Design, Synthesis, and Docking of Novel Tropane Hybrids as Potent Hsp90 Inhibitors with Potential Anti-Breast Cancer Activity.

BACKGROUND AND OBJECTIVE: Breast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF- 7 and MDA-MB-231). METHODS: Novel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened in vitro to determine their ability to inhibit the activity of Hsp90. RESULTS: All tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC50 values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC50 = 27.78 nM). Among all the compounds examined, tropane derivative 5 exhibited the highest level of Hsp90 inhibitory action, with an IC50 value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative 5 exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound 5 to effectively bind with the target Hsp90 enzyme. CONCLUSION: We have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.

Gender-specific responses in gene expression of Nile tilapia (Oreochromis niloticus) to heavy metal pollution in different aquatic habitats.

Monitoring heavy metal accumulation is essential for assessing the viability of aquatic ecosystems. Our methodology involved integrating analysis of immunological, stress, inflammatory, and growth-related gene expression in male and female Nile tilapia with on-site recordings of physicochemical parameters. Additionally, we assessed the effect of different physicochemical parameters on heavy metal bioavailability and residual concentration in fish and water. Samples of fish and water were gathered from three different localities: Lake Brullus, a brackish lake sited in northern Egypt; Lake Nasser, an artificial freshwater reservoir located in southern Egypt; and El-Qanater El-Khayria, a middle-freshwater location belonging to the Rashid branch of the river Nile. The assessment of heavy metal residues (Fe, Cu, Zn, Mn, and Ni) revealed that their concentrations were higher in fish specimens compared to their counterparts in water (except for Ni). In addition, Lake Brullus emerges as the most polluted area, exhibiting elevated levels of heavy metals concentrations in water and fish specimens. In contrast, Lake Nasser showed the least degree of heavy metals pollution. Gene expression analysis revealed gender-specific responses to heavy metal exposure at the three investigated water bodies. The expression of hepatic antioxidant genes (GST and MT) and inflammatory-related genes (CC-chemokine and TNFα) increased in males compared to females. In females, the immune and pro-inflammatory-related genes (IgM and CXC2-chemokine) transcripts were upregulated. Additionally, growth-related genes were downregulated in both Lake Brullus and El-Qanater; on the contrary, fish samples from Lake Nasser exhibited a normal expression pattern of growth-related genes. Stress-related genes (HSP70 and HSP27) showed significant downregulation in gills of both genders from Lake Brullus. The minimal presence of heavy metal contaminants in Lake Nasser seems to endorse the normal patterns of gene expression across all gene categories. A potential gender-specific gene expression response towards pollution was noticed in genes associated with inflammation and antioxidant activities. This highlights the importance of considering gender-related responses in future environmental assessments.

Novel tropane analogues as Hsp90 inhibitors targeting colon cancer: Synthesis, biological estimation, and molecular docking study.

New derivatives of tropane scaffold were prepared from the reaction of their thione or thioamide derivatives with α-halocarbonyl compounds. The structures of all new derivatives were assured and proved with their spectral data. The novel tropane derivatives were examined for their cytotoxicity on two colon tumor cell lines; Caco2 and HCT116 cells. The most active compounds 3, 4, 5, 9d and 14a displayed significant antitumor activities with IC50 range of 9.50 - 30.15 µM compared to doxorubicin. Moreover, they revealed reduced cytotoxic effect on WI-38 normal ones, signifying their great safety. With the aim of better understanding the inhibitory potential of such compounds on heat-shock protein 90 (Hsp90), there activities were assessed against such enzyme demonstrating high inhibitory activities with IC50 range of 56.58-78.85 nM. Western blotting was carried out to ensure the inhibitory activity on Hsp90, results showed that 3 markedly suppressed Hsp90 expression on Caco2 cell line. Additionally, a molecular docking analysis of the most potent derivatives at the Hsp90 binding site was carried out in order to approve the performed in vitro assays.

Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives linked morpholine moiety as CDK2 inhibitors.

