Synthesis and Molecular Dynamic Simulation of Novel Cationic and Non-cationic Pyrimidine Derivatives as Potential G-quadruplex-ligands.

BACKGROUND: Drug resistance has been a problem in cancer chemotherapy, which often causes shortterm effectiveness. Further, the literature indicates that telomere G-quadruplex could be a promising anti-cancer target. OBJECTIVE: We synthesized and characterized two new pyrimidine derivatives as ligands for G-quadruplex DNA. METHODS: The interaction of novel non-cationic and cationic pyrimidine derivatives (3a, b) with G-quadruplex DNA (1k8p and 3qsc) was explored by circular dichroism (CD) and ultraviolet-visible spectroscopy and polyacrylamide gel electrophoresis (PAGE) methods. The antiproliferative activity of desired compounds was evaluated by the MTT assay. Apoptosis induction was assessed by Propidium iodide (P.I.) staining and flow cytometry. Computational molecular modeling (CMM) and molecular dynamics simulation (MD) were studied on the complexes of 1k8p and 3qsc with the compounds. The van der Waals, electrostatic, polar solvation, solventaccessible surface area (SASA), and binding energies were calculated and analyzed. RESULTS: The experimental results confirmed that both compounds 3a and 3b interacted with 1k8p and 3qsc and exerted cytotoxic and proapoptotic effects on cancer cells. The number of hydrogen bonds and the RMSD values increased in the presence of the ligands, indicating stronger binding and suggesting increased structural dynamics. The electrostatic contribution to binding energy was higher for the cationic pyrimidine 3b, indicating more negative binding energies. CONCLUSION: Both experimental and MD results confirmed that 3b was more prone to form a complex with DNA G-quadruplex (1k8p and 3qsc), inhibit cell growth, and induce apoptosis, compared to the non-cationic pyrimidine 3a.

Targeted delivery of SN38 to breast cancer using amphiphilic diblock copolymers PHPMA-b-PBAEM as micellar carriers with AS1411 aptamer.

Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study presents a novel nanotherapeutic targeted DDS developed through the self-assembly of an amphiphilic di-block copolymer to deliver the chemotherapy drug SN38 specifically to breast cancer cells. The vehicle was constructed from the PHPMA-b-PEAMA diblock copolymer synthesized via RAFT polymerization. A single emulsion method was then used to encapsulate SN38 within nanoparticles (NPs) formed from the PHPMA-b-PEAMA copolymer. The AS1411 DNA aptamer was covalently bonded to the surface of the micellar NPs, producing a targeted DDS. Molecular dynamics (MD) simulation studies were also performed on the di block polymeric system, demonstrating that SN38 interacted well with the di block. The in vitro results demonstrated that AS1411- decorated SN38-loaded HPMA NPs were highly toxic to breast cancer cells while having a minimal effect on non-cancerous cells. Remarkably, in vivo studies elucidated the ability of the targeted DDS to enhance the antitumor effect of SN38, suppressing tumor growth and improving survival rates compared to free SN38.

Anticancer Potential of a Synthetic Quinoline, 9IV-c, by Inducing Apoptosis in A549 Cell and In vivo BALB/c Mice Models.

BACKGROUND: In a previous work from the author of this study, the compound of 9IV-c, ((E)-2-(3,4- dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) was synthesized, and the effects of potent activity on the multiple human tumor cell lines were evaluated considering the spindle formation together with the microtubule network. METHODS: Accordingly, cytotoxic activity, apoptotic effects, and the therapeutic efficiency of compound 9IV-c on A549 and C26 cell lines were investigated in this study. RESULTS: The compound 9IV-c demonstrated high cytotoxicity against A549 and C26 cell lines with IC50 = 1.66 and 1.21 µM, respectively. The flow cytometric analysis of the A549 cancer cell line treated with compound 9IVc showed that This compound induced cell cycle arrest at the G2/M phase and apoptosis. Western blotting analysis displayed that compound 9IV-c also elevated the Bax/Bcl-2 ratio and increased the activation of caspase-9 and -3 but not caspase-8. CONCLUSION: These data presented that the intrinsic pathway was responsible for 9IV-c -induced cell apoptosis. In vivo studies demonstrated that treatment with the compound of 9IV-c at 10 mg/kg dose led to a decrease in tumor growth compared to the control group. It was found that there was not any apparent body weight loss in the period of treatment. Also, in the vital organs of the BALB/c mice, observable pathologic changes were not detected.

Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway.

BACKGROUND: Colorectal cancer (CRC) remains a significant contributor to mortality, often exacerbated by metastasis and chemoresistance. Novel therapeutic strategies are imperative to enhance current treatments. The dysregulation of the PI3K/Akt signaling pathway is implicated in CRC progression. This study investigates the therapeutic potential of Wortmannin, combined with 5-fluorouracil (5-FU), to target the PI3K/Akt pathway in CRC. METHODS: Anti-migratory and antiproliferative effects were assessed through wound healing and MTT assays. Apoptosis and cell cycle alterations were evaluated using Annexin V/Propidium Iodide Apoptosis Assay. Wortmannin's impact on the oxidant/antioxidant equilibrium was examined via ROS, SOD, CAT, MDA, and T-SH levels. Downstream target genes of the PI3K/AKT pathway were analyzed at mRNA and protein levels using RTPCR and western blot, respectively. RESULTS: Wortmannin demonstrated a significant inhibitory effect on cell proliferation, modulating survivin, cyclinD1, PI3K, and p-Akt. The PI3K inhibitor attenuated migratory activity, inducing E-cadherin expression. Combined Wortmannin with 5-FU induced apoptosis, increasing cells in sub-G1 via elevated ROS levels. CONCLUSION: This study underscores Wortmannin's potential in inhibiting CRC cell growth and migration through PI3K/Akt pathway modulation. It also highlights its candidacy for further investigation as a promising therapeutic option in colorectal cancer treatment.

Dual-targeting CD44 and mucin by hyaluronic acid and 5TR1 aptamer for epirubicin delivery into cancer cells: Synthesis, characterization, in vitro and in vivo evaluation.

One of the revolutionized cancer treatment is active targeting nanomedicines. This study aims to create a dual-targeted drug delivery system for Epirubicin (EPI) to cancer cells. Hyaluronic acid (HA) is the first targeting ligand, and 5TR1 aptamer (5TR1) is the second targeting ligand to guide the dual-targeted drug delivery system to the cancer cells. HA is bound to highly expressed receptors like CD44 on cancer cells. 5TR1, DNA aptamer, is capable of recognizing MUC1 glycoprotein, which is overexpressed in cancer cells. The process involved binding EPI and 5TR1 to HA using adipic acid dihydrazide (AA) as a linker. The bond between the components was confirmed using 1H NMR. The binding of 5TR1 to HA-AA-EPI was confirmed using gel electrophoresis. The particle size (132.6 ± 9 nm) and Zeta Potential (-29 ± 4.4 mV) were measured for the final nanoformulation (HA-AA-EPI-5TR1). The release of EPI from the HA-AA-EPI-5TR1 nanoformulation was also studied at different pH levels. In the acidic pH (5.4 and 6.5) release pattern of EPI from the HA-AA-EPI-5TR1 nanoformulation was higher than physiological pH (7.4). The cytotoxicity and cellular uptake of the synthetic nanoformula were evaluated using MTT and flow cytometry analysis. Flow cytometry and cellular cytotoxicity studies were exhibited in a negative MUC1-cell line (CHO) and two positive MUC1+cell lines (MCF-7 and C26). Results confirmed that there is a notable contrast between the dual-targeted (HA-AA-EPI-5TR1) and single-targeted (HA-AA-EPI) nanoformulation in MCF-7 and C26 cell lines (MUC1+). In vivo studies showed that HA-AA-EPI-5TR1 nanoformulation has improved efficiency with limited side effect in C26 tumor-bearing mice. Also, Fluorescence imaging and pathological evaluation showed reduced side effects in the heart tissue of mice receiving HA-AA-EPI-5TR1 than free EPI. So, this targeted approach effectively delivers EPI to cancer cells with reduced side effects.

The Application of Kinesin Inhibitors in Medical Issues.

