A Novel PEtOx-Based Nanogel Targeting Prostate Cancer Cells for Drug Delivery.

This study focuses on creating a specialized nanogel for targeted drug delivery in cancer treatment, specifically targeting prostate cancer. This nanogel (referred to as SGK 636/Peptide 563/PEtOx nanogel) is created using hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) through a combination of living/cationic ring-opening polymerization (CROP) and alkyne-azide cycloaddition (CuAAC) "click" chemical reactions. A fluorescent probe (BODIPY) is also conjugated with the nanogel to monitor drug delivery. The characterizations through 1 H-NMR, and FT-IR, SEM, TEM, and DLS confirm the successful production of uniform, and spherical nanogels with controllable sizes (100 to 296 nm) and stability in physiological conditions. The biocompatibility of nanogels is evaluated using MTT cytotoxicity assays, revealing dose-dependent cytotoxicity. Drug-loaded nanogels exhibited significantly higher cytotoxicity against cancer cells in vitro compared to drug-free nanogels. Targeting efficiency is examined using both peptide-conjugated and peptide-free nanogels, with the intracellular uptake of peptide 563-conjugated nanogels by tumor cells being 60-fold higher than that of nanogels without the peptide. The findings suggest that the prepared nanogel holds great potential for various drug delivery applications due to its ease of synthesis, tunable functionality, non-toxicity, and enhanced intracellular uptake in the tumor region.

Synthesis and Evaluation of Novel Metacetamol Derivatives with Hydrazone Moiety as Anticancer and Antimicrobial Agents.

By exploiting the wide biological potential of the hydrazone scaffold, a series of hydrazone derivatives were synthesized, starting from N-(3-hydroxyphenyl)acetamide (metacetamol). The structures of the compounds were determined using IR, 1 H and 13 C-NMR, and mass spectroscopic methods. The obtained molecules (3 a-j) were evaluated for their anticancer potential against MDA-MB-231 and MCF-7 breast cancer cell lines. According to the CCK-8 assay, all tested compounds showed moderate to potent anticancer activity. Among them, N-(3-(2-(2-(4-nitrobenzylidene)hydrazinyl)-2-oxoethoxy)phenyl)acetamide (3 e) was found to be the most effective derivative with an IC50 value of 9.89 µM against MDA-MB-231 cell lines. This compound was further tested for its potential effects on the apoptotic pathway. Molecular docking studies was also carried out for 3 e in the colchicine binding pocket of tubulin. Additionally, compound 3 e also demonstrated effective antifungal activity, particularly against Candida krusei (MIC=8 µg/ml), indicating that nitro group at the 4th  position of the phenyl ring was the most preferable substituent for both cytotoxic and antimicrobial activity. Our preliminary findings suggest that compound 3 e could be exploited as a leading structure for further anticancer and antifungal drug development.

Thioethers: An Overview.

Spreading rapidly in recent years, cancer has become one of the causes of the highest mortality rates after cardiovascular diseases. The reason for cancer development is still not clearly understood despite enormous research activities in this area. Scientists are now working on the biology of cancer, especially on the root cause of cancer development. The aim is to treat the cancer disease and thus cure the patients. The continuing efforts for the development of novel molecules as potential anti-cancer agents are essential for this purpose. The main aim of this review was to present a survey on the medicinal chemistry of thioethers and provide practical data on their cytotoxicities against various cancer cell lines. The research articles published between 2001-2020 were consulted to prepare this review article; however, patent literature has not been included. The thioether-containing heterocyclic compounds may emerge as a new class of potent and effective anti-cancer agents in the future.

Evaluation of health-related knowledge, attitudes, and behaviors of undergraduate students by cardiovascular risk factors.

