Synthesis of dihydropyrimidin-2-one/thione library and cytotoxic activity against the human U138-MG and Rat C6 glioma cell lines

Canto, Rômulo Faria Santos; Bernardi, Andressa; Battastini, Ana Maria Oliveira; Russowsky, Dennis; Eifler‐Lima, Vera Lucia

doi:10.1590/s0103-50532011000700025

Cited by 53 publications

(27 citation statements)

References 22 publications

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“…Furthermore, the dioxide derivative (35) , like the dioxide derivative (24) (Table 2), and the saturated derivative (36) were bifunctional inductors (r H /B = 4.96 and r H /B = 2.05, respectively). In reference to the new derivatives of the tetrahydropyrimidine system we selected compounds where 2-thiocarbonyl and 4-phenyl groups were varied (derivatives (37–54) , Table 4) [27,28,36,37]. Unlike the parent tetrahydropyrimidinone (28) some of the 2-carbonyl derivatives, that is, (44) , (45) , (47) and (50) , were poor QR inductors.…”

Section: Resultsmentioning

confidence: 99%

New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

et al. 2015

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The increased activity of phase-II-detoxification enzymes, such as quinone reductase (QR) and glutation S-transferase (GST), correlates with protection against chemically induced carcinogenesis. Herein we studied 11 different chemotypes, pyrazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiazole, 1,3,4-oxathiazole, thienyl hydrazone, α,β-unsaturated-oxime, α,β-unsaturated-N-oxide, coumarin and α,β-unsaturated-carbonyl, as phase-II enzymes inducers in order to identify new pharmacophores with chemopreventive activity. Fifty-four compounds were analyzed on wild-type mouse-hepatoma Hepa-1c1c7 and on the aryl-hydrocarbon-nuclear-translocator (Arnt)-defective mutant BpRc1 cells. New monofunctional inducers of QR and GST were identified, the 1,2,5-oxadiazol-2-oxide (3), the 1,2,4-triazine-4-oxides (23) and (32) and the tetrahydropyrimidinones (28) and (49). It was confirmed that Nrf2 nuclear translocation is the operative molecular mechanism that allows compound (3) to exert protective effects via expression of downstream phase-II enzymes.

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Section: Resultsmentioning

confidence: 99%

New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

et al. 2015

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“…In recent years, compounds that specifically inhibit Eg5 function have been identified, such as 3,4-dihydropyrimidin-2(1H)-one (or thione) (DHPMs) [ 22 - 24 ]. These molecules comprise a class of heterocyclic compounds obtained through Biginelli reaction that has monastrol as their prototype [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…The Eg5 inhibitors therefore not interfere with other microtubule-dependent processes [ 27 , 28 ], which are the main reason for the neurotoxicity of anti-microtubule agents [ 29 ]. It was shown that monastrol has antitumor activity against diverse cancer cell types such as renal, breast and glioma cell lines [ 24 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of kinesin Eg5 inhibition by 3,4-dihydropyrimidin-2(1H)-one derivatives on various breast cancer cell features

et al. 2015

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BackgroundBreast cancer is a complex heterogeneous disease and is one of the leading causes of death among women. In addressing the need for treatments of this life-threatening illness, we studied 3,4-dihydropyrimidin-2(1H)-one (or thione) derivatives (DHPMs), a class of inhibitor molecules of the Eg5 motor spindle protein that shows pronounced antitumor activity against several cancer cell lines.MethodsAn in vitro screening was performed for identification of DHPMs with potent antitumor effects on MCF-7 and MDA-MB-231 cells and the selected DHPMs were evaluated for their inhibitory activity on Eg5 both in silico, using Molecular dynamics, and in vitro Eg5 inhibition assays. Analysis of cell death induction, proliferation, cell cycle and cancer stem cells (CSC) profile were performed by flow cytometry to assess the influence of the selected DPHMs on these important tumor features. Finally, the effects of DHPM treatment on tube formation were evaluated in vitro using HUVEC cells, and in vivo using a model on chorioallantoic membrane (CAM) of fertilized eggs.ResultsWe identified five DHPMs with pronounced inhibitory activity on Eg5 motor protein interfering with the proper mitotic spindle assembly during cell division. These compounds impair the correct conclusion of cell cycle of the breast cancer cells and showed to be selective for tumor cells. Moreover, DHPMs modulate the CD44+/CD24− phenotype leading to a decrease in the CSC population in MDA-MB-231 cells, an important effect since CSC are resistant to many conventional cancer therapies and play a pivotal role in tumor initiation and maintenance. This observation was confirmed by the results which demonstrated that DHPM treated cells had impaired proliferation and were unable to sustain angiogenesis events. Finally, the DHMP treated cells were induced to apoptosis, which is one of the most pursued goals in drug development.ConclusionsThe results of our study strongly suggest that DHPMs inhibit important tumorigenic features of breast cancer cells leading them to death by apoptosis. These findings firmly point to DHPM molecular architecture as a promising alternative against breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1274-1) contains supplementary material, which is available to authorized users.

