Nicotinonitrile-derived apoptotic inducers: Design, synthesis, X-ray crystal structure and Pim kinase inhibition

Aboukhatwa, Shaimaa M.; Ibrahim, Amera O.; Aoyama, Hiroshi; Al-Behery, Ahmed S.; Shaldam, Moataz A.; El-Ashmawy, Ghada; Tawfik, Haytham O.

doi:10.1016/j.bioorg.2022.106126

Cited by 15 publications

(9 citation statements)

References 99 publications

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“…The in vitro Pim-1 kinase inhibitory activity of the selected compounds was assessed using the Promega ADP-Glo kinase assay according to the manufacturer’s protocol. 54 The ADP formed from the kinase reaction is converted into ATP, which is converted into light by Ultra-Glo Luciferase. The luminescence signal positively correlates with the remaining kinase activity.…”

Section: Methodsmentioning

confidence: 99%

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

et al. 2023

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With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub-to two-digit micromolar potency (GI 50 down to 0.3 μM and LC 50 as low as 4 μM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity in vitro, with 4d being the most potent, having an average Ki value of 4 μM. Compound 4j showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms in vitro. Cytotoxicity of both 4d and 4j in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in 4j-treated colorectal carcinoma, HCT116, cells compared to the control. Compound 4j arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics. ■ HIGHLIGHTS• Hybrid chalcone-sulfonamides were designed as potential carbonic anhydrase inhibitors. • The derivatives inhibited cancer cell growth in the NCI-60 screen with high potency. • Up to 50-fold selectivity on cancer cells compared to normal cells was demonstrated. • Cell cycle arrest was observed at the G1/S phase in HCT116 colorectal carcinoma cells. • Nrf2 and ROS levels were elevated in response to one of the compounds in HCT116 cells.

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Section: Methodsmentioning

confidence: 99%

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

et al. 2023

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“…The Verlet cutoff-scheme [ 51 ] and the particle-mesh Ewald (PME) method [ 52 ] were used for searching the neighbor list and the long-range electrostatic interactions, respectively. The simulation parameters were set as in the literature [ 53 ], except for the production time, where 100 ns was applied. GROMACS utilities were used for the analysis of the MD simulations [ 54 ].…”

Section: Methodsmentioning

confidence: 99%

Papaverinol-N-Oxide: A Microbial Biotransformation Product of Papaverine with Potential Antidiabetic and Antiobesity Activity Unveiled with In Silico Screening

et al. 2023

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Bioconversion of biosynthetic heterocyclic compounds has been utilized to produce new semisynthetic pharmaceuticals and study the metabolites of bioactive drugs used systemically. In this investigation, the biotransformation of natural heterocyclic alkaloid papaverine via filamentous fungi was explored. Molecular docking simulations, using protein tyrosine phosphatase 1B (PTP1B), α-glucosidase and pancreatic lipase (PL) as target enzymes, were performed to investigate the antidiabetic potential of papaverine and its metabolites in silico. The metabolites were isolated from biotransformation of papaverine with Cunninghamella elegans NRRL 2310, Rhodotorula rubra NRRL y1592, Penicillium chrysogeneum ATCC 10002 and Cunninghamella blackesleeana NRRL 1369 via reduction, demethylation, N-oxidation, oxidation and hydroxylation reactions. Seven metabolites were isolated: namely, 3,4-dihydropapaverine (metabolite 1), papaveroline (metabolite 2), 7-demethyl papaverine (metabolite 3), 6,4′-didemethyl papaverine (metabolite 4), papaverine-3-ol (metabolite 5), papaverinol (metabolite 6) and papaverinol N-oxide (metabolite 7). The structural elucidation of the metabolites was investigated with 1D and 2D NMR and mass spectroscopy (EI and ESI). The molecular docking studies showed that metabolite 7 exhibited better binding interactions with the target enzymes PTP1B, α-glucosidase and PL than did papaverine. Furthermore, papaverinol-N-oxide (7) also displayed inhibition of α-glucosidase and lipase enzymes comparable to that of their ligands (acarbose and orlistat, respectively), as unveiled with an in silico ADMET profile, molecular docking and molecular dynamics studies. In conclusion, this study provides evidence for enhanced inhibition of PTP1B, α-glucosidase and PL via some papaverine fungal transformation products and, therefore, potentially better antidiabetic and antiobesity effects than those of papaverine and other known therapeutic agents.

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“…[39] By the action of ammonia, benzene sulfonyl chloride 2 was converted into sulfonamide 3. [40,41] The targeted 3cyanopyridin-2-one derivatives (6a-m and 8a-d) were obtained by a four-component one-pot condensation reaction [28] of sulfonamide 3, different aromatic aldehyde derivatives (5a-m and 7a-d), ethyl cyanoacetate 4 and anhydrous ammonium acetate in absolute ethanol.…”

Section: Chemistrymentioning

confidence: 99%

“…Following modified reported procedures, [28] HeLa cells using a colorimetric MTT cell viability assay. [42,54] 4.2.2 | Inhibition assay using CA and EGFR…”

Section: General Procedures For Synthesis Of 5-acetyl-2-methoxybenzen...mentioning

confidence: 99%

“…[20] The cyanopyridine scaffold has been discovered to possess a variety of bioactivities, including anti-inflammatory, antibacterial and anticancer properties. [21][22][23][24][25] Cyanopyridine-based derivatives showed various enzyme inhibition activities [26][27][28][29][30] including EGFR [31,32] and CA. [33][34][35] Among these derivatives, compound I has an IC 50 value of 0.6 μM on EGFR [32] and compound II showed good EGFR inhibition with an IC 50 value of 0.203 μM.…”

Section: Introductionmentioning

confidence: 99%

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Identification of 3‐(5‐cyano‐6‐oxo‐pyridin‐2‐yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity

Shaldam,

Khalil,

Almahli

et al. 2023

Archiv der Pharmazie

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New 5‐cyano‐6‐oxo‐pyridine‐based sulfonamides (6a–m and 8a–d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5‐cyanopyridine derivatives 6e and 6l on cell‐cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed.

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Nicotinonitrile-derived apoptotic inducers: Design, synthesis, X-ray crystal structure and Pim kinase inhibition

Cited by 15 publications

References 99 publications

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

Papaverinol-N-Oxide: A Microbial Biotransformation Product of Papaverine with Potential Antidiabetic and Antiobesity Activity Unveiled with In Silico Screening

Identification of 3‐(5‐cyano‐6‐oxo‐pyridin‐2‐yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity

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