AIM: To determine the presence of cardiovascular (CV) risk (CVR) factors in university students and evaluate how these factors are affected from the knowledge, attitudes, and habits of the individuals regarding healthy lifestyle. BACKGROUND: Starting from early ages, lifestyle habits such as lack of physical activity, unhealthy eating, and inappropriate drug use increase CV and metabolic risks of individuals. METHODS: In April-May 2018, sociodemographic characteristics of 770 undergraduate students, in addition to their knowledge, attitudes, and habits regarding their nutrition and physical activity status were obtained through face-to-face questionnaires. CVR factors were determined according to blood pressure, blood glucose, total cholesterol levels, and anthropometric measurements. Collected data were compared by CVR factor presence (CV[+] or CV[-]) in students. FINDINGS: The mean age of the participants was 22.3 ± 2.6 years. 59.6% were female and 71.5% were students of non-health sciences. In total, 274 individuals (35.9%) belonged to CV(+) group (mean risk number: 1.3 ± 0.5) with higher frequency in males (42.1% versus 31.6%, P < 0.05). The most common CVR factors were smoking (20.6%), high total cholesterol (7.5%), and hypertension/high blood pressure (6.0%). 15.5% of the participants regularly used at least one drug/non-pharmaceutical product. 11.3% complied the Mediterranean diet well. 21.9% of CV(+) stated consuming fast food at lunch compared to 14.3% of CV(-) (P < 0.05). 44.6% stated exercising below the CV-protective level. CONCLUSIONS: This study showed one-third of university students was at CVR, independent of their sociodemographic characteristics. Furthermore, the students appear to perform below expectations in terms of nutrition and physical activity. Extensive additional measures are needed to encourage young individuals for healthy nutritional and physical activity habits.

Synthesis and evaluation of tumor-homing peptides for targeting prostate cancer.

High toxicity caused by chemotherapeutic drugs and the acquisition of drug resistance by cancer cells are the major drawbacks in cancer therapy. A promising approach to overcome the posed barriers is conjugating tumor-homing peptides to drugs or nanocarriers. Such high-affinity peptides can specifically target surface markers overexpressed by cancer cells, ensuring a rapid and cancer-specific uptake of the drugs. Since prostate-specific membrane antigen (PSMA) is overexpressed by aggressive prostate cancer cells, targeting this surface protein with peptide conjugates can lead to the development of effective strategies against prostate cancer. In this study, we aimed to determine which PSMA-binding peptide among peptides 563, 562 and 9-mer, show the highest selectivity towards PSMA using 22Rv1 prostate cancer cells, a cell line with moderate PSMA levels. Tumor-homing peptides were synthesized by fluorenylmethoxycarbonyl-based solid-phase peptide synthesis (Fmoc-SPPS) strategy, and evaluated for their prostate cancer cell-specific targeting efficiencies by flow cytometry. Our results showed that the PSMA-binding capacity of peptide 563 was superior to those of 562, 9-mer, and 5-mer; therefore, can be utilized as a potent-targeting agent not only in the treatment of high PSMA positive but also moderate PSMA positive prostate cancer tumors.

Design and synthesis of novel (S)-Naproxen hydrazide-hydrazones as potent VEGFR-2 inhibitors and their evaluation in vitro/in vivo breast cancer models.

Naproxen is a common non-steroidal anti-inflammatory drug, which is the most usually used propionic acid derivative for the treatment of many types of diseases. In this study, a series of novel (S)-Naproxen derivatives bearing hydrazide-hydrazone moiety were designed, synthesized, and evaluated for anticancer activity. The structures of these compounds were characterized by spectral (1H-13C NMR, FT-IR, and HR-MS analyses) methods. All synthesized compounds were screened for anticancer activity against two different human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, (S)-2-(6-methoxynaphthalen-2-yl)-N'-{(E)-[2-(trifluoromethoxy)phenyl]methylidene} propanehydrazide (3a) showed the most potent anticancer activity against both cancer cell lines with a good selectivity (IC50 = 22.42 and 59.81 µM, respectively). Furthermore, the molecular modeling of these compounds was studied on Vascular Endothelial Growth Factor Receptor 2. Inhibition of VEGFR-2 and apoptotic protein Bcl-2 was investigated in MDA-MB-231 cells treated with compound 3a by using Western Blotting. Apoptosis was also detected by staining with DAPI in fluorescence microscopy. Flow Cytometry analyses related to cell cycle phases showed that a dramatic increase in S and M phases was established compared to untreated control cells indicating the cancer cell cycle arrest. The anticancer activity of compound 3a was investigated in the Ehrlich acid tumor model, a well-validated in vivo ectopic breast cancer model, in mice. Our results showed that compound 3a had anticancer activity and decreased the tumor volume in both low (60 mg/kg) and high (120 mg/kg) doses in mice.

Synthesis, molecular modeling, in vivo study and anticancer activity against prostate cancer of (+) (S)-naproxen derivatives.

