Novel N-bridged pyrazole-1-carbothioamides with potential antiproliferative activity: design, synthesis, in vitro and in silico studies

2021 ◽  
Vol 13 (20) ◽  
pp. 1743-1766
Author(s):  
Islam H El Azab ◽  
Essa M Saied ◽  
Alaa A Osman ◽  
Amir E Mehana ◽  
Hosam A Saad ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
In Silico ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Molecular Docking Study ◽  
In Silico Studies

Thiazole-substituted pyrazole is an important structural feature of many bioactive compounds, including antiviral, antitubercular, analgesic and anticancer agents. Herein we describe an efficient and facile approach for the synthesis of two series of 36 novel N-bridged pyrazole-1-phenylthiazoles. The antiproliferative activity of a set of representative compounds was evaluated in vitro against different human cancer cell lines. Among the identified compounds, compound 18 showed potent anticancer activity against the examined cancer cell lines. The in silico molecular docking study revealed that compound 18 possesses high binding affinity toward both SK1 and CDK2. Overall, these results indicate that compound 18 is a promising lead anticancer compound which may be exploited for development of antiproliferative drugs.

scholarly journals Discovery of New Pyrazolopyridine, Furopyridine, and Pyridine Derivatives as CDK2 Inhibitors: Design, Synthesis, Docking Studies, and Anti-Proliferative Activity

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3923
Author(s):  
Adel A.-H. Abdel-Rahman ◽  
Amira K. F. Shaban ◽  
Ibrahim F. Nassar ◽  
Dina S. EL-Kady ◽  
Nasser S. M. Ismail ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Molecular Docking Study ◽  
Human Cancer Cell Lines ◽  
Hct 116 ◽  
Mcf 7

New pyridine, pyrazoloyridine, and furopyridine derivatives substituted with naphthyl and thienyl moieties were designed and synthesized starting from 6-(naphthalen-2-yl)-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridine-3-carbonitrile (1). The chloro, methoxy, cholroacetoxy, imidazolyl, azide, and arylamino derivatives were prepared to obtain the pyridine-−C2 functionalized derivatives. The derived pyrazolpyridine-N-glycosides were synthesized via heterocyclization of the C2-thioxopyridine derivative followed by glycosylation using glucose and galactose. The furopyridine derivative 14 and the tricyclic pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine 15 were prepared via heterocyclization of the ester derivative followed by a reaction with formamide. The newly synthesized compounds were evaluated for their ability to in vitro inhibit the CDK2 enzyme. In addition, the cytotoxicity of the compounds was tested against four different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549). The CDK2/cyclin A2 enzyme inhibitory results revealed that pyridone 1, 2-chloro-6-(naphthalen-2-yl)-4-(thiophen-2-yl)nicotinonitrile (4), 6-(naphthalen-2-yl)-4-(thiophen-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (8), S-(3-cyano-6-(naphthaen-2-yl)-4-(thiophen-2-yl)pyridin-2-yl) 2-chloroethanethioate (11), and ethyl 3-amino-6-(naphthalen-2-yl)-4-(thiophen-2-yl)furo[2,3-b]pyridine-2-carboxylate (14) are among the most active inhibitors with IC50 values of 0.57, 0.24, 0.65, 0.50, and 0.93 µM, respectively, compared to roscovitine (IC50 0.394 μM). Most compounds showed significant inhibition on different human cancer cell lines (HCT-116, MCF-7, HepG2, and A549) with IC50 ranges of 31.3–49.0, 19.3–55.5, 22.7–44.8, and 36.8–70.7 μM, respectively compared to doxorubicin (IC50 40.0, 64.8, 24.7 and 58.1 µM, respectively). Furthermore, a molecular docking study suggests that most of the target compounds have a similar binding mode as a reference compound in the active site of the CDK2 enzyme. The structural requirements controlling the CDK2 inhibitory activity were determined through the generation of a statistically significant 2D-QSAR model.

Synthesis, Antiproliferative activity, and apoptotic profile of New Derivatives from the Meta Stable Benzoxazinone Scaffold

2021 ◽  
Vol 21 ◽  
Author(s):  
Amira El-Sayed ◽  
Maher El-Hashash ◽  
Wael El-Sayed
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Human Fibroblasts ◽  
Cancer Cell Lines ◽  
Selectivity Index ◽  
Human Cancer Cell Lines