With the aim of developing cyclin-dependent kinase 2 (CDK2) inhibitors with strong antibreast cancer efficacy, new tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives were synthesized. The newly synthesized tri- and tetracyclic derivatives were achieved from the reaction of 4-(4-morpholin-4-yl-phenyl)-1,3,4,5,6,7-hexahydro-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-thione (5) with α-haloketone derivatives as hydrazonyl chlorides, phenacyl bromide derivatives, chloroacetone, and ethyl substituted acetate derivatives. The MCF-7 and MDA-MB-231 breast cancer cell lines were utilized to examine the anticancer properties. Compounds 5 and 8 were shown to be the most effective, with half-maximal inhibitory concentration (IC50 ) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. Mechanistic studies showed that 5 and 8 caused tumor cell death by inducing apoptosis and they also produced cancer arrest in the S phase of the cell cycle. In addition, compounds 5 and 8 showed strong anti-CDK2 action (IC50 = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC50 = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.

Impact of Dietary Administration of Seaweed Polysaccharide on Growth, Microbial Abundance, and Growth and Immune-Related Genes Expression of The Pacific Whiteleg Shrimp (Litopenaeus vannamei).

This work aims to determine the impact of dietary supplementation of polysaccharide, extracted from brown seaweeds Sargassum dentifolium on growth indices, feed utilization, biochemical compositions, microbial abundance, expressions of growth and immunity-related genes, and stress genes of the Pacific Whiteleg shrimp Litopenaeus vannamei. A total of 360 post-larvae of L. vannamei were randomly distributed into a 12-glass aquarium (40 L of each) at a stocking density of 30 shrimp with an initial weight of (0.0017 ± 0.001 g). During the 90-day experiment trial, all shrimp larvae were fed their respective diets at 10% of total body weight, three times a day. Three experimental diets were prepared with different seaweed polysaccharide (SWP) levels. The basal control diet had no polysaccharide level (SWP0), while SWP1, SWP2, and SWP3 contained polysaccharides at concentrations of 1, 2, and 3 g kg-1 diet, respectively. Diets supplemented with polysaccharide levels showed significant improvements in weight gain and survival rate, compared to the control diet. Whole-body biochemical composition and the microbial abundance (the total count of heterotrophic bacteria and Vibrio spp.) of L. vannamei showed significant differences among polysaccharide-treated diets compared to the control. At the end of the feeding experiment, the dietary supplementation of polysaccharide levels enhanced the expression of growth-related genes (Insulin-like growth factors (IGF-I, IGF-II), immune-related genes (ß -Glucan-binding protein (ß-Bgp), Prophenoloxidase (ProPO), Lysozyme (Lys), and Crustin), and stress genes (Superoxide dismutase (SOD) and Glutathione peroxidase (GPx) in the muscle tissue of L. vannamei. However, the current study concluded that the inclusion rate of 2 g kg-1 of polysaccharide as a dietary additive administration enhanced both weight gain and survival rate of L. vannamei, while the incorporation level of 3 g kg-1 reduces the abundance of pathogenic microbes and enhances the growth-, immunity- and stress-related gene expressions of L. vannamei.

Probiotic Potential of the Marine Isolate Enterococcus faecium EA9 and In Vivo Evaluation of Its Antisepsis Action in Rats.

This study aims to obtain a novel probiotic strain adapted to marine habitats and to assess its antisepsis properties using a cecal ligation and puncture (CLP) model in rodents. The marine Enterococcus faecium EA9 was isolated from marine shrimp samples and evaluated for probiotic potential after phenotypical and molecular identification. In septic animals, hepatic and renal tissues were histologically and biochemically evaluated for inflammation and oxidative stress following the probiotic treatment. Moreover, gene expressions of multiple signaling cascades were determined using RT-PCR. EA9 was identified and genotyped as Enterococcus faecium with a 99.88% identity. EA9 did not exhibit any signs of hemolysis and survived at low pH and elevated concentrations of bile salts. Moreover, EA9 isolate had antibacterial activity against different pathogenic bacteria and could thrive in 6.5% NaCl. Septic animals treated with EA9 had improved liver and kidney functions, lower inflammatory and lipid peroxidation biomarkers, and enhanced antioxidant enzymes. The CLP-induced necrotic histological changes and altered gene expressions of IL-10, IL-1ß, INF-γ, COX-2, SOD-1, SOD-2, HO-1, AKT, mTOR, iNOS, and STAT-3 were abolished by the EA9 probiotic in septic animals. The isolate Enterococcus faecium EA9 represents a promising marine probiotic. The in vivo antisepsis testing of EA9 highlighted its potential and effective therapeutic approach.