In this study, (S)-naproxen thiosemicarbazides (3a-d), 1,2,4-triazoles (4a-c), triazole-thioether hybride compounds (5a-p) were synthesized and their structures (3a, 3d, 4a and 5a-p) were confirmed by FT-IR, 1H NMR,13C NMR, HR-Mass spectra and elemental analysis. These compounds are designed to inhibit methionine amino peptidase-2 (MetAP2) enzyme in prostate cancer. These compounds (3d, 5a-p) evaluated against androgen-independent prostate adenocarcinoma (PC-3, DU-145) and androgen-dependent prostate adenocarcinoma (LNCaP) cell lines by using MTS method. Compounds 5a, 5b, 5d and 5e showed 14.2, 5.8, 10.8 and 8.4 µM anticancer activity against PC-3 cell lines, compounds 5e, 5g and 5n presented anticancer activity against DU-145 cell lines 18.8, 12.25 and 10.2 µM, and compounds 5g, 5m and 5n exhibited anticancer activity against LNCaP cell lines 12.25, 22.76 and 2.21 µM, respectively. Consequently, of these results, compounds 5e and 5n showed the highest activities against androgen dependent and independent prostate cancer cell lines, so these compounds could be potent small molecules against prostate cancer. Furthermore, mitogen-activated protein kinase (MAPK) pathway activation, AKT (protein kinase B) phosphorylation and androgen receptor activation of compound 5n (SGK636) were investigated in LNCaP cells by using Western blot method. Compound 5n (SGK636) was also tested against mRNA expression analysis of the Bax, Bcl-2, Caspase 3, Caspase 9 by using real-time PCR analysis. Compound 5n was given to nude male mice with cancer in comparison to the control group. Compound 5n was found to reverse the malignant phenotype in the nude male mice, whereas the prostate cancer progressed in the control group. Analysis of some blood parameters in the study showed that they were within the normal values with respect to the control. The blood values of the animals treated according to the control group also exhibited compliance with the blood limit values. Molecular docking and dynamics simulation of compound 5n binding to Methionine Aminopeptidase 2 (MetAP2) enzyme rationalized its potential activity. In addition, inhibition assay MetAP2 enzyme of compound 5n was evaluated. Taken together, we suggest compound 5n to be a potential candidate for prostate cancer therapy.

Anticancer and Antimicrobial Activities of Naproxen and Naproxen Derivatives.

This review explains the effects of naproxen and the naproxen moiety in important biological activities. Naproxen, 2-(6-methoxynaphthalen-2-yl)propionic acid, is one of the most utilized propionic acid derivatives to the cure of many injuries or pains. Naproxen is a non-steroidal antiinflammatory drug (NSAID), which is generally used among the NSAIDs. Even though it has gastrointestinal side effects, naproxen has been safely used for many years because of the good cardiovascular sight. In the past years, except for anti-inflammatory effects, other pharmacological activities of naproxen, especially anticancer and antimicrobial activities, gain the attention of researchers. Naproxen shows its activity by inhibiting the COX-2 enzyme. There is significant interest in the possibility that COX-2 inhibitors might retard or prevent the development of various cancer types, which is often characterized by COX-2 expression. The activities of both naproxen and new molecules derived from naproxen were frequently investigated.

Synthesis and Anticancer and Antimicrobial Evaluation of Novel Ether-linked Derivatives of Ornidazole.

OBJECTIVES: Some novel 1-(2-methyl-5-nitro-1H-imidazol-1-yl)-3-(substituted phenoxy)propan-2-ol derivatives (3a-g) were designed and synthesized. MATERIALS AND METHODS: Compounds 3a-g were obtained by refluxing ornidazole (1) with the corresponding phenolic compounds (2a-g) in the presence of anhydrous K2CO3 in acetonitrile. RESULTS: Following the structure elucidation, the in vitro antimicrobial activity and cytotoxic effects of compounds 3a-g on K562 leukemia and NIH/3T3 mouse embryonic fibroblast cells were measured. As a part of this study, the compliance of the compounds with the drug-likeness properties was evaluated. The physico-chemical parameters (log P, TPSA, nrotb, number of hydrogen bond donors and acceptors, logS) were calculated using the software OSIRIS. CONCLUSION: All the synthesized compounds except 3a showed significant activity (MIC=4-16 µg mL-1) against the bacterial strain Bacillus subtilis as compared to the standard drug, whereas antileukemic activities were rather limited. Furthermore, all the compounds were nontoxic and the selectivity index outcome indicated that the antileukemic and antimicrobial effects of the compounds were selective with good estimated oral bioavailability and drug-likeness scores.

Synthesis, molecular docking and evaluation of novel sulfonyl hydrazones as anticancer agents and COX-2 inhibitors.