Background: Cancer exerts a huge strain on the health system. The emerging resistance to the current chemotherapies demands the continuous development of new anticancer agents with lower cost, higher efficacy, and greater specificity. Objective: Development of selective small molecules targeted anticancer agents Methods: The behavior of benzoxazinone 2 towards nitrogen nucleophiles such as hydrazine hydrate, formamide, ethanolamine, aromatic amines, and thiosemcarbazide was described. The behavior of the amino quinazolinone 3 towards carbon electrophiles and P2S5 was also investigated. The antiproliferative activity of 17 new benzoxazinone derivatives was examined against the growth of three human cancer cell lines; liver HepG2, breast MCF-7, and colon HCT-29, in addition to the normal human fibroblasts WI-38 and the selectivity index was calculated. The possible molecular pathways such as the cell cycle and apoptosis were investigated. Results: Derivatives 3, 7, 8, 10, 13, and 15 had a significant (less than 10 µM) antiproliferative activity against the three cancer cell lines investigated. Derivative 7 showed the best antiproliferative profile comparable to that of doxorubicin. The selectivity index for all the effective derivatives ranged from ~5-12 folds indicating high selectivity against the cancer cells. Derivative 15 caused ~ 7-fold and 8-fold inductions in the expression of p53 and caspase3, respectively. It also caused a ~ 60% reduction in the expression of both topoisomerase II (topoII) and cyclin-dependent kinase 1 (cdk1). Derivatives 3, 7, and 8 had a similar profile; ~ 6-8-fold increases in the expression of p53 and caspase3 but these compounds were devoid of any significant effect on the expression of topoII and cdk1. Derivatives 10 and 13 were also similar and resulted in a ~6-fold elevation in the expression of caspase3, and more than 60% downregulation in the expression of topoII. The results of the gene expression of topoII and caspase 3 were confirmed by the measurement of the topoII concentration and caspase3 activity in the HepG2 cells. Conclusion: Six derivatives exerted their antiproliferative activity by arresting the cell cycle (decreasing cdk1), preventing the DNA duplication (downregulating topo II), and by inducing apoptosis (inducing p53 and caspase3). One common feature in all the six active derivatives is the presence of free amino group. These compounds have merit for further investigations.

scholarly journals DESIGN AND SYNTHESIS OF NOVEL 2, 3-DISUBSTITUTED QUINAZOLINES: EVALUATION OF IN VITRO ANTICANCER ACTIVITY AND IN SILICO STUDIES

2019 ◽  
pp. 174-179
Author(s):  
SIVA JYOTHI BUGGANA ◽  
MANI CHANDRIKA PATURI ◽  
RAJENDRA PRASAD VVS
Keyword(s):  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Spectroscopic Techniques ◽  
Chlorine Substitution ◽  
In Silico Studies ◽  
Quinazoline Derivatives

Objective: In this study, a series of novel 2,3-disubstituted quinazolines (4a-4l) were synthesized using standard procedures and elucidated through different spectroscopic techniques. Methods: Obtained compounds were evaluated for their cytotoxicity against human breast cancer (MDA-MB-231) and ovarian cancer (SK-O-V3) cell lines using MTT assay. Docking studies with JAK2 protein were performed to elucidate the possible mechanistic insights into these novel quinazoline derivatives. Results: Moderate-to-good in vitro cytotoxic potentials of the newly synthesized molecules were reported against selected human cancer cell lines. Among the tested molecules, compound 4e showed good cytotoxic activity against MD-AMB-231 (14.2 ± 0.86 μM) and against SK-O-V3 (17.7 ± 0.62 μM). Conclusion: The in vitro studies of the newly synthesized quinazoline derivatives reported considerable cytotoxic potentials against both breast and ovarian cancer cell lines and SAR studies suggest that quinazoline derivatives with heterocyclic benzothiazole nucleus with hydrophilic acetamide linkage at the 3rd position could probably increase the cytotoxic potentials and the presence of chlorine substitution could add more benefit. With the reported bioactivities of these derivatives, further studies on the derivatization could elucidate the broader cytotoxic potentials.

scholarly journals Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

2021 ◽  
Vol 14 (11) ◽  
pp. 1177
Author(s):  
Tarek S. Ibrahim ◽  
Azizah M. Malebari ◽  
Mamdouh F. A. Mohamed
Keyword(s):  
Cell Cycle ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Hydroxamic Acid ◽  
Phenyl Group ◽  
Cancer Cell Lines ◽  
Anticancer Activities ◽  
Molecular Docking Study

Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug resistance. Therefore, in this work, based on introducing 3,4,5-trimethoxy phenyl group as a part of the CAP moiety, in addition to incorporating 4–6 aliphatic carbons linker and using COOH or hydroxamic acid as ZBG, 12 novel EGFR/HDAC hybrid inhibitors 2a–c, 3a–c, 4a–c and 5a–c were designed, constructed, and evaluated for their anticancer activities against 4 cancer cell lines (HepG2, MCF-7, HCT116 and A549). Among all, hybrids with hydroxamic acid 4a–c and 5a, exhibited the highest inhibition against all cancer cell lines with IC50 ranging from 0.536 to 4.892 μM compared to Vorinostat (SAHA) with IC50 ranging from 2.43 to 3.63 μM and Gefitinib with IC50 ranging from 1.439 to 3.366 μM. Mechanistically, the most potent hybrids 4a–c and 5a were further tested for their EGFR and HDACs inhibitory activities. The findings disclosed that hybrid 4b displayed IC50 = 0.063 µM on the target EGFR enzyme which is slightly less potent than the standard Staurosporine (IC50 = 0.044 µM). Furthermore, hybrid 4b showed less HDAC inhibitory activity IC50 against HDAC1 (0.148), 2 (0.168), 4 (5.852), 6 (0.06) and 8 (2.257) than SAHA. In addition, the investigation of apoptotic action of the most potent hybrid 4b showed a significant increase in Bax level up to 3.75-folds, with down-regulation in Bcl2 to 0.42-fold, compared to the control. Furthermore, hybrid 4b displayed an increase in the levels of Caspases 3 and 8 by 5.1 and 3.15 folds, respectively. Additionally, the cell cycle analysis of hybrid 4b revealed that it showed programmed cell death and cell cycle arrest at G1/S phase. Moreover, all these outcomes together with the molecular docking study recommended the rationalized target hybrids 4a–c and 5a, particularly 4b, may be considered to be promising lead candidates for discovery of novel anticancer agents via dual inhibition of both EGFR/HDAC enzymes.

Fungal metabolites of xanthohumol with potent antiproliferative activity on human cancer cell lines in vitro

2013 ◽  
Vol 21 (7) ◽  
pp. 2001-2006 ◽  
Author(s):  
Tomasz Tronina ◽  
Agnieszka Bartmańska ◽  
Beata Filip-Psurska ◽  
Joanna Wietrzyk ◽  
Jarosław Popłoński ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Fungal Metabolites ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

Synthesis and in vitro antiproliferative activity of novel 1-benzhydrylpiperazine derivatives against human cancer cell lines

2009 ◽  
Vol 44 (3) ◽  
pp. 1223-1229 ◽  
Author(s):  
C.S. Ananda Kumar ◽  
S.B. Benaka Prasad ◽  
K. Vinaya ◽  
S. Chandrappa ◽  
N.R. Thimmegowda ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

scholarly journals INHIBITORY ACTIVITIES OF CAMELLIA MISTLETOE (K. JAPONICA) EXTRACTS ON PANCREATIC LIPASE, TYROSINASE AND CANCER CELL PROLIFERATION

2017 ◽  
Vol 9 (10) ◽  
pp. 187
Author(s):  
Min Young Kim
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Lipase ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Human Cancer ◽  
Mistletoe Extracts ◽  
Inhibitory Activities ◽  
Lipase Inhibition

Objective: The objective of this study was undertaken to examine pancreatic lipase and tyrosinase inhibitory activities of Camellia mistletoe (Korthalsella japonica) extracts and conduct their antiproliferative activity on several human cancer (Hela, A375, HCT 116, HepG2 and A549) and normal cells (TK6) lines.Methods: The lipase inhibitory activity of acts of Camellia mistletoe extracts were determined from the hydrolytic reaction of p-nitrophenyl butyrate with pancreatic lipase and cytotoxicity against human cancer and normal cell lines were also evaluated using the MTT assay. The in vitro tyrosinase inhibitor potency of Camellia mistletoe extracts was estimated using mushroom tyrosinase.Results: Both methanol and ethanol extracts of Camellia mistletoe exhibited an inhibitory effect on lipase inhibition activity with IC50 values of 0.39 and 0.49 mg/ml, respectively. Moreover, Camellia mistletoe extracts were judged to be strongly active against the cancer cell lines, while they had no antiproliferative activity against the normal human cell lines. However, they had little inhibitory effects on tyrosinase activity.Conclusion: Camellia mistletoe extracts could be the good sources of natural lipase inhibition and anticancer agents with a great potential to be used in food and therapeutic fields.

Copper(ii) complexes based on tripodal pyridyl amine derivatives as efficient anticancer agents

2019 ◽  
Vol 43 (16) ◽  
pp. 6186-6196 ◽  
Author(s):  
Salah S. Massoud ◽  
Febee R. Louka ◽  
Ada F. Tusa ◽  
Nicole E. Bordelon ◽  
Roland C. Fischer ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Anticancer Agents ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines

The in vitro cytotoxicity of a series of chlorido-Cu(ii) complexes based on tripod pyridyl N4-donor derivatives revealed significant-to-moderate cytotoxicity against human cancer cell lines with the best results obtained for [Cu(BQPA)Cl]ClO4/PF6 (5-ClO4/PF6) with IC50 values of 4.7–10.8 μM.

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