI

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Chalcones are easily accessible synthetic building blocks that are used in various heterocyclic syntheses. The rearrangement reaction using an oxidant is a characteristic conversion of chalcones, but applications to organic synthesis have been limited. Here, the development of a new method for synthesizing 3-acylindoles and azaisoflavones using a chalcone rearrangement strategy with hypervalent iodine reagents was described. Furthermore, the obtained new insight was applied to the selective synthesis of two benzofuran isomers from 2-hydroxychalcone derivatives and have demonstrated this method to the synthesis of the natural product, puerariafuran.

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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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A convenient synthesis of cis-restricted combretastatin analogues with pyrazole and isoxazole cores

Cited by 17 publications

References 17 publications

Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents

Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents

Development of Synthetic Methods for Heterocyclic Compounds Using the Oxidative Rearrangement of Chalcones and Application to Total Synthesis

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

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