In trying to develop new anticancer agents, a series of sulfonylhydrazones were synthesized. All synthesized compounds were checked for identity and purity using elemental analysis, TLC and HPLC and were characterized by their melting points, FT-IR and NMR spectral data. All synthesized compounds were evaluated for their cytotoxic activity against prostate cancer (PC3), breast cancer (MCF-7) and L929 mouse fibroblast cell lines. Among them, N'-[(2-chloro-3-methoxyphenyl)methylidene]-4-methylbenzenesulfonohydrazide (3k) showed the most potent anticancer activity against both cancer cells with good selectivity (IC50 = 1.38 µM on PC3 with SI = 432.30 and IC50 = 46.09 µM on MCF-7 with SI = 12.94). Further investigation confirmed that 3k displayed morphological alterations in PC3 and MCF-7 cells and promoted apoptosis through down-regulation of the Bcl-2 and upregulation of Bax expression. Additionally, compound 3k was identified as the most potent COX-2 inhibitor (91% inhibition) beside lower COX-1 inhibition. Molecular docking of the tested compounds represented important binding modes which may be responsible for their anticancer activity via inhibition of the COX-2 enzyme. Overall, the lead compound 3k deserves further development as a potential anticancer agent. Sulfonylhydrazones was synthesized and N'-[(2-chloro-3-methoxyphenyl)methylidene]-4- methylbenzenesulfonohydrazide (3k) was identified as the most potent anticancer agent and COX-2 inhibitor. In addition, this compound docked inside the active site of COX-2 succesfully.

Synthesis, Anticancer Activity on Prostate Cancer Cell Lines and Molecular Modeling Studies of Flurbiprofen-Thioether Derivatives as Potential Target of MetAP (Type II).

BACKGROUND: Prostate cancer is still one of the serious causes of mortality and morbidity in men. Despite recent advances in anticancer therapy, there is a still need of novel agents with more efficacy and specificity in the treatment of prostate cancer. Because of its function on angiogenesis and overexpression in the prostate cancer, methionine aminopeptidase-2 (MetAP-2) has been a potential target for novel drug design recently. OBJECTIVE: A novel series of Flurbiprofen derivatives N-(substituted)-2-(2-(2-fluoro-[1,1'- biphenyl]-4-il)propanoyl)hydrazinocarbothioamide (3a-c), 4-substituted-3-(1-(2-fluoro-[1,1'-biphenyl]- 4-yl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (4a-d), 3-(substitutedthio)-4-(substituted-phenyl)- 5-(1-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl)-4H-1,2,4-triazole (5a-y) were synthesized. The purpose of the research was to evaluate these derivatives against MetAP-2 in vitro and in silico to obtain novel specific and effective anticancer agents against prostate cancer. METHODS: The chemical structures and purities of the compounds were defined by spectral methods (1H-NMR, 13C-NMR, HR-MS and FT-IR) and elemental analysis. Anticancer activities of the compounds were evaluated in vitro by using MTS method against PC-3 and DU-143 (androgenindependent human prostate cancer cell lines) and LNCaP (androgen-sensitive human prostate adenocarcinoma) prostate cancer cell lines. Cisplatin was used as a positive sensitivity reference standard. RESULTS: Compounds 5b and 5u; 3c, 5b and 5y; 4d and 5o showed the most potent biological activity against PC3 cancer cell line (IC50= 27.1 µM, and 5.12 µM, respectively), DU-145 cancer cell line (IC50= 11.55 µM, 6.9 µM and 9.54 µM, respectively) and LNCaP cancer cell line (IC50= 11.45 µM and 26.91 µM, respectively). Some compounds were evaluated for their apoptotic caspases protein expression (EGFR/PI3K/AKT pathway) by Western blot analysis in androgen independent- PC3 cells. BAX, caspase 9, caspsase 3 and anti-apoptotic BcL-2 mRNA levels of some compounds were also investigated. In addition, molecular modeling studies of the compounds on MetAP-2 enzyme active site were evaluated in order to get insight into binding mode and energy. CONCLUSION: A series of Flurbiprofen-thioether derivatives were synthesized. This study presented that some of the synthesized compounds have remarkable anticancer and apoptotic activities against prostate cancer cells. Also, molecular modeling studies exhibited that there is a correlation between molecular modeling and anticancer activity results.

Synthesis, molecular modeling, in vivo study, and anticancer activity of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-naproxen.

