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Multicomponent Domino Synthesis, Anticancer Activity and Molecular Modeling Simulation of Complex Dispirooxindolopyrrolidines.

ABSTRACT: A series of spirooxindolopyrrolidine fused N-styrylpiperidone heterocyclic hybrids has been synthesized in excellent yield via a domino multicomponent protocol that involves one-pot three component 1,3-dipolar cycloaddition and concomitant enamine reactions performed in an inexpensive ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([bmim]Br). Compounds thus synthesized were evaluated for their cytotoxicity against U-937 tumor cells. Interestingly; compounds 5i and 5m exhibited a better cytotoxicity than the anticancer drug bleomycin. In addition; the effect of the synthesized compounds on the nuclear morphology of U937 FaDu cells revealed that treatment with compounds 5a?m led to their apoptotic cell death.

SUBMITTER: Arumugam N

PROVIDER: S-EPMC6100567 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Multicomponent Domino Synthesis, Anticancer Activity and Molecular Modeling Simulation of Complex Dispirooxindolopyrrolidines.

Arumugam Natarajan N Almansour Abdulrahman I AI Suresh Kumar Raju R Govindasami Periyasami P Al-Thamili Dhaifallah M DM Krishnamoorthy Rajapandian R Periasamy Vaiyapuri Subbarayan VS Alshatwi Ali A AA Mahalingam S M SM Thangamani Shankar S Menéndez J Carlos JC

Molecules (Basel, Switzerland) 20180505 5

A series of spirooxindolopyrrolidine fused N-styrylpiperidone heterocyclic hybrids has been synthesized in excellent yield via a domino multicomponent protocol that involves one-pot three component 1,3-dipolar cycloaddition and concomitant enamine reactions performed in an inexpensive ionic liquid, namely 1-butyl-3-methylimidazolium bromide ([bmim]Br). Compounds thus synthesized were evaluated for their cytotoxicity against U-937 tumor cells. Interestingly; compounds 5i and 5m</ ...[more]

PMID: 29734741

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Project description:Cell division cycle 25 (Cdc25) and mitogen-activated protein kinase kinase 7 (MKK7) are enzymes involved in intracellular signaling but can also contribute to tumorigenesis. We synthesized and characterized the biological activity of 1,4-naphthoquinones structurally similar to reported Cdc25 and(or) MKK7 inhibitors with anticancer activity. Compound 7 (3-[(1,4-dioxonaphthalen-2-yl)sulfanyl]propanoic acid) exhibited high binding affinity for MKK7 (Kd?=?230?nM), which was greater than the affinity of NSC 95397 (Kd?=?1.1??M). Although plumbagin had a lower binding affinity for MKK7, this compound and sulfur-containing derivatives 4 and 6-8 were potent inhibitors of Cdc25A and Cdc25B. Derivative 22e containing a phenylamino side chain was selective for MKK7 versus MKK4 and Cdc25?A/B, and its isomer 22f was a selective inhibitor of Cdc25?A/B. Docking studies performed on several naphthoquinones highlighted interesting aspects concerning the molecule orientation and hydrogen bonding interactions, which could help to explain the activity of the compounds toward MKK7 and Cdc25B. The most potent naphthoquinone-based inhibitors of MKK7 and/or Cdc25?A/B were also screened for their cytotoxicity against nine cancer cell lines and primary human mononuclear cells, and a correlation was found between Cdc25?A/B inhibitory activity and cytotoxicity of the compounds. Quantum chemical calculations using BP86 and ?B97X-D3 functionals were performed on 20 naphthoquinone derivatives to obtain a set of molecular electronic properties and to correlate these properties with cytotoxic activities. Systematic theoretical DFT calculations with subsequent correlation analysis indicated that energy of the lowest unoccupied molecular orbital E(LUMO), vertical electron affinity (VEA), and reactivity index ? of these molecules were important characteristics related to their cytotoxicity. The reactivity index ? was also a key characteristic related to Cdc25?A/B phosphatase inhibitory activity. Thus, 1,4-naphthoquinones displaying sulfur-containing and phenylamino side chains with additional polar groups could be successfully utilized for further development of efficacious Cdc25?A/B and MKK7 inhibitors with anticancer activity.

Project description:BackgroundThe amide derivatives of nonsteroidal anti-inflammatory drugs have been reported to possess antitumor activity. The present work describes the synthesis of dexibuprofen amide analogues (4a-j) as potential anticancer agents.MethodsThe title amides (4a-j) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.ResultsThe brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide (4e) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide (4g) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative 4e exhibited excellent growth inhibition of cancer cells with IC50 value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds 4e and 4g showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds 4e and 4g. The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g. The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.ConclusionBased upon our wet lab and dry lab findings we propose that dexibuprofen analogue 4e may serve as a lead structure for the design of more potent anticancer drugs.

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Multicomponent Domino Synthesis, Anticancer Activity and Molecular Modeling Simulation of Complex Dispirooxindolopyrrolidines.

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Multicomponent Domino Synthesis, Anticancer Activity and Molecular Modeling Simulation of Complex Dispirooxindolopyrrolidines.

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