Kinesins are a group of motor proteins in charge of several crucial functions in the cell. These proteins often bind to microtubules and perform their functions using the energy produced by ATP hydrolysis. One function of mitotic kinesin, a subclass of kinesin that is expressed during cell division at the mitotic phase, is to create the mitotic spindle. Uncontrolled cell growth is one trait of cancerous cells. Traditional anticancer medications still used in clinics include taxanes (paclitaxel) and vinca alkaloids (vincristine, vinblastine), which interfere with microtubule dynamics. However, because non-dividing cells like post-mitotic neurons contain microtubules, unwanted side effects like peripheral neuropathy are frequently found in patients taking these medications. More than ten members of the mitotic kinesin family play distinct or complementary roles during mitosis. The mitotic kinesin family's KSP, or Eg5, is regarded as its most dramatic target protein. The current work systematically reviews the use of kinesin inhibitors in the medical field. The challenges of KSP and the practical solutions are also examined, and the outcomes of the previous works are reported. The significant gaps and shortcomings of the related works are also highlighted, which can be an onset topic for future works.

Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder that leads to growth cysts in the kidney, ultimately resulting in loss of function. Currently, no effective drug therapy can be safely used in the clinic. So, looking for effective therapeutic drugs is urgent for treating ADPKD. Our natural product library was prepared based on the ZINC-15 database. Lipinski's rule of five, drug-likeness, and toxicity screening of the designed library were evaluated. Swiss model online server was used for modeling of GANAB target. Finally, docking-based screening against ADPKD targets was done by MOE 2019 software. The top 14 favorable druglike and non-toxic hits were selected for docking studies. Our results showed that compound-10 (ZINC 6073947) as a sesquiterpene coumarin had more negative binding interaction into the active site of PPARG, OXSR1, GANAB, AVPR2, and PC2 with docking scores of -8.22, -7.52, -6.98, -6.61 and -6.05 kcal/mol, respectively, in comparison to Curcumin, as a natural product that is now in phase 4 clinical trial in ADPKD disease, with an affinity of -8.03, -6.42, -6.82, -5.84 and -5.10 kcal/mol, respectively. Furthermore, seven sesquiterpene coumarins similar to compound 10 were generated and docked. Farnesiferol B (16), compared to compound-10, showed binding affinity of -8.16, -6.4, -7.46, -6.92, and -6.11 kcal/mol against the above targets, respectively. Molecular dynamics, which was done on the compound-10 and 16 (Farnesiferol B) in complex with PPARG, GANAB, and AVPR2, showed more negative binding free-energy than Pioglitazone, Miglitol, and Tolvaptan as FDA-approved drugs for each target, respectively.Communicated by Ramaswamy H. Sarma.

Signal amplification strategies in biosensing of extracellular vesicles (EVs).

Extracellular vesicles (EVs) are membrane-enclosed vesicles secreted from mammalian cells. EVs act as multicomponent delivery vehicles to carry a wide variety of biological molecular information and participate in intercellular communications. Since elevated levels of EVs are associated with some pathological states such as inflammatory diseases and cancers, probing circulating EVs holds a great potential for early diagnostics. To this end, several detection methods have been developed in which biosensors have attracted great attentions in identification of EVs due to their simple instrumentation, versatile design and portability for point-of-care applications. The concentrations of EVs in bodily fluids are extremely low (i.e. 1-100 per µl) at early stages of a disease, which necessitates the use of signal amplification strategies for EVs detection. In this way, this review presents and discusses various amplification strategies for EVs biosensors based on detection modalities including surface plasmon resonance (SPR), calorimetry, fluorescence, electrochemical and electrochemiluminescence (ECL). In addition, microfluidic systems employed for signal amplification are reviewed and discussed in terms of their design and integration with the detection methods.

A novel and easy to prepare azo-based bioreductive linker and its application in hypoxia-sensitive cationic liposomal doxorubicin: Synthesis, characterization, in vitro and in vivo studies in mice bearing C26 tumor.

This study designed and synthesized a cost-effective azo-based hypoxia-sensitive linker (AHSL) using commercially accessible, inexpensive raw materials and simple methods to apply in cationic nanoliposomes. Then, AHSL was post-inserted into the cationic liposome (Cat-lip), and PEG-Azo-Cat-lip was prepared and characterized using DLS. The decrease in the zeta-potential of formulation from + 18.4 mV for Cat-lip to + 6.1 mV and the increase in the size of the PEG-Azo-Cat-lip indicated the successful post insertion of AHSL into the liposomes. The Doxorubicin (Dox) release study showed that PEGylation results in a more stable PEG-Azo-Cat-lip than the Cat-lip. The increased cytotoxicity of the PEG-Azo-Cat-lip in the hypoxic condition also indicated the cleavage of the AHSL in the hypoxic environment. In vivo biodistribution using animal imaging has shown higher tumor accumulation of the MPEG-Azo-Cat-lip than Cat-lip during the 120 h of the study. The results of anti-tumor activities and biosafety of the formulations also showed the higher efficiency of the MPEG-Azo-Cat-lip compared with the Cat-lip. The results of this study indicated the antitumor efficacy of this hypoxia-sensitive which merits further investigation.