A new series of 1,2,4-triazole containing hydrazide-hydrazones derived from (S)-naproxen ( 7a-m) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier-transform infrared spectroscopy, 1 H-nuclear magnetic resonance (NMR), 13 C-NMR, and high-resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase-2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU-145, and LNCaP) using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU-145 and LNCaP cancer cell lines with IC50 values of 26.0, 34.5, and 48.8 µM, respectively. Compounds 7b, 7k, and 7m showed anticancer activity against cancer cell lines PC3 and DU-145 with IC50 values of 43.0, 36.5, 29.3 µM and 49.8, 49.1, 31.6 µM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC50 values of 43.4 and 34.5 µM, respectively. To assess the biodistribution in mice of IRDye800, dye-labeled compound 7a or 100 µM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.

Recent Advances in Apoptosis: THE Role of Hydrazones.

The process of programmed cell death in higher eukaryotes (apoptosis), is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered as a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Apoptosis seems to play an important key role in the progression of several human diseases like Alzheimer's disease, Parkinson's disease and many types of cancer. Promotion of apoptosis may be a good approach for the prevention of cancer cell proliferation. In early studies, antitumor compounds have been found to induce the apoptotic process in tumor cells. On the other hand, several hydrazones were reported to have lower toxicity than hydrazides due to the blockage of -NH2 group. Therefore, the design of hydrazones that activate and promote apoptosis is an attractive strategy for the discovery and development of potential anticancer agents. The aim of this review is to provide a general overview of current knowledge and the connection between apoptosis and hydrazone. It is also the guide for the apoptotic activities of new hydrazone derivatives.

Synthesis, Molecular Docking and Anticancer Activity of Diflunisal Derivatives as Cyclooxygenase Enzyme Inhibitors.

Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new diflunisal thiosemicarbazides and 1,2,4-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3), colon carcinoma (HCT-116), human breast cancer (T47D), breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically, the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds 6, 10, 15 and 16 did not show cytotoxic effects for the HEK293 cell line. Among them, compounds 15 and 16 demonstrated anticancer activity for the breast cancer cell line T47D, whereas compounds 6 and 10 which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line, consistent with the literature. However, no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound 16 displayed activity against the HCT-116 cell line. Therefore, it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition, molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds 15, and 16. Both 15 and 16 showed high selectivity and affinity toward COX-2 isozyme over COX-1, which is in agreement with the experimental results.

Synthesis, anticancer activity, and molecular modeling of etodolac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors.

A series of (R,S)-1-{[5-(substituted)sulfanyl-4-substituted-4H-1,2,4-triazole-3-yl]methyl}-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indoles (5a-v) were designed and synthesized using a five-step synthetic protocol that involves substituted benzyl chlorides and (R,S)-5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl]-4-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10-5 M (10 µM) for 24 h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC50 = 7.22 and 5.10 µM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k, 5s, and 5v showed the most potent biological activity against the PC3 cancer cell line (IC50 = 8.18, 3.10, and 4.00 µM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase-3, -9, and -8 protein expression and activation in the apoptosis pathway for 6, 12, and 24 h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.

A Novel Anti-Hepatitis C Virus and Antiproliferative Agent Alters Metabolic Networks in HepG2 and Hep3B Cells.

A series of novel diflunisal hydrazide-hydrazones has been reported together with their anti-hepatitis C virus and antiproliferative activities in a number of human hepatoma cell lines. However, the mechanisms underlying the efficacy of these agents remain unclear. It was chosen to investigate the lead diflunisal hydrazide-hydrazone, 2',4'-difluoro-4-hydroxy-N'- [(pyridin-2-yl)methylidene]biphenyl-3-carbohydrazide (compound 3b), in two cultured human hepatoma cell lines-HepG2 and Hep3B-using a metabolomic protocol aimed at uncovering any effects of this agent on cellular metabolism. One sub-therapeutic concentration (2.5 µM) and one close to the IC50 for antimitotic effect (10 µM), after 72 h in cell culture, were chosen for both compound 3b and its inactive parent compound diflusinal as a control. A GCMS-based metabolomic investigation was performed on cell lysates after culture for 24 h. The intracellular levels of a total of 42 metabolites were found to be statistically significantly altered in either HepG2 or Hep3B cells, only eight of which were affected in both cell lines. It was concluded that compound 3b affected the following pathways-purine and pyrimidine catabolism, the glutathione cycle, and energy metabolism through glycolysis and the pentose phosphate pathway. Although the metabolomic findings occurred after 24 h in culture, significant cytotoxicity of compound 3b to both HepG2 and Hep3B cells at 10 µM were reported not to occur until 72 h in culture. These observations show that metabolomics can provide mechanistic insights into the efficacy of novel drug candidates prior to the appearance of their pharmacological effect.

