In vitro cytotoxicity screening of some 3-substituted-4-oxo-imidazolidin-2-(1H)-thione derivatives as anticancer drug.

Aim: This study aimed to investigate the in vitro antitumor activity of new series of 2-thiohydanotin derivatives (7 and 9) against two cancer cell lines.Materials & methods: A new series of 2-thioxoimidazolidine derivatives (3-9) were synthesized and investigated for its structure through spectral analysis and also tested against (HepG-2) and (HCT-116) cell line.Results: Among the synthesized compounds, compound 7 halted liver cancer cells at the G0/G1 phase and triggered apoptosis of liver cancer. Contrarily, compound 9 caused colon cancer cells to be arrested at the S phase and trigger apoptosis. Also, they had a good inhibitory effect on (Nrf2).Conclusion: Both compounds had attractive lead molecules for the creation of colon and liver cancer medications.

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In vitro anti-breast cancer study of hybrid cinnamic acid derivatives bearing 2-thiohydantoin moiety.

Aim: To synthesize new hybrid cinnamic acids (10a, 10b and 11) and ester derivatives (7, 8 and 9) and investigate their anti-breast cancer activities.Materials & methods: Compounds 7-11 were evaluated (in vitro) for their cytotoxic activities against the MCF-7 cell line. A flow cytometry examination was performed. Protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), topoisomerase II and caspase-9 were measured by qRT-PCR. Molecular docking studies were conducted.Results: Several components were discovered to be active, mainly component 11, which induced arrest in the cell cycle at phase S, greatly decreased the expression of Nrf2 and topoisomerase II; and upregulated the expression of caspase-9.Conclusion: The newly thiohydantoin-cinnamic acid hybrids can contribute to creating promising candidates for cancer drugs.

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Association between estrogen receptor alpha and aryl hydrocarbon receptor gene polymorphisms in the prognosis of breast cancer in Egypt.

Breast cancer is the most malignant tumor among women in the world. Single nucleotide polymorphisms (SNPs) might better predict breast cancer prognosis. PvuII (T/C substitution), XbaI (A/G substitution), and aryl hydrocarbon (AhR) (G/A substitution) were evaluated as possible genetic prognostic factors for breast cancer. The aim of the current study was to assess the relation between PvuII (rs2234693), XbaI (rs9340799), and aryl hydrocarbon receptor gene polymorphisms AhR (rs2066853) in breast cancer prognosis. This was a case-control study that included 120 breast cancer patients classified into two groups. The first group included 60 patients with good prognostic factors, and the second group included 60 patients with poor prognostic factors. Blood samples were taken from all study participants to perform the genotyping assay. We found that positive genotypes of PvuII, XbaI, and AhR polymorphisms were strongly associated with better prognostic factors for breast cancer patients, while negative genotypes of PvuII and XbaI were more and significantly prevalent in poor prognostic breast cancer patients. We conclude that PvuII T/C, XbaI G/A, and AhR G/A alleles may be prognostic for breast cancer progression.

Design and Synthesis of Novel Pyridine-Based Compounds as Potential PIM-1 Kinase Inhibitors, Apoptosis, and Autophagy Inducers Targeting MCF-7 Cell Lines: In Vitro and In Vivo Studies.

2-((3-Cyano-4,6-dimethylpyridin-2-yl)oxy)acetohydrazide 1 was used as the precursor for the synthesis of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2. The latter was alkylated with different alkylating agents to produce the S-alkylated products 3-6. Galactosylation of 5-thioxo-1,3,4-oxadiazol-2-yl)methoxy)nicotinonitrile 2 produces a mixture of S- and N-galactosides 8 and 9. The hydrazide 1 is converted to azide 10, coupled with glycine methyl ester hydrochloride and a set of amines to produce the target coupled amides 11-15. New compounds were assigned using NMR and elemental analysis. Compound 12 had potent cytotoxicity with IC50 values of 0.5 and 5.27 µM against MCF-7 and HepG2 cell lines compared with doxorubicin, which displayed the following IC50: 2.14 and 2.48 µM for the mentioned cell lines, respectively. Regarding the molecular target, compound 12 exhibited potent PIM-1 inhibition activity with 97.5% with an IC50 value of 14.3 nM compared to Staurosporine (96.8%, IC50 = 16.7 nM). Moreover, compound 12 significantly activated apoptotic cell death in MCF-7 cells, increasing the cell population by total apoptosis by 33.43% (23.18% for early apoptosis and 10.25% for late apoptosis) compared to the untreated control group (0.64%), and arresting the cell cycle at S-phase by 36.02% compared to control 29.12%. Besides, compound 12 caused tumor inhibition by 42.1% in solid tumors in the SEC-bearing mice. Results disclosed that compound 12 significantly impeded cell migration and cell proliferation by interfering with PIM-1 enzymatic activity via considerable apoptosis-induction, which made it an attractive lead compound for the development of chemotherapeutics to treat breast cancer.

Synthesis of new substituted pyridine derivatives as potent anti-liver cancer agents through apoptosis induction: In vitro, in vivo, and in silico integrated approaches.