Growth Performance, Immune-Related and Antioxidant Genes Expression, and Gut Bacterial Abundance of Pacific White Leg Shrimp, Litopenaeus vannamei, Dietary Supplemented With Natural Astaxanthin.

The current study examines the effect of dietary supplementation of ethanolic extract of Arthrospira platensis NIOF17/003, which is mainly natural astaxanthins (97.50%), on the growth performance, feed utilization, bacterial abundance, and immune-related and antioxidant gene expressions of the Pacific white leg shrimp, Litopenaeus vannamei. A total of 360 healthy L. vannamei postlarvae (0.19 ± 0.003 g) were divided into four groups (0, 2, 4, and 6 g natural astaxanthins/kg diet) each in three replicates, at an initial density of 30 PLs per tank (40 L capacity). The shrimp were fed the tested diets three times a day at a rate of 10% of their total body weight for 90 days. Diets supplemented with different astaxanthin levels significantly improved shrimp growth performance and feed conversion ratio compared to the control diet. No significant differences were observed in survival rates among all experimental groups. The immune-related genes (prophenoloxidase, lysozyme, beta-glucan binding protein, transglutaminase, and crustin) mRNA levels were significantly upregulated in groups fed with different concentrations of the natural astaxanthins in a dose-dependent manner. The prophenoloxidase gene is the highest immune-upregulated gene (14.71-fold change) in response to astaxanthin supplementation. The superoxide dismutase mRNA level was significantly increased with increasing dietary astaxanthin supplementation. In addition, increasing astaxanthin supplementation levels significantly reduced the count of heterotrophic bacteria and Vibrio spp. in the culture water and shrimp intestine. Overall, the current results concluded that diet supplementation with natural astaxanthin, extracted from Arthrospira platensis, enhanced the growth performance, immune response, and antioxidant status of L. vannamei.

Design, synthesis, cytotoxicity, and molecular docking studies of novel thiazolyl-hydrazone derivatives as histone lysine acetyl-transferase inhibitors and apoptosis inducers.

Compounds containing both thiazole and arylsulfone moieties are recognized for their high biological activity and ability to fight a variety of ailments. Thus, in this context, new derivatives of (thiazol-2-yl)hydrazone with an arylsulfone moiety were synthesized as CPTH2 analogs with potent anti-histone lysine acetyl-transferase activity. Compounds 3, 4, 10b, and 11b showed an excellent inhibitory effect on P300 (E1A-associated protein p300), compared to CPTH2. Among all the tested derivatives, compound 10b revealed the highest activity against both P300 and pCAF. In addition, the new hits were tested for anticancer efficacy against two leukemia cell lines. Most of them showed a moderate to potent antitumor effect on the k562 and CCRF-CEM cell lines. Interestingly, the activity of compound 10b against the k562 cell line was found to be higher than that of CPTH2. Furthermore, it showed a good safety profile, better than CPTH2 on normal cells. Molecular docking analysis was carried out to reveal the crucial binding contacts in the inhibition of the P300 and pCAF enzymes.

Comparing genetic markers efficiencies for discrimination between two commercially important holothuroids in the Mediterranean Sea, Holothuria polii and Holothuria sanctori.