Macromolecular Drug Targets in Cancer Treatment and Thiosemicarbazides as Anticancer Agents.

Cancer is known as abnormal cell division and consisting of a group of diseases on various organ tissues. Many therapies are available in cancer treatment such as chemotherapy, radiotherapy etc. Without damaging normal tissue, there is a huge need for specified anticancer drugs which have effect only on abnormal cancer cells. Therefore, advances in anticancer drug discovery in treating cancer in the recent years, directed towards to the macromolecular targets. Heterocyclic molecules, such as fluconazole, acetazolamide, etc., have a significant role in health care and pharmaceutical drug design. Thiosemicarbazides (NH₂-NH-CSNH₂) are the simplest hydrazine derivatives of thiocarbamic acid and are not only transition compounds, but they are also very effective organic compounds. Thiosemicarbazides possess an amide and amine protons, carbonyl and thione carbons. These structures have attracted the attention of the researchers in the development of novel compounds with anticonvulsant, antiviral, anti-inflammatory, antibacterial, antimycobacterial, antifungal, antioxidant and anticancer activities. Recently, a number of thiosemicarbazides are available commercially as anticancer drugs for novel anticancer drug discovery. Antineoplastic or anticancer drugs prevent or inhibit the maturation and proliferation of neoplasms. These observations have been guiding the researchers for the development of new thiosemicarbazides that possess anticancer activity.

Synthesis of Diflunisal Thiazolidinones as Anticancer Agents.

A series of diflunisal 4-thiazolidinones were synthesized. Some selected compounds were determined at one dose towards the full panel of 60 human cancer cell lines by National Cancer Institute. 2',4'-Difluoro-4-hydroxy-N-[4-oxo-2-(thiophen-2-yl)-1,3-thiazolidin-3-yl]biphenyl- 3-carboxamide (4a) demonstrated the most marked effect on K-562 cancer cell line with 58.59 % growth inhibition at 10 µM. Compound 4a was evaluated in vitro using the MTT colorimetric method against human leukemia cell line K-562 and mouse embryonic fibroblasts cell line NIH- 3T3 at different doses for cell viability and growth inhibition. Compound 4a exhibited anticancer activity with IC50 value of 5.2 µM against K-562 cells and did not display cytotoxicity towards NIH-3T3 cells compared with diflunisal. In addition, this compound could be an interesting prototype as an antiproliferative agent.

Synthesis of novel diflunisal hydrazide-hydrazones as anti-hepatitis C virus agents and hepatocellular carcinoma inhibitors.

Hepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. We have previously identified the hydrazide-hydrazone scaffold as a promising hepatitis C virus (HCV) and hepatocelluler inhibitor. Herein we describe the design a number of 2',4'-difluoro-4-hydroxy-N'-(arylmethylidene) biphenyl-3-carbohydrazide (3a-t) as anti-HCV and anticancer agents. Results from evaluation of anti-HCV activity indicated that most of the synthesized hydrazone derivatives inhibited viral replication in the Huh7/Rep-Feo1b and Huh 7.5-FGR-JCI-Rluc2A reporter systems. Antiproliferative activities of increasing concentrations of 2',4'-difluoro-4-hydroxy-N'-(2-pyridyl methylidene)biphenyl-3-carbohydrazide 3b and diflunisal (2.5-40 µM) were assessed in liver cancer cell lines (Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475) with sulforhodamine B assay for 72 h. Compound 3b with 2-pyridinyl group in the hydrazone part exhibited promising cytotoxic activity against all cell lines with IC50 values of 10, 10.34 16.21 4.74, 9.29 and 8.33 µM for Huh7, HepG2, Hep3B, Mahlavu, FOCUS and SNU-475 cells, respectively, and produced dramatic cell cycle arrest at SubG1/G0 phase as an indicator of apoptotic cell death induction.

Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells.

Tolmetin hydrazide and a novel series of tolmetin hydrazide-hydrazones 4a-l were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, (1)H NMR) methods. N'-[(2,6-Dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti-cancer activity with an IC50 value of 76 µM against colon cancer line HT-29 (ATCC, HTB-38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase-3, caspase-8, caspase-9, and annexin-V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti-cancer activity of this compound was due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT-29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site.