Liver cancer is the most common type of cancer in many countries. New studies and statistics show rising liver cancer worldwide, so it is essential to seek new agents for this type of cancer. PIM1 has an attractive target in the discovery of cancer medications as it is very much expressed in a variety of malignancies and influences such as tumorigenesis, cell cycle progression, cellular proliferation, apoptosis, and cell migration. Accordingly, a series of pyridones and pyridine-amides were synthesized and tested for anti-liver cancer activity. In the synthetic strategy 4,6-diaryl-3-cyano-2-pyridones 3a-n were synthesized using one-pot four component synthetic method. Structural modifications were done on 4,6-diphenyl-3-cayno-2-pyridone 3a to enhance the activity. Alkylation in the presence of K2CO3 afforded the O-alkylated products 4-6. The acetoxy hydrazide 7 was synthesized and cyclized into 1,3,4-oxadiazolethione 8 which alkylated on sulfur to give 10. Azide-coupling method was used to couple the 2-(pyridin-2-yloxy)acetohydrazide 7 to different amines and amino acid esters to furnish the products 12a-e and 13a-b. The synthesized derivatives were subjected to cytotoxic screening against HepG2 and THLE-2 cells, Compounds 10, 12e and 13a have a remarkable cytotoxic activity with IC50 values (10.7-13.9 µM). Compound 7 was found to be more cytotoxic by showing the lowest IC50 value of 7.26 compared to 5-FU (IC50 = 6.98 µM). It inhibited cell growth by 76.76%. Additionally, it significantly stimulated apoptotic liver cancer cell death with 49.78-fold (22.90% compared to 0.46% for the control) arresting cell cycle Pre-G1 with 35.16% of a cell population, compared to 1.57% for the control. Moreover, it validated the intrinsic apoptosis through upregulation of P53, and other related genes, with inhibition of anti-apoptotic genes through PIM-1 inhibition.

Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation.

A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 1. An interesting cyclization was obtained when the amino-ester 1 reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[2,3-d][1,3]thiazin-4-one 3. Acylation of the amino-ester 1 with chloroacetyl chloride in DCM and Et3N afforded the acylated ester 4. The amino-ester 1 was cyclized to benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one 8, which was reacted with some alkylating agents leading to alkylation at nitrogen 9-13. Hydrazide 14 was utilized as a synthon for the synthesis of the derivatives 15-19. Chloro-thieno[2,3-d]pyrimidine 20 was synthesized and reacted with the hydrazine hydrate to afford the hydrazino derivative 21, which was used as a scaffold for getting the derivatives 22-28. Nucleophilic substitution reactions were used for getting the compounds 29-35 from chloro-thieno[2,3-d]pyrimidine 20. In the way of anticancer therapeutics development, the requisite compounds were assessed for their cytotoxicity in vitro against MCF-7 and HepG-2 cancer cell lines. Twelve compounds showed an interesting antiproliferative potential with IC50 from 23.2 to 95.9 µM. The flow cytometric analysis results showed that hit 4 induces the apoptosis in MCF-7 cells with a significant 26.86% reduction in cell viability. The in vivo study revealed a significant decrease in the solid tumor mass (26.6%) upon treatment with compound 4. Moreover, in silico study as an agonist for inhibitors of JAK2 and prediction study determined their binding energies and predicted their physicochemical properties and drug-likeness scores.

Effect of tramadol addiction alone and its co-abuse with cannabis on urinary excretion of Copper, Zinc, and Calcium among Egyptian addicts.

BACKGROUND: The use of illicit drugs has become a worldwide health problem. Substances with the potential to be abused may have direct or indirect effects on physiologic mechanisms that lead to organ system dysfunction and diseases. OBJECTIVE: The present study aims to investigate the structural and reabsorption integrity of the nephron among Egyptian addicts of tramadol alone and coabused with cannabis. METHODS: Sixty-five males were included in the study, they were classified into control group (G1=19), tramadol addicts group (G2=18), and tramadol coabused with cannabis addicts group (G3=28). Parameters investigated for structural integrity were urinary levels ofleucineaminopeptidase and N-acetyl-ß-D-glucosaminidase, and urinary parameters for reabsorption integrity were levels of copper and zinc as well as calcium, also urinary creatinine was measured. In addition, urinary levels of tramadol and tetrahydrocannabinol were estimated. RESULTS: Among the two addicted groups, all measured parameters were not significantly different in comparison with the control group except for urinary calcium excretion which was found to be significantly increased among the two addicted groups. CONCLUSION: Both tramadol addiction alone or coabused with cannabis causes increased urinary excretion of calcium, indicating reabsorption dysfunction of calcium without affecting structural integrity along the nephron.

Molecular modeling studies and synthesis of novel methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)alkanoates with potential anti-cancer activity as inhibitors for methionine synthase.

Cobalamin-dependant cytosolic enzyme methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine (Hcy) to produce methionine and tetrahydrofolate (THF). MetS is over-expressed in the cytosol of certain breast and prostate tumour cells. Methionine used as a source of one carbon atom for the building of the DNA of the tumour cells, structural protein and enzymes. In this study, we designed, synthesized and evaluated the cytotoxic activity of a series of substituted methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)acetate and dipeptide that mimic the substructure of MTHF. These inhibitors were docked in to the MTHF binding domain in such the same way as MTHF in its binding domain. The free energies of the binding were calculated and compared to the IC50 values. This series has been developed by dicyclohexylcarbodiimide (DCC) and azide coupling methods of amino acid esters with carboxylic acid derivatives, respectively. Compound methyl 3-hydroxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetamido)propanoate exhibited the highest IC50 value 20 µg/mL against PC-3 cell line and scored the lowest free energy of the binding (-207.19 kJ/mol).