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Exploring the Anti-Cancer Mechanism of Novel 3,4'-Substituted Diaryl Guanidinium Derivatives.

ABSTRACT: We previously identified a guanidinium-based lead compound that inhibited BRAF through a hypothetic type-III allosteric mechanism. Considering the pharmacophore identified in this lead compound (i.e., "lipophilic group", "di-substituted guanidine", "phenylguanidine polar end"), several modifications were investigated to improve its cytotoxicity in different cancer cell lines. Thus, several lipophilic groups were explored, the di-substituted guanidine was replaced by a secondary amine and the phenyl ring in the polar end was substituted by a pyridine. In a structure-based design approach, four representative derivatives were docked into an in-house model of an active triphosphate-containing BRAF protein, and the interactions established were analysed. Based on these computational studies, a variety of derivatives was synthesized, and their predicted drug-like properties calculated. Next, the effect on cell viability of these compounds was assessed in cell line models of promyelocytic leukaemia and breast, cervical and colorectal carcinomas. The potential of a selection of these compounds as apoptotic agents was assessed by screening in the promyelocytic leukaemia cell line HL-60. The toxicity against non-tumorigenic epithelial MCF10A cells was also investigated. These studies allowed for several structure-activity relationships to be derived. Investigations on the mechanism of action of representative compounds suggest a divergent effect on inhibition of the MAPK/ERK signalling pathway.

SUBMITTER: Previtali V

PROVIDER: S-EPMC7767381 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Exploring the Anti-Cancer Mechanism of Novel 3,4'-Substituted Diaryl Guanidinium Derivatives.

Previtali Viola V Mihigo Helene B HB Amet Rebecca R McElligott Anthony M AM Zisterer Daniela M DM Rozas Isabel I

Pharmaceuticals (Basel, Switzerland) 20201221 12

We previously identified a guanidinium-based lead compound that inhibited BRAF through a hypothetic type-III allosteric mechanism. Considering the pharmacophore identified in this lead compound (i.e., "lipophilic group", "di-substituted guanidine", "phenylguanidine polar end"), several modifications were investigated to improve its cytotoxicity in different cancer cell lines. Thus, several <i>lipophilic groups</i> were explored, the <i>di-substituted guanidine</i> was replaced by a secondary ami ...[more]

PMID: 33371382

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Project description:Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized 3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reported for the synthesis of these derivatives, employing cobalt ferrite (CoFe 2 O 4 @SiO 2 -SO 3 H) magnetic nanoparticles under microwave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessed against the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonic kidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxic molecule against the MCF-7 cell line (IC 50 of 0.17 μg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showed excellent cytotoxic activities against the AGS cell line, with an IC 50 of 4.90 and 4.97 μg/mL, respectively. Although they are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showed that the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential of the candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridine derivatives, compound 5m had the most free energy of binding (-9.52 kcal/mol) and lowest Ki (0.105 μM), and among the pyrimidine derivatives, compound 4r had the most free energy of binding (-7.67 kcal/mol) and lowest Ki (2.39 μM). Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding site via H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM and pyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpful in the further design of DHPMs and pyridine derivatives as potential anticancer agents.

Project description:Objectives:The novel 1,5-diaryl-1,4-pentadien-3-one derivatives were studied for analgesic, anti-inflammatory and anticancer potential to establish their role in pain, inflammatory disorders and cancer. Materials and Methods:Two 1,5- diaryl-1,4-pentadien-3-one derivatives: (1E,4E)- 5-(4-fluoro phenyl)-1-(4-methoxyphenyl)- 2-methylpenta-1,4-dien-3-one (A2K2A17) and (1E,4E)-5-(4-nitrophenyl)-1-(4-nitrophenyl)-2-ethylhexa-1,4-dien-3-one (A11K3A11) were synthesized and characterized via 1H NMR and 13C NMR techniques. Molecular docking, anti-inflammatory, analgesic and anticancer activities were performed using Auto Doc Vina, carrageenan mediated paw edema and formalin induced chronic inflammation, acetic acid induced writhings and hotplate assay and brine-shrimp lethality assay. Results:A2K2A17 and A11K3A11 showed high computational affinities (binding energy > -9.0 Kcal/mol) against COX-1, kappa receptor and braf kinase domain. A2K2A17 and A11K3A11 exhibited moderate docking affinities (binding energy > -8.0 Kcal/mol) against COX-2, human capsaicin receptor, tumor necrosis factor, lipoxygenase, colony stimulating factor, delta receptor, cyclin dependent protein kinase-2, mitogen activated kinase, mu receptor and kit kinase domain. A2K2A17 and A11K3A11 possess low docking affinities (binding energy > -7.0 Kcal/mol) against purinoceptor, platelets-derived growth Factor-1 and vascular-endothelial growth factor. In analgesic activity, A2K2A17 (1-30 mg/kg) and A11K3A11 (1-10 mg/kg) decreased acetic acid induced writhes and prolonged the latency time (P<0.01, P<0.001 vs saline group) respectively. A2K2A17 (10-30 mg/kg) and A11K3A11 (1-10 mg/kg) reduced carrageenan as well as formalin mediated edema (P<0.01, P<0.001). A2K2A17 found effective for cytotoxicity assay with LC50 value 1.5 µg/ml. Conclusion:The in silico, in vitro and in vivo studies on A2K2A17 and A11K3A11 reports their computational binding affinities against targets as well as the analgesic, anti-inflammatory and the anticancer effects.

Dataset Information

Exploring the Anti-Cancer Mechanism of Novel 3,4'-Substituted Diaryl Guanidinium Derivatives.

Publications

Exploring the Anti-Cancer Mechanism of Novel 3,4'-Substituted Diaryl Guanidinium Derivatives.

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