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Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study.

ABSTRACT: New α,β-unsaturated ketones 4a,b; 5a-c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10-11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS^•+). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC₅₀] ≅5.5-18.1 µΜ), in addition to significantly high ABTS^•+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC₅₀ values of 0.56 and 1.6 µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC₅₀ values of 4.66 and 2.16 µM, respectively, compared with sorafenib reference drug (IC₅₀ = 1.28 µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.

SUBMITTER: El-Husseiny WM

PROVIDER: S-EPMC6010098 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study.

El-Husseiny Walaa M WM El-Sayed Magda A-A MA Abdel-Aziz Naglaa I NI El-Azab Adel S AS Ahmed Esam R ER Abdel-Aziz Alaa A-M AA

Journal of enzyme inhibition and medicinal chemistry 20181201 1

New α,β-unsaturated ketones 4a,b; 5a-c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10-11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS<sup>•+</sup>). Compounds 6a, 6b, 7, and 8b ex ...[more]

PMID: 29455554

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Project description:The reaction of a {W(CO)5 }-stabilized phosphinophosphonate 1, (CO)5 WPH(Ph)P(O)(OEt)2 , with ethynyl- (2 a-f) and diethynylketones (7-11, 18, and 19) in the presence of lithium diisopropylamide (LDA) is examined. Lithiated 1 undergoes nucleophilic attack in the Michael position of the acetylenic ketones, as long as this position is not sterically encumbered by bulky (iPr)3 Si substituents. Reaction of all other monoacetylenic ketones with lithiated 1 results in the formation of 2,5-dihydro-1,2-oxaphospholes 3 and 4. When diacetylenic ketones are employed in the reaction, two very different product types can be isolated. If at least one (Me)3 Si or (Et)3 Si acetylene terminus is present, as in 7, 8, and 19, an anionic oxaphosphole intermediate can react further with a second equivalent of ketone to give cumulene-decorated oxaphospholes 14, 15, 24, and 25. Diacetylenic ketones 10 and 11, with two aromatic acetylene substituents, react with lithitated 1 to form exclusively ethenyl-bridged bisphospholes 16 and 17. Mechanisms that rationalize the formation of all heterocycles are presented and are supported by DFT calculations. Computational studies suggest that thermodynamic, as well as kinetic, considerations dictate the observed reactivity. The calculated reaction pathways reveal a number of almost isoenergetic intermediates that follow after ring opening of the initially formed oxadiphosphetane. Bisphosphole formation through a carbene intermediate G is greatly favored in the presence of phenyl substituents, whereas the formation of cumulene-decorated oxaphospholes is more exothermic for the trimethylsilyl-containing substrates. The pathway to the latter compounds contains a 1,3-shift of the group that stems from the acetylene terminus of the ketone substrates. For silyl substituents, the 1,3-shift proceeds along a smooth potential energy surface through a transition state that is characterized by a pentacoordinated silicon center. In contrast, a high-lying transition state TS(E'-F')R=Ph of 37 kcal mol(-1) is found when the substituent is a phenyl group, thus explaining the experimental observation that aryl-terminated diethynylketones 10 and 11 exclusively form bisphospholes 16 and 17.

Dataset Information

Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study.

Publications

Synthesis, antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study.

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