Sea cucumber (bche-de-mer, Echinodermata: Holothuroidea) is one of the top internationally traded seafood varieties. Besides its direct nutritional benefits, it is continuously used in the traditional medicine in different areas and cultures in the world. This world-wide interest triggered various issues related to stocks declining and risks of species extinction. For these reasons, the current study was designed to provide molecular tools for accurate discrimination between two sea cucumber species that prevail the Mediterranean of these echinoderms in Egypt, that are Holothuria polii and H. sanctori. The power of three gene markers, i.e., 16S rDNA, 28S rDNA, and Histone H3 in achieving accurate DNA-based identification, as well as elucidating clear phylogenetic and genetic diversity differences between those two species was assessed. Among the three genes, 16S rDNA showed the highest potentials as genetic and phylogenetic species discrimination marker. Both 28S rDNA and H3 exhibited the least number of holothuroid reference sequences in the GenBank database. For genetic diversity within each species population, 16S rDNA exhibited the best potentials, followed by H3. 28S rDNA showed no genetic polymorphism at all. Moreover, the collective data of both H3 and 16S rDNA suggested a possible role of asexual reproduction behavior in H. sanctori in the reduction of genetic diversity, as a possible response to overfishing. Hence, the current research can recommend the simultaneous application of both 16S rDNA and H3 as accurate markers for genetic discrimination among H. polii, H. sanctori and other different holothuroid species.

Novel sulfonyl thiazolyl-hydrazone derivatives as EGFR inhibitors: Design, synthesis, biological evaluation and molecular docking studies.

New hydrazonoyl-sulfonylthiazoles were designed and synthesized as EGFR inhibitors. The new sulfonylthiazole derivatives were assessed in vitro to measure their effect on EGFR. They revealed marked inhibitory activity against EGFR kinase having IC50 range from 0.037 to 0.317 µM compared to reference drug dasatinib (IC50 = 0.077 µM). Six derivatives of the newly synthesized compounds showed potent inhibitory activity relative to dasatinib. Furthermore, the new hits were examined concerning their cytotoxic effect on human breast cancer cell line (MCF7), hepatic cancer cell line (HepG2) using MTT assay. N-(2-Benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-thiazol-2-yl)-hydrazine (IC50 = 1.24 µM) revealed higher potency than dasatinib (IC50 = 11.6 µM) against MCF7cell line. Besides, N-(2-benzenesulfonyl-1-phenyl-ethylidene)-N'-(4-methyl-5-p-tolylazo-thiazol-2-yl)-hydrazine exhibited excellent cytotoxicity against HepG2cell line (IC50 = 3.61 µM), exceeding that of dasatinib (IC50 = 14.10 µM). In addition to low cytotoxic effect on normal (WI-38) cells, describing the high safety profiles of these compounds. Moreover, molecular docking was done in order to determine the possible binding modes of such compounds inside the binding site of EGFR.

Pharmacological Effects of Marine-Derived Enterococcus faecium EA9 against Acute Lung Injury and Inflammation in Cecal Ligated and Punctured Septic Rats.

Microorganisms obtained from the marine environment may represent a potential therapeutic value for multiple diseases. This study explored the possible protective role of marine-derived potential probiotic Enterococcus faecium EA9 (E. faecium) against pulmonary inflammation and oxidative stress using the cecal ligation and puncture (CLP) model of sepsis in Wistar rats. Animals were pretreated with E. faecium for 10 days before either sham or CLP surgeries. Animals were sacrificed 72 hours following the surgical intervention. The histological architecture of lung tissues was evaluated as indicated by the lung injury score. In addition, the extend of pulmonary edema was determined as wet/dry weight ratio. The inflammatory cytokines were estimated in lung tissues, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß) using the enzyme-linked-immunosorbent-assay (ELISA) technique. Moreover, markers for lipid peroxidation such as thiobarbituric acid reaction substances (TBARs), and endogenous antioxidants, including reduced glutathione (GSH) were determined in lung tissues. Finally, the enzymatic activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) were assayed in the lungs. Pretreatment with E. faecium markedly attenuated CLP-induced lung injury and pulmonary edema. Markers for inflammation, including TNF-α, IL-6, and IL-1ß were augmented in the lung tissues of CLP animals, while E. faecium ameliorated their augmented levels. E. faecium pretreatment also restored the elevated TBARS levels and the prohibited CAT, SOD, and GPx enzymatic activities in CLP animals. GSH levels were corrected by E. faecium in CLP animals. The inflammatory and lipid peroxidation mediators were positively correlated, while antioxidant enzymatic activities were negatively correlated with CLP-induced lung injury and pulmonary edema. Collectively, marine-derived Enterococcus faecium EA9 might be considered as a prospective therapeutic tool for the management of pulmonary dysfunction associated with sepsis.

