Synthesis of new thienylpicolinamidine derivatives and possible mechanisms of antiproliferative activity

Ismail, Mohamed A.; Abdel‐Rhman, Mohamed H.; Abdelwahab, Ghada A.; Hamama, Wafaa S.; El-Shafeai, Heba M.; El‐Sayed, Wael M.

doi:10.1039/d0ra08796c

Cited by 8 publications

(3 citation statements)

References 57 publications

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“…With the cumulative understanding of the cell cycle and apoptotic pathways, more effective small molecule targeted therapies are developed. [3] Chalcophene derivatives have been reported for their antimicrobial, [4][5][6][7] antimutagenic, [8,9] specific recognition of G-quadruplex DNA, [10][11][12] and anticancer [13][14][15][16][17] activities. Thiophenebased derivatives have been reported as anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antiproliferative Activity, Apoptotic Profiling, and In‐silico ADME of New Thienylbenzamidine Derivatives

et al. 2021

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Twelve new thienylbenzamidines and their analogues 4 a-i, 7, and 12 a, b were synthesized and their anti-proliferative activity was evaluated against 60 cancer cell lines. The tested compounds showed potent anticancer activity against most cancer cell lines with median growth inhibition (GI 50 ) < 2 μM. Leukemia and renal cancer cell lines were the most responsive. Compound 12 a was the most active exhibiting GI 50, total growth inhibition (TGI), and median lethal concentration (LC 50 ) at 1.65, 3.71, and 9.3 μM, respectively. The benzamidine derivatives exerted their anti-proliferative activity without causing any toxicity in normal human lung fibroblast (WI-38) cells. The selectivity index (SI) ranged from 5.6 to 59.0 fold. Compound 4 h was the most selective compound (SI = 59), and it was the least cytotoxic to WI-38 cells. The cationic compounds 4 c, 4 h, 4 i, 7, and 12 b with high SI were selected for further mechanistic studies. Compounds 4 c, 4 h, and 4 i exerted their antiproliferative activity by inducing the cell cycle arrest (elevated p53 and downregulated cyclin-dependent kinase 1 (cdk1)) and inducing apoptosis (elevated caspase 3). Compounds 7 and 12 b exerted their activity by inhibiting the growth and proliferation of cancer cells through inhibiting both topoisomerase II (topoII) and thioredoxin reducta-se1 (txnrd1). Finally, in silico predictions of the physicochemical, pharmacokinetic and drug-likeness profiles of these new derivatives proved the oral availability and the inability to cross the blood-brain barrier.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Antiproliferative Activity, Apoptotic Profiling, and In‐silico ADME of New Thienylbenzamidine Derivatives

et al. 2021

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“…The pharmacokinetic behavior of these compounds is mainly attributed to the pyridine ring. [6][7][8][9][10] The antiproliferative activities of furanylnicotinamidine derivatives have been previously reported. [11] Arylthiophene derivatives were synthesized and shown to exhibit a wide range of biological activities.…”

Section: Introductionmentioning

confidence: 99%

“…MS(EI) m/e (rel.int. ); 277 (M + , 7), 193(6), 160(6), 82(22), 79(53), 77 (100).4-[5-(5-Chloropyridin-2-yl)thiophen-2-yl]benzaldehyde(10)…”

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Synthesis of new thienylnicotinamidines: Proapoptotic profile and cell cycle arrest of HepG2 cells

Ismail

Abdelwahab

Hamama

et al. 2022

Archiv der Pharmazie

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Fourteen new thienylnicotinamidines and their analogs 5a–5k, 12, 13a, and 13b were prepared and their antiproliferative potential was evaluated against the growth of 60 cancer cell lines. The tested compounds had a strong antiproliferative efficacy against almost all cancer cell lines, with the average GI50 at ~2.20 µM. The effect of the thienylnicotinamidines on the growth of normal lung fibroblast cells (WI‐38) indicated that these derivatives are safe to the normal cells. The selectivity index (SI) ranges from 5.5‐ to 42.0‐fold. The conceivable mechanisms of action of the effective compounds 5d, 5f, 5g, 5i, 5j, and 5k with high SI were investigated. Although the thienylnicotinamidines are similar in structure, they could be divided into three groups as per their effects on gene expression: The first group (5d and 5f) elevated p53 and caspase 3 expression, the second group (5g and 5i) elevated p53 expression, and the last group (5j and 5k) elevated p53 and reduced topoII expression. Many thienylnicotinamides inhibited the vascular endothelial growth factor receptor‐2 (VEGFR‐2) in cell lysates at concentrations comparable to or better than pazopanib. The data of caspase 3 expression were confirmed by measuring the protein level by Western blot and the activity of the cleaved active enzyme. The ability to arrest the cell cycle and induce apoptosis was confirmed by flow cytometry. Taken together, two derivatives, 5d and 5f, with a distinctive VEGFR‐2 inhibitory activity and a proapoptotic and cell cycle arrest profile merit further investigations.

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Design and synthesis of novel bichalcophene derivatives with double anchoring groups for dye-sensitized solar cell applications: sensitization and co-sensitization with N-719

Abdelhamed

Ismail

Abdel‐Latif

et al. 2022

J Mater Sci: Mater Electron

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Synthesis of new thienylpicolinamidine derivatives and possible mechanisms of antiproliferative activity

Abstract: Three thienylpicolinamidine derivatives 4a–c were prepared from their corresponding picolinonitriles 3a–c on treatment with lithium trimethylsilylamide, LiN(TMS)2, followed by a de-protection step using ethanol/HCl (gas).

Cited by 8 publications

References 57 publications

Synthesis, Antiproliferative Activity, Apoptotic Profiling, and In‐silico ADME of New Thienylbenzamidine Derivatives

Synthesis, Antiproliferative Activity, Apoptotic Profiling, and In‐silico ADME of New Thienylbenzamidine Derivatives

Synthesis of new thienylnicotinamidines: Proapoptotic profile and cell cycle arrest of HepG2 cells

Design and synthesis of novel bichalcophene derivatives with double anchoring groups for dye-sensitized solar cell applications: sensitization and co-sensitization with N-719

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