Dual-targeted and controlled release delivery of doxorubicin to breast adenocarcinoma: In vitro and in vivo studies.

Doxorubicin (DOX) is a chemotherapeutic drug that belongs to the anthracyclines family. Cardiotoxicity is one of the main limiting factor of prescribing DOX. To reduce its side effects and enhance the drug delivery to the targeted tissues, we aimed to establish a new targeted and controlled release drug delivery system for treatment of breast cancer. In this article, we tried to synthesize a new nanoplatform consisted of DOX conjugate with hydrazide and disulfide bonds to the hyaluronic acid (HA). Firstly, 4,4'-Dithiodibutyric acid (DTBH) was conjugated with HA. Then, 3-aminophenyl boronic acid monohydrate (APBA) was conjugated with DTBH-HA. Subsequently, DOX was added to DTBH-HA-APBA. HA is a natural polymer with the ability to target CD44, a cell surface adhesion receptor, which are highly overexpressed on the surface of variety of cancer cells. Other targeting agent, APBA can target sialic acid on the cancer cells surface and improve the tumor uptake. Formation of The DTBH-HA-APBA conjugate was confirmed by proton nuclear magnetic resonance (1H NMR) spectroscopy. Scanning emission electron microscopy (SEM) images of the DOX-DTBH-HA-APBA displayed a spherical shape with an average diameter of about 70 nm. In vitro drug release study showed considerably different release pattern of DOX from the formulation at acidic pH (5.4) which was higher than normal pH (7.4). Cellular uptake and cellular cytotoxicity analysis were examined in human breast adenocarcinoma cell line (MCF-7) and mouse breast cancer cells (4T1) as positive cell lines and Chinese Hamster Ovary cells (CHO) as negative cell line. Results confirmed that there is a remarkable difference between dual-targeted (DOX-DTBH-HA-APBA) and single targeted (DOX-DTBH-HA) formulations in both positive cell lines regarding internalization and cytotoxicity. In vivo studies indicated that dual-targeted formulation has the best efficacy with minimum side effects in mouse model. Fluorescence imaging of organs revealed that DOX-DTBH-HA-APBA showed greater DOX accumulation compared with DOX-DTBH-HA and free DOX in tumor site. Also, pathological evaluation indicated that there is no observable cardiotoxicity with final formulation.

Corrigendum to "3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity".

[This corrects the article DOI: 10.1155/2021/6480804.].

In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening.

Microtubules play a critical role in mitosis and cell division and are regarded as an excellent target for anticancer therapy. Although microtubule-targeting agents have been widely used in the clinical treatment of different human cancers, their clinical application in cancer therapy is limited by both intrinsic and acquired drug resistance and adverse toxicities. In a previous work, we synthesized compound 9IV-c, ((E)-2-(3,4-dimethoxystyryl)-6,7,8-trimethoxy-N-(3,4,5-trimethoxyphenyl)quinoline-4-amine) that showed potent activity against multiple human tumor cell lines, by targeting spindle formation and/or the microtubule network. Accordingly, in this study, to identify potent tubulin inhibitors, at first, molecular docking and molecular dynamics studies of compound 9IV-c were performed into the colchicine binding site of tubulin; then, a pharmacophore model of the 9IV-c-tubulin complex was generated. The pharmacophore model was then validated by Güner-Henry (GH) scoring methods and receiver operating characteristic (ROC) analysis. The IBScreen database was searched by using this pharmacophore model as a screening query. Finally, five retrieved compounds were selected for molecular docking studies. These efforts identified two compounds (b and c) as potent tubulin inhibitors. Investigation of pharmacokinetic properties of these compounds (b and c) and compound 9IV-c displayed that ligand b has better drug characteristics compared to the other two ligands.

Smac peptide and doxorubicin-encapsulated nanoparticles: design, preparation, computational molecular approach and in vitro studies on cancer cells.