Synthesis of Thiazolyl-N-phenylmorpholine Derivatives and their Biological Activities.

BACKGROUND: Morpholine and thiazole rings are two heterocycles which are wellknown with a wide spectrum of different biological activities, especially antitumor activity. OBJECTIVE: The aim of the work is to design and synthesize hybrid heterocyclic compounds of morpholine and thiazole moieties via the reaction of morpholino-thiosemicarbazone derivatives with various α-halocarbonyl compounds and screening their antitumor activity against three tumor cell lines namely, TK-10, MCF-7 and UACC-62. METHODS: An efficient synthesis of a series of N-phenylmorpholine derivatives linked with thiazole moiety was accomplished. The reaction of N-subistituted-2-(N-phenylmorpholine)ethylidene) hydrazine- 1-carbothioamide (thiosemicarbazone derivative) with acetyl and ester-hydrazonoyl chlorides, α-chloroketones, or α-bromoesters afforded the corresponding thiazole derivatives pendent to N-phenylmorpholine moiety in good to excellent yields. RESULTS: Mass, 1H NMR, 13C NMR, and elemental analysis were used to confirm the structure of all the new derivatives. The antitumor activities of synthesized N-phenylmorpholine-thiazole derivatives were investigated against three tumor cells namely, TK-10, MCF-7 and UACC-62. The results of such investigation indicated that some derivatives showed good potential to inhibit the growth of the two cells of the tested tumor cells. One of the tested compounds, N-ethyl thiosemicarbazone derivative 7 revealed potent growth inhibition of all the three tumor cells. CONCLUSION: We have succeeded to synthesize a series of N-phenylmorpholine derivatives pendant to thiazole moiety as antitumor agents.

Novel anti-tubercular and antibacterial based benzosuberone-thiazole moieties: Synthesis, molecular docking analysis, DNA gyrase supercoiling and ATPase activity.

Herein, molecular hybridization strategy was utilized in the design of new benzosuberone-thiazole derivatives. The structures of the synthesized hybrids were determined on the basis of elemental and spectral analyses. These compounds were evaluated for their antibacterial activities against five bronchitis causing bacteria in addition to their anti-tubercular activities. Most compounds revealed promising activities. Amongst active compounds, benzosuberone-dithiazole derivatives 22a and 28 with MIC value = 1.95 µg/ml against H. influenza, M. pneumonia, and B. pertussis displayed four times the activity of ciprofloxacin (MIC = 7.81 µg/ml) against H. influenza, twice the activity of ciprofloxacin (MIC = 3.9 µg/ml) against M. pneumonia and were equipotent to ciprofloxacin against B. pertussis (MIC = 1.95 µg/ml). Additionally, benzosuberone-dithiazole derivatives 22a and 27 were the most promising anti-tubercular among the tested compounds with MIC values of 0.12 and 0.24 µg/ml, respectively against sensitive M. tuberculosis in addition to high activity against resistant strain of M. tuberculosis (MIC = 0.98 and 1.95 µg/ml, respectively) compared to isoniazid (MIC = 0.12 µg/ml against sensitive M. tuberculosis and no activity against resistant M. tuberculosis). Cytotoxicity study of the active dithiazole derivatives 22a, 27 and 28 against normal human lung cells (WI-38) indicated their high safety profile as showed from their high IC50 values (IC50 = 107, 74.8, and 117 µM, respectively). Furthermore, DNA gyrase supercoiling and ATPase activity assays showed that 22a, 27 and 28 have the potential to inhibit DNA gyrase at low micromolar levels (IC50 = 3.29-15.64 µM). Molecular docking analysis was also carried out to understand the binding profiles of the synthesized compounds into the ATPase binding sites of bacterial and mycobacterial DNA gyraseB.

Synthesis of Azoloquinazolines and Substituted Benzothiazepine as Antimicrobial Agents.

