Novel 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives as potent anticancer agents – Synthesis, molecular structure, QSAR studies and metabolic stability

Pogorzelska, Aneta; Sławiński, Jarosław; Żołnowska, Beata; Szafrański, Krzysztof; Kawiak, Anna; Chojnacki, Jarosław; Ulenberg, Szymon; Zielińska, Joanna; Bączek, Tomasz

doi:10.1016/j.ejmech.2017.06.059

Cited by 19 publications

(14 citation statements)

References 35 publications

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“…Some of the most important of them are: inhibition of vascular endothelial growth factor receptor (VEGFR) (Pazopanib) [9], inhibition of prosurvival BCL-2 family proteins (Wenetoklaks) [10], inhibition of histone deacetylases (Belinostat) [11], selective and specific inhibition of mutated serine/threonine-protein kinase BRAF V600 (Vemurafenib and Dabrafenib) [12] and the disturbing of the splicing process (Indisulam) [13] ( Figure 1). Our efforts for a long time have been focused on extensive research on the antineoplastic activity of 2-mercaptobenzenensulfonamide derivatives [14][15][16][17]. Recently, we synthesized a large group of 2-(benzylthio)-4-chloro-5-[(5-(substituted)-1,3,4-oxadiazol-2-yl)]benzenesulfonamides, and found that among them a series of (E)-2-(benzylthio)-4-chloro-5-(5-styryl-1,3,4-oxadiazol-2yl)benzenesulfonamides display significant antitumor activity [18].…”

Section: Introductionmentioning

confidence: 99%

“…Finally, we decided to check the significance of the sulfonamide moiety in the meta position relative to the oxadiazole ring by synthesizing analogous compounds based on the 4benzenesulfonamide and 2,4-dichlorobenzene scaffold ( Figure 2). Our efforts for a long time have been focused on extensive research on the antineoplastic activity of 2-mercaptobenzenensulfonamide derivatives [14][15][16][17]. Recently, we synthesized a large group of 2-(benzylthio)-4-chloro-5-[(5-(substituted)-1,3,4-oxadiazol-2-yl)]benzenesulfonamides, and found that among them a series of (E)-2-(benzylthio)-4-chloro-5-(5-styryl-1,3,4-oxadiazol-2-yl)benzenesulfonamides display significant antitumor activity [18].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis, Anticancer Evaluation and Structure-Activity Analysis of Novel (E)- 5-(2-Arylvinyl)-1,3,4-oxadiazol-2-yl)benzenesulfonamides

Szafrański

Sławiński

Tomorowicz

et al. 2020

IJMS

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To learn more about the structure–activity relationships of (E)-3-(5-styryl-1,3,4-oxadiazol-2-yl)benzenesulfonamide derivatives, which in our previous research displayed promising in vitro anticancer activity, we have synthesized a group of novel (E)-5-[(5-(2-arylvinyl)-1,3,4-oxadiazol-2-yl)]-4-chloro-2-R1-benzenesulfonamides 7–36 as well as (E)-4-[5-styryl1,3,4-oxadiazol-2-yl]benzenesulfonamides 47–50 and (E)-2-(2,4-dichlorophenyl)-5-(2-arylvinyl)-1,3,4-oxadiazols 51–55. All target derivatives were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. The obtained results were analyzed in order to explain the influence of a structure of the 2-aryl-vinyl substituent and benzenesulfonamide scaffold on the anti-tumor activity. Compound 31, bearing 5-nitrothiophene moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 0.5, 4, and 4.5 µM, respectively. Analysis of structure-activity relationship showed significant differences in activity depending on the substituent in position 3 of the benzenesulfonamide ring and indicated as the optimal meta position of the sulfonamide moiety relative to the oxadizole ring. In the next stage, chemometric analysis was performed basing on a set of computed molecular descriptors. Hierarchical cluster analysis was used to examine the internal structure of the obtained data and the quantitative structure–activity relationship (QSAR) analysis with multiple linear regression (MLR) method allowed for finding statistically significant models for predicting activity towards all three cancer cell lines.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis, Anticancer Evaluation and Structure-Activity Analysis of Novel (E)- 5-(2-Arylvinyl)-1,3,4-oxadiazol-2-yl)benzenesulfonamides

Szafrański

Sławiński

Tomorowicz

et al. 2020

IJMS

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“…Cancer, the most debilitating disease, has advanced to such a level that it has become one of the universal cause of human suffering and death all over the world [ 6 , 7 ]. The huge arsenal of synthetic, semi-synthetic, and naturally-occurring agents for treating neoplastic diseases suffers from two major limitations; the first one being the lack of selectivity of conventional chemotherapeutic agents to cancer tissues, causing unwanted side effects [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of antimicrobial, antitubercular and anticancer activities of 2-(1-benzoyl-1H-benzo[d]imidazol-2-ylthio)-N-substituted acetamides

