Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells

Wilson, Jennifer M.; Henderson, Graham; Black, Fiona; Sutherland, Andrew; Ludwig, Robert L.; Vousden, Karen H.; Robins, David J.

doi:10.1016/j.bmc.2006.10.011

Cited by 36 publications

(33 citation statements)

References 12 publications

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“…13 The 10-aryl-5-deazaflavin derivatives were preliminarily reported to act as inhibitors of E3 activity of HMD2 in tumors that retain wide-type P53. 16 b) by heating with Vilsmeier reagent at 90 °C for three hours, and for the preparation of 2-alkylamino-2-deoxoflavin- 5-oxides (9a,b) by nitrosative cyclization involving excess NaNO 2 in glacial acetic acid for 2-3 hours.…”

Section: Introductionmentioning

confidence: 99%

Antitumor studies. Part 4: Design, synthesis, antitumor activity, and molecular docking study of novel 2-substituted 2-deoxoflavin-5-oxides, 2-deoxoalloxazine-5-oxides, and their 5-deaza analogs

Ali

Ashida

Nagamatsu

2008

Bioorganic & Medicinal Chemistry

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Abstract-Various novel 10-alkyl-2-deoxo-2-methylthioflavin-5-oxides and their 2-alkylamino derivatives were prepared by facile nitrosative cyclization of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones followed by nucleophilic replacement of the 2-methylthio moiety by different amines, and acidic hydrolysis of the 2-methylthio moiety afforded the corresponding flavin derivatives. 2-Deoxo-2-methylthio-5-deazaalloxazines and 2-deoxo-2-methylthioalloxazine-5-oxides were also prepared by Vilsmeier reaction and by nitrosation of 6-anilino-2-methylthiopyrimidin-4(3H)-ones, respectively. Then, they were subjected to nuceleophilic replacement with appropriate amines to produce the corresponding 2-alkylamino derivatives. Regiospecific N 3 -alkylation of 2-deoxo-2-methylthioalloxazine-5-oxides was carried out with various alkylating agents in the usual way. The antitumor activities against CCRF-HSB-2 and KB tumor cells have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.

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Section: Introductionmentioning

confidence: 99%

Antitumor studies. Part 4: Design, synthesis, antitumor activity, and molecular docking study of novel 2-substituted 2-deoxoflavin-5-oxides, 2-deoxoalloxazine-5-oxides, and their 5-deaza analogs

Ali

Ashida

Nagamatsu

2008

Bioorganic & Medicinal Chemistry

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“…5-Deazaflavin derivatives have been shown to activate p53 through inhibition of the p53-specific ubiquitin E3 ligase HDM2 [3], which catalyzes the initial step in p53 degradation ( Figure 1). Aiming to expand the group of p53 activators interrupting the p53-HDM2 signaling pathway, we are reporting herein a novel steroidal scaffold that incorporates a heterocyclic ring system fused onto ring D. For the most potent p53 activators previously reported see Yang et al [4], Kitagaki et al [5], and Wilson et al [3].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of androstanopyridine and pyrimidine compounds as novel activators of the tumor suppressor protein p53

Hussein

Amr²,

Abdalla³

et al. 2015

Zeitschrift Für Naturforschung C

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A series of androstane derivatives 2-16 were synthesized from 3β-hydroxyandrostan-17-one derivatives (1a-e). Compounds (1a,b) were treated with ethyl cyanoacetate, cyanoacetamide, or malononitrile and gave the corresponding derivatives 2-7, respectively. Additionally, compounds (1a-e) were condensed with cyanothioacetamide, urea, or guanidine hydrochloride afforded the corresponding derivatives 8-12, which then by Moffat oxidation gave the oxidized derivatives 9, 11 and 13, respectively. Finally, compound (1) condensed with acetyl acetone or ethyl acetoacetate gave cyclohexene derivatives (14a-c) and (15a,b), respectively. Compound 15 was oxidized with a Moffat oxidizing agent and afforded the corresponding oxidized compound 16. The newly synthesized compounds activated the tumor suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2.

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“…required positions, [10][11][12] or undergoing multi-step syntheses from the appropriately substituted aromatic building blocks. [13,14] 1-Deazariboflavin [15,16] 4 and 5-deazariboflavin [17][18][19] 5 have been previously synthesized. However, their application in biological systems and their physicochemical characterization is still limited due to synthetic difficulties, and improvement of their generation is clearly needed.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Electrochemical Properties of Structurally Modified Flavin Compounds

2008

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Four structurally modified flavin compounds have been synthesized and characterized for their redox potential by chemical reduction with sodium dithionite. Besides the previously reported 1-and 5-deazariboflavin, a 7,8-didemethyl derivative and an 8-isopropylriboflavin have been obtained. The synthesis of these compounds started in all cases from appropriately substituted anilines that were condensed with the ribityl chain, followed by completion of the annealed threering structure. The didemethyl-and the isopropyl compounds gave absorption maxima similar to riboflavin (436 and 448 nm, respectively), whereas 1-deazariboflavin

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Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells

Cited by 36 publications

References 12 publications

Antitumor studies. Part 4: Design, synthesis, antitumor activity, and molecular docking study of novel 2-substituted 2-deoxoflavin-5-oxides, 2-deoxoalloxazine-5-oxides, and their 5-deaza analogs

Antitumor studies. Part 4: Design, synthesis, antitumor activity, and molecular docking study of novel 2-substituted 2-deoxoflavin-5-oxides, 2-deoxoalloxazine-5-oxides, and their 5-deaza analogs

Synthesis of androstanopyridine and pyrimidine compounds as novel activators of the tumor suppressor protein p53

Synthesis and Electrochemical Properties of Structurally Modified Flavin Compounds

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