Identification and characterization of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones as inhibitors of the fatty acid transporter FATP4

Blackburn, Christopher; Guan, Bing; Brown, James A.; Cullis, Courtney; Condon, Stephen M.; Jenkins, Tracy J.; Peluso, Stéphane; Ye, Yingchun; Gimeno, Ruth E.; Punreddy, Sandhya; Sun, Ying; Wu, Hui; Hubbard, Brian K.; Kaushik, Virendar K.; Tummino, Peter J.; Sanchetti, Praveen; Sun, Dong; Daniels, Tom; Tozzo, Effie; Balani, Suresh K.; Raman, Prakash

doi:10.1016/j.bmcl.2006.03.102

Cited by 66 publications

(41 citation statements)

References 21 publications

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“…[28] Preparation of homologue 6, which bears a free carboxylic group at position 5, was achieved through the mild saponification of the corresponding 2-cyanoethyl ester Biginelli product 5. [29,30] Condensation of DHPMs with chloroacetyl chloride and the appropriate benzaldehydes in the presence of sodium acetate in acetic acid/acetic anhydride medium at reflux provided the final thiazolopyrimidines 35-59 and 67-74 as Z isomers, as previously described (Scheme 1). [31][32][33][34] To avoid esterification of the phenolic functions introduced as R 4 and/or R 3 moieties, the…”

Section: Resultsmentioning

confidence: 99%

Development of Novel Thiazolopyrimidines as CDC25B Phosphatase Inhibitors

et al. 2009

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The development of CDC25 phosphatase inhibitors is an interesting approach toward new antitumor agents, as CDC25 play key roles in cell-cycle regulation and are overexpressed in numerous cancers. We previously reported a novel compound belonging to the thiazolopyrimidine family that inhibits CDC25 activity with an IC(50) value of 13 microM and displays cytotoxic properties against HeLa cells. Structural modifications were subsequently conducted on this new pharmacophore which led to a library of 45 thiazolopyrimidines. Regarding the in vitro effects, 14 compounds inhibit CDC25B with IC(50)<20 microM, with the most efficient inhibitor 44 improving the potency to 4.5 microM. Steady-state kinetics were performed and showed a mixed inhibition pattern for all tested compounds. Furthermore, 44 was able to revert the bypass of genotoxicity-induced G(2) arrest upon CDC25B overexpression, indicating that this compound targets the dual-specificity phosphatase in cultured cells. Finally, the cytotoxic activities of the compounds were determined against two human cancer cell lines. The results indicate that the prostatic LNCaP cell line is more sensitive to these derivatives than the pancreatic adenocarcinoma MiaPaCa-2 line. With its interesting enzymatic and cellular properties, compound 44 appears to be a promising CDC25B inhibitor for further development.

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Section: Resultsmentioning

confidence: 99%

Development of Novel Thiazolopyrimidines as CDC25B Phosphatase Inhibitors

et al. 2009

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“…27). Cyclopentyl ester 7 proved to be a potent inhibitor of the fatty acid transporter FATP4 (the S-enantiomer showed to be B100 times more potent than the R-enantiomer) 28 . The analogs 8a and 8b both exhibited a strong in vitro antioxidant activity 29 and derivative 9 plays a role in the activation of chaperones that block Ab aggregation and thus might have a favorable therapeutic effect on neurodegenerative diseases like the Alzheimer disease 30,31 .…”

Section: Introductionmentioning

confidence: 99%

Automated generation of a dihydropyrimidine compound library using microwave-assisted processing

Dallinger

Kappe

2007

Nat Protoc

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Here we report the generation of a small focused library of 12 diversely functionalized dihydropyrimidine (DHPM) derivatives via one-pot three-component Biginelli cyclocondensation of b-ketoesters, aldehydes and (thio)ureas. By applying controlled microwave heating under sealed vessel conditions using a fully automated microwave instrument including a gripper and liquid handler, the sequential synthesis of DHPMs can be performed in a shorter reaction time (10-20 min per one DHPM derivative) compared to conventional heating methods, which normally require several hours of reflux heating. The solid products either crystallize directly upon cooling or can be precipitated upon addition of water, requiring only filtration for isolation. In this way, the DHPM derivatives are obtained in high purity and no further purification by recrystallization or chromatography is necessary. This can be ascribed to the microwave heating technology where less side-product formation is often seen. The preparation of this 12-membered DHPM library can be carried out within B9 h.