Yadav

Lim

Ramasamy

et al. 2018

Chemistry Central Journal

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BackgroundThe study describes the synthesis, characterization, in vitro antimicrobial and anticancer evaluation of a series of 2-(1-benzoyl-1H-benzo[d]imidazol-2-ylthio)-N-substituted acetamide derivatives. The synthesized derivatives were also assessed for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The compounds found active in in vitro study were assessed for their in vivo antitubercular activity in mice models and for their inhibitory action on vital mycobacterial enzymes viz, isocitrate lyase, pantothenate synthetase and chorismate mutase.ResultsCompounds 8, 9 and 11 emerged out as excellent antimicrobial agents in antimicrobial assays when compared to standard antibacterial and antifungal drugs. The results of anticancer activity displayed that majority of the derivatives were less cytotoxic than standard drugs (tamoxifen and 5-fluorouracil) towards MCF7 and HCT116 cell lines. However, compound 2 (IC50 = 0.0047 µM/ml) and compound 10 (IC50 = 0.0058 µM/ml) showed highest cytotoxicity against MCF7 and HCT116 cell lines, respectively. The results of in vivo antitubercular activity revealed that a dose of 1.34 mg/kg was found to be safe for the synthesized compounds. The toxic dose of the compounds was 5.67 mg/kg while lethal dose varied from 1.81 to 3.17 mg/kg body weight of the mice. Compound 18 inhibited all the three mycobacterial enzymes to the highest level in comparison to the other synthesized derivatives but showed lesser inhibition as compared to streptomycin sulphate.ConclusionsA further research on most active synthesized compounds as lead molecules may result in discovery of novel anticancer and antitubercular agents.

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“…In the cited publications, in addition to new chemical entities, results of the structure-activity relationships have also been presented (6,7,(9)(10)(11). A study to model metabolic stability of arylpiperazines has also been conducted (13), not only describing an approach that can be applied to other compounds (14)(15)(16)(17) but also identifying the best chemometric technique to conduct such research (18).…”

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confidence: 99%

In Vitro approach for identification of a leading cytochrome P450 isoenzyme responsible for biotransformation of novel arylpiperazine drug candidates and their inhibition potency towards CYP3A4.

Ulenberg¹,

Belka²,

Georgiev³

et al. 2020

Acta Poloniae Pharmaceutica - Drug Research

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The aim of this study was to identify cytochrome P450 (CYP) isoforms that participate in the metabolism of some novel arylpiperazine derivatives developed by authors as well as their potency to inhibit reactions catalyzed by identified lead metabolizing enzyme. Such studies allow to predicting possible drug-drug interactions that might occur during co-administration of studied compounds with other drugs that are metabolized by an identified enzyme. The compounds were incubated in vitro together with the isolated CYP isoforms. After the incubation, samples were analyzed by liquid chromatography coupled with mass spectrometry. The results showed the main contribution of CYP3A4 isoform in biotransformation of the investigated derivatives. With CYP3A4 being the main CYP isoform responsible for the metabolism of arylpiperazine derivatives and at the same time being the main metabolizing enzyme for almost 50% of all drugs, a high chance of in vivo drug-drug interactions emerged. Therefore, IC 50 values were also determined using testosterone hydroxylation as a probe reaction, specific for CYP3A4. The resulting values ranged from 6.13 to 15.85 µM, which places studied derivatives as moderate or weak inhibitors of CYP3A4. Those results, combined with the conclusion that all of the arylpiperazine derivatives are also metabolized to some extent by other CYP isoforms (providing alternative metabolic pathways), result in a conclusion that studied arylpiperazines might be safe for co-administration with other CYP3A4 substrates.

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Novel 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives as potent anticancer agents – Synthesis, molecular structure, QSAR studies and metabolic stability

Cited by 19 publications

References 35 publications

Synthesis, Anticancer Evaluation and Structure-Activity Analysis of Novel (E)- 5-(2-Arylvinyl)-1,3,4-oxadiazol-2-yl)benzenesulfonamides

Synthesis, Anticancer Evaluation and Structure-Activity Analysis of Novel (E)- 5-(2-Arylvinyl)-1,3,4-oxadiazol-2-yl)benzenesulfonamides

Synthesis and evaluation of antimicrobial, antitubercular and anticancer activities of 2-(1-benzoyl-1H-benzo[d]imidazol-2-ylthio)-N-substituted acetamides

In Vitro approach for identification of a leading cytochrome P450 isoenzyme responsible for biotransformation of novel arylpiperazine drug candidates and their inhibition potency towards CYP3A4.

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