An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties

Porta, Federica; Facchetti, Giorgio; Ferri, Nicola; Gelain, Arianna; Meneghetti, Fiorella; Villa, Stefania; Barlocco, Daniela; Masciocchi, D.; Asai, Akira; Miyoshi, Nao; Marchianò, Silvia; Kwon, Byoung Mog; Jin, Yena; Gandin, Valentina; Marzano, Cristina; Rimoldi, Isabella

doi:10.1016/j.ejmech.2017.03.017

Cited by 37 publications

(35 citation statements)

References 62 publications

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“…A list of papers published in the last five years, together with a summary, is reported in Table 2 . Multiple strategies, involving different protein regions, have been followed aiming to design potent and selective inhibitors of the STAT3 functions [ 59 , 60 , 61 , 62 ].…”

Section: Drug Designmentioning

confidence: 99%

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Sgrignani

Garofalo

Matkovic

et al. 2018

IJMS

112

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Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and activator of transcription” (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention.

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Section: Drug Designmentioning

confidence: 99%

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Sgrignani

Garofalo

Matkovic

et al. 2018

IJMS

112

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“…The latter were coupled with the suitable benzoyl chlorides in the presence of sodium hydride to afford the products 1-12 and the amide 18 (Figure 2 AlphaScreen-based assay. Several literature works have reported that oxadiazole-based derivatives can inhibit the signal transducer and activator of transcription 3 (STAT3) transcription factor, by binding to its SH2 domain (10,(17)(18)(19). Therefore, the potential inhibitory activity of the most interesting compounds (1,2 and 4) was tested at 30 µM concentration by an AlphaScreen-based assay, though without positive results (data not shown).…”

Section: Resultsmentioning

confidence: 98%

Unravelling the Antiproliferative Activity of 1,2,5-oxadiazole Derivatives

et al. 2019

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Background: Our efforts, focused on the discovery of novel antiproliferative agents, led to the identification of an interesting oxadiazole derivative, MD77. Aim: To complete the studies concerning the antiproliferative profile of MD77 , we developed several new derivatives. Materials and Methods: The substitution pattern around the phenyl rings of this compound was analysed through the synthesis of positional isomers and of analogues bearing different substituents at the para positions (2-12). Results: The results of the antiproliferative activity of these derivatives versus HCT-116 and HeLa cancer cell lines shed light on the effects of the presence, nature and position of such substituents. Notably, derivative 4, a regioisomer of 1 in which the substituents at the para positions of the phenyl rings were inverted, showed the best antiproliferative profile, exhibiting a significant activity also against MCF7 and MDA-MB 468 cancer cell lines. Conclusion: Preliminary results showed the ability of compound 4 to counteract human recombinant topoisomerase II α relaxation activity.

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“…Amides 21, 27 and 31 were synthesized as previously reported (2). N-(4-(4-chlorophenyl)-1,2,5-oxadiazol-3-yl)heptanamide (15 (17). Benzaldehyde (0.306 mmol) was added to 30a (0.153 mmol) in acetic acid (4 ml) and the solution was stirred at room temperature for 3 h. The reaction was cooled at 0˚C and NaBH4 (0.306 mmol) was added; the resulting mixture was stirred for 1 h. Afterwards, a solution of 2N NaOH was added, and the mixture was extracted with ethyl acetate (3×2 ml), dried over Na 2 SO 4 (14).…”

Section: Synthesis Of 125-oxadiazol-3-amines (30a-c)mentioning

confidence: 99%

“…AlphaScreen-based assay. Considering that several examples of oxadiazole derivatives targeting the SH2 domain of STAT3 have been reported (15,16), the compounds endowed with the most interesting antiproliferative activity were tested by the AlphaScreen-based assay to evaluate their potential inhibition of the interaction between the SH2 domain and pTyr-containing peptides, at 30 μM concentration. The obtained data indicated that the derivatives did not interact with the SH2 domain (unpublished data).…”

Section: Antiproliferative Activity On Hct-116 and Hela Cell Linesmentioning

confidence: 99%

Exploring the Biological Activity of a Library of 1,2,5-Oxadiazole Derivatives Endowed With Antiproliferative Activity

et al. 2018

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Background/Aim: The identification of a series of oxadiazole-based compounds as promising antiproliferative agents has been previously reported. The aim of this study was to explore the SAR of newly synthesized oxadiazole derivatives and identify their molecular targets. Materials and Methods: A small library of 1,2,5-oxadiazole derivatives was synthetized and their antiproliferative activity was tested by MTT assay. Their interaction with topoisomerase I was evaluated and a molecular docking study was performed. Results: Several candidates showed cytotoxicity towards two human tumor cell lines, and HeLa (cervix adenocarcinoma). Some derivatives exhibited inhibitory effects on the catalytic activity of topoisomerase I and this effect was supported by docking studies. Conclusion: The enzyme inhibition results, although not directly related to cytotoxicity, suggest that a properly modified 1,2,5 oxadiazole scaffold could be considered for the development of new antitopo I agents.Cancer is one of the main causes of morbidity and mortality worldwide, causing approximately 1 in 6 deaths (1). Materials and MethodsChemistry. Reagents and solvents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without further purification.

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An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties

Cited by 37 publications

References 62 publications

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Unravelling the Antiproliferative Activity of 1,2,5-oxadiazole Derivatives

Exploring the Biological Activity of a Library of 1,2,5-Oxadiazole Derivatives Endowed With Antiproliferative Activity

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