BACKGROUND & OBJECTIVE: Quinazolines and their fused systems are noteworthy in pharmaceutical chemistry due to their wide range of biological activities. METHODS: A direct and efficient approach for the synthesis of new series of fused quinazolines with triazole, thiazole, benzimidazole and tetrazole has been preceded via the reaction of quinazoline thione derivative with halogenated compounds or cyclocondensation of arylidene of quinazoline derivative with heterocyclic amines. Also, dibenzo[b,e][1,4]thiazepine derivatives was synthesized through the reaction of 2,6-bis-(2-chloro-benzylidene)-cyclohexanone with o-aminothiophenol. RESULTS: The structures of all new synthesized heterocyclic compounds were confirmed and discussed on the bases of spectral data. The utility of the preparation and design of the above mentioned compounds has been shown to be clear in the results of their antimicrobial activity which revealed that some derivatives have potent activity exceeding or similar to the activity of the reference drugs. CONCLUSION: The insertion of triazole or thiazole moieties to be fused with quinazoline ring helps to enhance its antimicrobial activity.

New 4-phenylcoumarin derivatives as potent 3C protease inhibitors: Design, synthesis, anti-HAV effect and molecular modeling.

A new series of 4-phenylcoumarin derivatives was synthesized starting from (2-oxo-4-phenyl-2H-chromen-7-yloxy) acetic acid hydrazide 3. Evaluation of the target compounds for their antiviral activity against hepatitis A virus revealed that the ethylthiosemicarbazide derivative 7b was the most potent virucidal agent (IC50 = 3.1 µg/ml, TI = 83). The Schiff's bases 14c and 14b demonstrated the highest virustatic effects against viral adsorption and replication, respectively (14c; IC50 = 8.5 µg/ml, TI = 88 and 14b; IC50 = 10.7 µg/ml, TI = 91). Furthermore, compounds 7b, 14b and 14c were tested against HAV 3C protease and showed significant inhibition effects (Ki = 1.903, 0.104 and 0.217 µM, respectively). The remarkable inhibitory effect expressed by the three target compounds against HAV 3C protease prompted us to expand our research on HRV 3C protease, a structurally related enzyme of the same family, and interestingly, the three target compounds displayed significant inhibitory effect against HRV 3C protease (IC50 = 16.10, 4.13 and 6.30 µM, respectively). Moreover, the active compounds 7b, 14b and 14c were docked within the pocket site of HAV 3C protease (PDB code: 2HAL) illustrating a strong H-profile with the key amino acids Gly170 and Cys172 similar to the co-crystallized ligand. Furthermore, 3D-pharmacophore and quantitative structure activity relationship (QSAR) models were generated to explore the structural requirements for the observed antiviral activity.

Design, Synthesis and Anticancer Activity of New Thiazole-Tetrazole or Triazole Hybrid Glycosides Targeting CDK-2 via Structure-Based Virtual Screening.

BACKGROUND & OBJECTIVE: The target tetrazole glycosides were synthesized by construction of ring system by cycloaddition reaction of benzothiazole-linked nitrile derivative and sodium azide followed by N-glycosylation process and deprotection. METHODS: The triazole glycosides were prepared by applying click approach involving dipolar cycloaddition of benzothiazole possessing alkyne functionality and different glycosyl azides. The products incorporating acyclic analogs of sugar moieties were synthesized through alkylation using acyclic oxygenated halides. RESULTS: The anticancer activity was studied against human breast adenocarcinoma cells (MCF-7) and human normal Retina pigmented epithelium cells (RPE-1). High activities were revealed by three compounds with IC50 values 11.9-16.5 µM compared to doxorubicin (18.6 µM) in addition to other four derivatives with good inhibition activities. CONCLUSION: Enzyme docking investigation was performed into cyclin-dependent kinase 2 (CDK2); a potential target for cancer medication. Compounds which have possessed highest activities revealed good fitting inside the binding site of the protein molecular surface and showed minimum binding energy.

ZnO Nanoparticles Catalyst in the Synthesis of Bioactive Fused Pyrimidines as Anti-breast Cancer Agents Targeting VEGFR-2.

