Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53–MDM2 interaction. Part 1

Wang, Weisi; Shangguan, Shihao; Qiu, Ni; Hu, Chunqi; Zhang, Lei; Hu, Yongzhou

doi:10.1016/j.bmc.2013.03.061

Cited by 34 publications

(13 citation statements)

References 16 publications

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“…As a matter of fact, a progressive increase of hydrophobicity from sulfaguanidine to sulfathiazole due to the presence of the heterocyclic moieties was observed, which suggests an increasing affinity to bind to the MDM2-p53 complex, as also indicated by Wang et al 23 …”

Section: Resultssupporting

confidence: 62%

Antimicrobial sulfonamides clear latent Kaposi sarcoma herpesvirus infection and impair MDM2–p53 complex formation

et al. 2017

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Kaposi Sarcoma Herpesvirus (KSHV), also known as Human Herpesvirus 8, is the causative agent of Kaposi sarcoma; this malignant angiosarcoma is usually treated with conventional anti-tumor agents, which can control disease evolution, but do not clear the latent KSHV episome that binds to cellular DNA. Some commercial antibacterial sulfonamides were tested for the ability to suppress latent KSHV. qPCR and cytofluorometry assays were used for detecting both viral DNA and the latency factor LANA in BC3 cells, respectively. The capacity of sulfonamides to impair MDM2-p53 complex formation was detected by an ELISA method. The analysis of variance was performed according to one-way ANOVA with Fisher as a post-hoc test. Here we show that sulfonamide antibiotics are able to suppress the KSHV latent state in permanently-infected BC3 lymphoma-cells and interfere with the formation of the MDM2-p53 complex, which KSHV seemingly needs to support latency and to trigger tumor cell transformation. These findings detected a new molecular target for the activity of sulfonamides and offer a new potential perspective for treating KSHV-induced lymphoproliferative diseases.

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Section: Resultssupporting

confidence: 62%

Antimicrobial sulfonamides clear latent Kaposi sarcoma herpesvirus infection and impair MDM2–p53 complex formation

et al. 2017

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“…Grasberger and co-workers (2005) first reported 1,4-benzodiazepine-2,5-diones as inhibitors of p53-MDM2 interaction [118]. Compound 21 discovered by high-throughput screening of over 338000 compounds achieved a promising IC 50 value [119]. Modifications of this scaffold led to significant increases in potency.…”

Section: Agents Interrupting the Mdm2-p53-interactionmentioning

confidence: 99%

The role of p53 in cancer drug resistance and targeted chemotherapy

et al. 2016

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Cancer has long been a grievous disease complicated by innumerable players aggravating its cure. Many clinical studies demonstrated the prognostic relevance of the tumor suppressor protein p53 for many human tumor types. Overexpression of mutated p53 with reduced or abolished function is often connected to resistance to standard medications, including cisplatin, alkylating agents (temozolomide), anthracyclines, (doxorubicin), antimetabolites (gemcitabine), antiestrogenes (tamoxifen) and EGFR-inhibitors (cetuximab). Such mutations in the TP53 gene are often accompanied by changes in the conformation of the p53 protein. Small molecules that restore the wild-type conformation of p53 and, consequently, rebuild its proper function have been identified. These promising agents include PRIMA-1, MIRA-1, and several derivatives of the thiosemicarbazone family. In addition to mutations in p53 itself, p53 activity may be also be impaired due to alterations in p53s regulating proteins such as MDM2. MDM2 functions as primary cellular p53 inhibitor and deregulation of the MDM2/p53-balance has serious consequences. MDM2 alterations often result in its overexpression and therefore promote inhibition of p53 activity. To deal with this problem, a judicious approach is to employ MDM2 inhibitors. Several promising MDM2 inhibitors have been described such as nutlins, benzodiazepinediones or spiro-oxindoles as well as novel compound classes such as xanthone derivatives and trisubstituted aminothiophenes. Furthermore, even naturally derived inhibitor compounds such as a-mangostin, gambogic acid and siladenoserinols have been discovered. In this review, we discuss in detail such small molecules that play a pertinent role in affecting the p53-MDM2 signaling axis and analyze their potential as cancer chemotherapeutics.

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“…From a mechanistic point of view, when a reaction rate is enhanced under aqueous conditions, the acceleration is attributed to either the repulsive forces arising from hydrophobicity of the reactants 30 or to activation of electron donating functional groups through H-bonding with water molecules. 31 To study the role of these effects in the present work, we next altered the composition of the aqueous medium to investigate the effect of different additives on the progress of the reaction (entries [9][10][11][12][13][14]. In these cases, an early work-up procedure was used (after 0.5 h) so that a better comparison of the results could be concluded.…”

Section: Resultsmentioning

confidence: 99%

A facile four-component Gewald reaction under organocatalyzed aqueous conditions

Abaee¹,

Cheraghi²

2013

Arkivoc

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In the presence of water and triethylamine, a four-component process involving ethyl cyanoacetate, an α-methylene carbonyl compound, a primary or a secondary amine, and elemental sulfur leads to efficient room-temperature formation of 2-amino-3-carboxamide derivatives of thiophene in short time periods. The products, which precipitate from the reaction mixtures, are easily obtained by simple filtration and recrystallization from ethyl acetate/hexanes.

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Design, synthesis and biological evaluation of novel 3,4,5-trisubstituted aminothiophenes as inhibitors of p53–MDM2 interaction. Part 1

Cited by 34 publications

References 16 publications

Antimicrobial sulfonamides clear latent Kaposi sarcoma herpesvirus infection and impair MDM2–p53 complex formation

Antimicrobial sulfonamides clear latent Kaposi sarcoma herpesvirus infection and impair MDM2–p53 complex formation

The role of p53 in cancer drug resistance and targeted chemotherapy

A facile four-component Gewald reaction under organocatalyzed aqueous conditions

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