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Section: Introductionmentioning

confidence: 99%

“…2 Moreover, this class of heterocycles revealed other pharmacological activities such as anti-inflammatory, 3 calcium channel modulators, 4 antifungal and antibacterial, 5 melanin concentrating hormone receptor (MCH1-R) antagonists, 6 chemical modulators of heat shock protein 70 (Hsp 70), 7 hepatitis B replication inhibitors, 8 and inhibitors of the fatty acid transporters. 9 This set of potentialities linked to the possibility of chemical modulation in all positions of the dihydropirimidinone/thione rings make DHPMs a privileged structure, justifying the great interest in their synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…This revealed the potential of this compound as antitumor prototype and since that, some SAR (structure activity relationship) studies concerning this interaction have been performed. 9 This set of potentialities linked to the possibility of chemical modulation in all positions of the dihydropirimidinone/thione rings make DHPMs a privileged structure, justifying the great interest in their synthesis.The original three component reaction of DHPMs consisted of a simple one-pot condensation of benzaldehyde 4b, ethyl acetoacetate 5 and urea 6b (Schemes 1 and 2), catalyzed by few drops of hydrochloric acid under refluxing In this context, we have reported the synthesis of a small library of DHPM, including monastrol (1a), using a Lewis acid as catalyst and this series was evaluated against seven human cancer cell lines. 21 The results showed that the oxo-monastrol analogue (2a) just shows cytostatic activity, while monastrol (1a) was cytotoxic against the seven cancer cell lines.…”

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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

Canto¹,

Bernardi²,

Battastini³

et al. 2011

J. Braz. Chem. Soc.

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Duas séries de 4-aril-3,4-diidropirimidin-2(1H)-(tio)onas incluindo monastrol (1a), foram sintetizadas por uma metodologia não agressiva ao meio ambiente baseada no uso combinado de ácido cítrico ou ácido oxálico na presença de TEOF (ortoformato de trietila). A atividade como inibidores da proliferação celular da quimioteca de compostos foi avaliada em duas linhagens de gliomas (U138-MG-humana e C6-rato). Os compostos derivados da tiouréia 1f e 1d mostraram atividade citotóxica maior do que a do monastrol. O composto derivado da uréia 2d apresentou a maior atividade citotóxica dentre todos os compostos analisados.Two series of 4-aryl-3,4-dihydropyrimidin-2(1H)-(thio)ones including monastrol (1a), have been synthesized by an environment-friendly methodology based on the combined use of citric acid or oxalic acid and TEOF (triethylorthoformate). The library was evaluated as inhibitor of cell proliferation on two glioma cell lines (human-U138-MG and Rat-C6). The compounds derived from thiourea 1f and 1d were more cytotoxic than monastrol. The compound derived from urea 2d showed the highest cytotoxic activity among the analyzed compounds.Keywords: dihydropyrimidin-2(1H)-ones, Biginelli reaction, triethylorthoformate, TEOF, monastrol, cancer, glioma IntroductionThe 4-aryl-3,4-dihydropyrimidin-2(1H)-ones (DHPMs) are a class of compounds that has a huge interest in the medicinal chemistry community in recent years.Using high throughput screening (HTS) Mayer et al.1 have evaluated a library of 16,330 small molecules that vary in functional groups and charge. These findings have lead to discover a small molecule which they named monastrol, whose acts by inhibiting the motility of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. This revealed the potential of this compound as antitumor prototype and since that, some SAR (structure activity relationship) studies concerning this interaction have been performed. 9 This set of potentialities linked to the possibility of chemical modulation in all positions of the dihydropirimidinone/thione rings make DHPMs a privileged structure, justifying the great interest in their synthesis.The original three component reaction of DHPMs consisted of a simple one-pot condensation of benzaldehyde 4b, ethyl acetoacetate 5 and urea 6b (Schemes 1 and 2), catalyzed by few drops of hydrochloric acid under refluxing In this context, we have reported the synthesis of a small library of DHPM, including monastrol (1a), using a Lewis acid as catalyst and this series was evaluated against seven human cancer cell lines. 21 The results showed that the oxo-monastrol analogue (2a) just shows cytostatic activity, while monastrol (1a) was cytotoxic against the seven cancer cell lines. We have also found that the 3,4-methylenodioxy derivative (piperastrol, 1c) was approximately 30 times more potent than monastrol (1a) against five of the seven tested cancer cell lines, and it was also more potent than the positive control doxorrubicine against three of the tested cell lines (Figur...

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Identification and characterization of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones as inhibitors of the fatty acid transporter FATP4

Cited by 66 publications

References 21 publications

Development of Novel Thiazolopyrimidines as CDC25B Phosphatase Inhibitors

Development of Novel Thiazolopyrimidines as CDC25B Phosphatase Inhibitors

Automated generation of a dihydropyrimidine compound library using microwave-assisted processing

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

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