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“…The great interest in pyrimidine and dihydropyrimidine (DHPM) derivatives lies in the fact that these classes of compounds has, in principle, pronounced biological activity [164,165]. Consequently, diverse methodologies have been developed to improve the synthesis of this attractive family of compounds [166].…”

Section: Pyrimidine-based Anticancer Heterocyclic Systemsmentioning

confidence: 99%

Synthesis of Biologically Active Molecules through Multicomponent Reactions

et al. 2020

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Focusing on the literature progress since 2002, the present review explores the highly significant role that multicomponent reactions (MCRs) have played as a very important tool for expedite synthesis of a vast number of organic molecules, but also, highlights the fact that many of such molecules are biologically active or at least have been submitted to any biological screen. The selected papers covered in this review must meet two mandatory requirements: (1) the reported products should be obtained via a multicomponent reaction; (2) the reported products should be biologically actives or at least tested for any biological property. Given the diversity of synthetic approaches utilized in MCRs, the highly diverse nature of the biological activities evaluated for the synthesized compounds, and considering their huge structural variability, much of the reported data are organized into concise schemes and tables to facilitate comparison, and to underscore the key points of this review.Molecules 2020, 25, 505 2 of 71 acetylcholinesterase inhibitors, anti-HIV, antimicrobial, antioxidant, anti-mycobacterial and anticancer activities ( Figure 1). It is noteworthy that 64% and 16% of the supporting literature found for this review correspond to heterocyclic structures with anticancer and antimicrobial activities, respectively. Scheme 2. Three-component synthesis of 3,4-dihydropyrimidinones/thiones type 7 under microwave irradiation, for anti-inflammatory activity.Patil et al., reported a one-pot pseudo-five-component synthesis of highly functionalized tetrahydropyridines 9 using Cu(OTf) 2 as catalyst, Scheme 3. In vitro anti-inflammatory activity of the obtained compounds 9 was determined against matrix metalloproteinases (MMPs) as MMP-2 and MMP-9 by using gelatin zymography [29]. Scheme 3. Multicomponent Cu(OTf) 2 catalyzed synthesis of substituted tetrahydropyridines 9 for anti-inflammatory activity.A highly diastereoselective synthesis (exclusively the cis isomer is formed), of chromeno β-lactam hybrids 13/14 was also achieved by an efficient one-pot three-component reaction between either 5,5-dimethylcyclohexane-1,3-dione (10a) or 4-hydroxycoumarin (10b), diverse benzaldehydes 11 and malononitrile (12), in the presence of DABCO under reflux conditions (Scheme 4). Scheme 4. Three-component synthesis of β-lactam hybrids 13/14 for anti-inflammatory activity.The synthesized compounds (13 in 80-95% yield) and (14 in 82-95% yield) were screened for anti-inflammatory activity (as well as for anticancer activity, please see Section 3.13.13. Compound 13b (Ar = 4-ClC 6 H 4 , Ar 1 = 4-MeC 6 H 4 ) was the most active of all the chromeno β-lactam hybrids 13/14 tested, with a 19.8 anti-inflammatory ratio, although, it resulted less active than the reference drug dexamethasone corticosteroid used for the treatment of rheumatoid and skin inflammation [30].

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Synthesis of dihydropyrimidin-2-one/thione library and cytotoxic activity against the human U138-MG and Rat C6 glioma cell lines

Cited by 53 publications

References 22 publications

New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

Impact of kinesin Eg5 inhibition by 3,4-dihydropyrimidin-2(1H)-one derivatives on various breast cancer cell features

Synthesis of Biologically Active Molecules through Multicomponent Reactions

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