BACKGROUND: Pyrimidines emerged as a remarkable class of heterocyclic compounds that have reinforced the pharmaceutical chemistry with various bioactive antitumor agents. Moreover, pyrimidine scaffold displayed VEGFR-2 inhibitory activity. Also, nano-sized catalysts are used in organic reactions in order to speed up the catalytic process. OBJECTIVE: We were interested herein to synthesize a new series of fused pyrimidines using ZnO(NPs) to investigate their antitumor efficiency against breast MCF7 cancer and their VEGFR- 2 inhibition properties. METHOD: A simple and efficient method for the synthesis of fused pyrimidines was developed using zinc oxide nanoparticles ZnO(NPs) in refluxing ethanol. RESULTS: The proposed structures of all new fused pyrimidines are in agreement with their spectral data. Antitumor evaluation of newly fused pyrimidine derivatives against breast MCF-7 cancer was performed. It was apparent that the 2-phenylpyrazolo[1,5-a]pyrimidine derivatives 9a (IC50 = 9.12±1.16 µg/ml), 9c (IC50 = 9.10±1.07 µg/ml) and 9d (IC50 = 9.60±1.22 µg/ml) exhibited equipotent antitumor activity as Tamoxifen (IC50 = 9.11±0.90 µg/ml). Also, the inhibitory activity of the novel fused pyrimidine derivatives on VEGFR-2 as well as Tamoxifen was determined using breast cancer cell line MCF-7. The data was obvious that 2-phenylpyrazolo[1,5-a]pyrimidine derivatives 9a, 9c and 9d exhibited noticeable VEGFR-2 inhibitory effect with % inhibition ranging from 80-84 % versus Tamoxifen 93.5%. CONCLUSION: We succeeded in this context to synthesize new fused pyrimidines using ZnO(NPs) as anti-breast cancer agents targeting VEGFR-2.

Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells.

A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3f, 7a and 7b, showed higher cytotoxic effect (IC50 = 4.3-21.2 µg/mL) than the reference drug doxorubicin (IC50 = 26.1 µg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC50 = 25.2 and 28.0 µg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3f with potent and selective anticancer effects towards MCF-7 cells (IC50 = 11.1, 16.7 and 21.2 µg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC50 values of 9.37, 2.89 and 6.13 µM, respectively, compared to the reference drug colchicine (IC50 = 6.93 µM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100 ps. MD results of compound 3a showed that it reached the stable state after 30 ps which was in agreement with the calculated potential and kinetic energy of compound 3a.

Triazolopyrimidines and Thiazolopyrimidines: Synthesis, Anti-HSV-1, Cytotoxicity and Mechanism of Action.

BACKGROUND: Several commercial drugs utilized in the treatment of HSV containing pyrimidine moiety. Because of the ineffectiveness of virus drugs due to the resistance of the patient's immune system, there is a pressing need to prepare new compounds that are effective in the treatment of various viruses. RESULTS: Merged pyrimidine derivatives were designed by one pot synthesis of pyrimidinethione derivative with halogenated compounds. The structure of all prepared compounds was characterized by their spectroscopic data and also, their ability to inhibit the in vitro replication of HSV-1 was estimated. Amongst the tested compounds 2-acetyl-3-methyl-5-(p-tolyl)indeno[1,2-d]thiazolo[3,2- a]pyrimidin-6(5H)-one (9b) and ethyl 3-methyl-6-oxo-5-(p-tolyl)-5,6-dihydroindeno[1,2-d]thiazolo- [3,2-a]pyrimidine-2-carboxylate (9c), caused viral inhibition over 90%. Furthermore, the selectivity indices of the tested compounds are high and have weak cytotoxicity (all samples were checked, not chosen on cytotoxicity basis, we only utilize secure concentrations of every compound). CONCLUSION: We succeeded in this context to synthesize a new series of potent fused pyrimidine derivatives as anti-HSV-1.

Synthesis of 2-phenylazonaphtho[1,8-ef][1,4]diazepines and 9-(3-arylhydrazono)pyrrolo[1,2-a]perimidines as antitumor agents.

Two series of naphtho[1,8-ef][1,4]diazepines and pyrrolo[1,2-a]perimidines were prepared starting from 1,8-diaminonaphthalene and hydrazonoyl chlorides. The structures of the products were determined on the basis of their spectral data and elemental analyses. The mechanism of formation of such products was also discussed. The prepared compounds were screened for their antitumor activity against three cell lines, namely, MCF-7, TK-10 and UACC-62, and some derivatives showed promising activity.