Design and Synthesis of Novel Trichloromethylated N‐Azolylmethyl‐1H‐pyrimidin‐2‐ones and Related N‐Methylenaminones.

Zanatta, Nilo; Flores, Darlene C.; Amaral, Simone S.; Bonacorso, Hélio G.; Martins, Marcos A. P.; Flores, Alex F. C.

doi:10.1002/chin.200617158

Cited by 3 publications

(8 citation statements)

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“…Intrigued by this, we performed experiments to verify the influence of using compounds known to favor N -alkylation; that is, without any substituent at the 6-position of the pyrimidin-2(1 H )-one ring. 35 For this, pyrimidin-2(1 H )-ones 1n – o were reacted with 4-(iodomethyl)pyrimidines 6c – d under the standard conditions ( Scheme 4 a). Again, no formation of either N -alkylated or O -alkylated product was detected.…”

Section: Resultsmentioning

confidence: 99%

“… 18 , 23 , 34 When the same reaction was performed with a more complex alkylating agent (5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, a brominated enone), only the N -alkylated pyrimidine was observed. 35 The use of derivatives of this brominated enone as resourceful and selective alkylating agents for several other complex nucleophiles (e.g., vinylic amines, 36 pyrazoles, and others 37 ) has already been explored. Thus, inspired by the selectivity observed previously in obtaining N -alkylated derivatives, 35 this present work started to study the reactivity of its counterpart, the O -alkylated pyrimidines ( 3 ) containing a β-enaminone moiety, in a [3 + 3] cyclocondensation reaction with 2-methylisothiourea sulfate ( Scheme 1 , route 1), and the selectivity of 4-(halomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines 6 as O -alkylating agents of 4-(trifluoromethyl)pyrimidin-2(1 H )-ones 1 ( Scheme 1 , route 2).…”

Section: Introductionmentioning

confidence: 99%

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Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1H)-ones Using 4-(Iodomethyl)pyrimidines

et al. 2022

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This study reports two strategies for preparing O -alkyl derivatives of 6-substituted-4-(trifluoromethyl)pyrimidin-(1 H )-ones: a linear protocol of alkylation, using a CCC -building block followed by [3 + 3]-type cyclocondensation with 2-methylisothiourea sulfate and a convergent protocol based on direct alkylation, using 4-(iodomethyl)-2-(methylthio)-6-(trihalomethyl)pyrimidines. It was found that the cyclocondensation strategy is not feasible; thus, the direct chemoselective O -alkylation was performed, and 18 derivatives of the targeted pyrimidines were obtained in 70–98% yields. The structure of the products was unambiguously determined via single crystal X-ray analyses and two-dimensional nuclear magnetic resonance experiments.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1H)-ones Using 4-(Iodomethyl)pyrimidines

et al. 2022

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“…In fact, compound 7 had already been obtained in a previous work. 37 Curiously, using the same conditions, pyrimidines 1 failed to react with 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one (a trifluoromethylated analogue of enone 4).…”

Section: Resultsmentioning

confidence: 99%

“…36 However, the low solubility of this compound made further studies difficult. Thus, as an extension of that study 37 we now synthesize a series of derivatives of compound 7 in order to generate new compounds with increased solubility and potential for biological activity.…”

Section: Introductionmentioning

confidence: 99%

N -Alkylation of 4-Trichloromethylpyrimidinones: Synthesis of Some New and Interesting Modified Nucleoside Analogues

Zanatta

Brondani²,

Amaral³

et al. 2009

Organic Chemistry Insights

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The N 1-alkylation of 4-(trichloromethyl)pyrimidin-2(1H)-one, 4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin-2(1H)-one, and 5-bromo-4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin-2(1H)-one with selected alkylating agents such as 2-chloroacetamide, diethyl 2-bromomalonate, and 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, is presented. Further reactions of 1-[5,5,5-trichloro-2-methoxy-4-oxo-penten-2-yl]4-trichloromethyl-pyrimidin-2(1H)-one with primary amines and aminoalcohols furnished a series of unexpected new acyclic nucleoside analogues.

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“…The ion Ca 2+ plays a vital role in ER function; therefore, an alteration in its homeostasis might result in ER stress, as well as in an unfolded protein response. 15−17 Here, we demonstrated the cytotoxic effect of an N-alkylated pyrimidine analogue with two trichloromethyl groups (Figure 1; compound 3) synthesized previously 18 on several leukemia cell lines, in order to investigate cell death pathways regarding oxidative stress and apoptosis.…”

Section: ■ Introductionmentioning

confidence: 86%

Antitumoral Activity of a Trichloromethyl Pyrimidine Analogue: Molecular Cross-Talk between Intrinsic and Extrinsic Apoptosis

Winter

Pizzol

Filippin-Monteiro

et al. 2014

Chem. Res. Toxicol.

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Acute lymphoblastic leukemia (ALL) is a malignant disorder caused by the proliferation of lymphoid progenitor cells and is the most common cancer in children. Cytotoxic nucleoside analogues are important chemotherapeutic agents, which are used in many cancers, including leukemias. In this study, we investigated the effects of the synthetic nucleoside analogue 1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethyl-pyrimidin-2(1H)-one, named compound 3 or C3, on leukemia cell lines. The compound stimulated cell death by apoptosis, evidenced by DNA fragmentation, phosphatidylserine externalization, and caspase-3 activation. Compound 3 seemed to trigger several cell death pathways. The mitochondrial pathway was evidenced through a disturbance of mitochondrial membrane potential, strong cytochrome c liberation, decrease of antiapoptotic Bcl-2 protein expression, and caspase-9 activation. The C3 also induced caspase-8 and -12 activation, an increase in the intracellular calcium level, and an overproduction of reactive oxygen species. Increased caspase 8 activity suggests that the extrinsic pathway was activated and that the ROS production and enzyme activity alteration (glutathione S-transferase, glutathione peroxidase, catalase, and glutathione reductase) might be related to oxidative stress. Finally, the increase in calcium release, CHOP expression, and caspase-12 activity might characterize endoplasmic reticulum stress. Compound 3 was likewise cytotoxic to leukemic and melanoma human cell lines. Taken together, the results contribute to further understanding the new pyrimidine analogue as a potential chemotherapeutic drug or lead molecule.

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Design and Synthesis of Novel Trichloromethylated N‐Azolylmethyl‐1H‐pyrimidin‐2‐ones and Related N‐Methylenaminones.

Cited by 3 publications

References 1 publication

Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1H)-ones Using 4-(Iodomethyl)pyrimidines

Chemoselective O-Alkylation of 4-(Trifluoromethyl)pyrimidin-2(1H)-ones Using 4-(Iodomethyl)pyrimidines

N -Alkylation of 4-Trichloromethylpyrimidinones: Synthesis of Some New and Interesting Modified Nucleoside Analogues

Antitumoral Activity of a Trichloromethyl Pyrimidine Analogue: Molecular Cross-Talk between Intrinsic and Extrinsic Apoptosis

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