The N-terminal sequence of the Smac (second-mitochondria derived activator) protein is known to be involved in binding to the BIR3 (Baculovirus IAP repeat) domain of the IAPs (inhibitors of apoptosis proteins), and antagonized their function. Short peptides derived from N-terminal residues of Smac have shown to sensitize cancer cells to chemotherapeutic agents. In this regard, small library including 6-mer peptides were designed using docking to the BIR3 domain of cIAP1 in silico. Molecular dynamics simulation studies were also done on top-scored hits (SmacAQ, SmacIQ) using Desmond 2017-2 for 150 ns simulation time. These two peptides were conveniently synthesized using solid phase peptide synthesis on Fmoc-Gln (Trt)-Wang resin. Furthermore, we encapsulated DOX (doxorubicin) and synthesized peptides in PLGA: PLGA-PEG (9:1) NPs (nanoparticles) followed by MD (molecular dynamic) studies to understand the NP structure and the interactions between either DOX or peptide with polymeric nanoparticles during 100 ns simulation. Finally, the cytotoxic activity of these peptides in combination with DOX against two cancer cell lines including MCF7 and C26 were investigated. As a result, we found that DOX or peptide-loaded NPs had stable structure during the simulation. MD simulation also showed that alanine at N-terminal of Smac could be replaced with isoleucine without alternation of biological activity which was in agreement with in vitro experiments. Moreover, NPs-SmacIQ and NPs-SmacAQ significantly enhanced the cytotoxicity effect of NPs-DOX in vitro (p < 0.001).Communicated by Ramaswamy H. Sarma.

Coumarins and Quinolones as Effective Multiple Targeted Agents Versus Covid-19: An In Silico Study.

BACKGROUND: The Covid-19 virus emerged a few months ago in China, and infections rapidly escalated into a pandemic. OBJECTIVE: To date, there is no selective antiviral agent for the management of pathologies associated with covid-19 and the need for an effective agent against it is essential. METHODS: In this work, two home-made databases from synthetic quinolines and coumarins were virtually docked against viral proteases (3CL and PL), human cell surface proteases (TMPRSS2 and furin) and spike proteins (S1 and S2). Chloroquine, a reference drug without a clear mechanism against coronavirus was also docked on mentioned targets and the binding affinities compared with title compounds. RESULTS: The best compounds of synthetic coumarins and quinolines for each target were determined. All compounds against all targets showed binding affinity between -5.80 to -8.99 kcal/mol in comparison with the FDA-approved drug, Chloroquine, with binding affinity of -5.7 to -7.98 kcal/mol. Two compounds, quinoline-1 and coumarin-24, were found to be effective on three targets - S2, TMPRSS2 and furin - simultaneously, with good predicted affinity between -7.54 to -8.85 kcal/mol. In silico ADME studies also confirmed good oral absorption for them. Furthermore, PASS prediction was calculated and coumarin-24 had higher probable activity (Pa) than probable inactivity (Pi) with acceptable protease inhibitory as well as good antiviral activity against Hepatitis C virus (HCV), Human immunodeficiency virus (HIV) and influenza. CONCLUSION: Quinoline-1 and Coumarin-24 have the potential to be used against Covid-19. Hence these agents could be useful in combating covid-19 infection after further in vitro and in vivo studies.

The Protective Effect of Natural Compounds on Doxorubicin-Induced Cardiotoxicity via Nicotinamide Adenine Dinucleotide Phosphate Oxidase Inhibition.

OBJECTIVES: Doxorubicin (DOX) is widely prescribed for the treatment of several human cancers. Unfortunately, cumulative doses of DOX are the main cause of myocardial dysfunction. Although preclinical and pharmaceutical studies were performed to investigate the potential of natural compounds in minimizing DOX toxicity, a comprehensive review of them is not available. This review can help the researchers for an effective search strategy. KEY FINDINGS: Oxidative stress and p53 play an important role in DOX-associated cardiotoxicity. DOX activates nicotinamide adenine dinucleotide phosphate NADPH oxidase (NOX) in the heart, resulting in excessive reactive oxygen species that can induce cardiomyocyte apoptosis through phosphorylation of p53, DNA damage and/or mitogen-activated protein kinases-mediated cardiomyocyte apoptosis. Although a few chemical drugs with high efficacy are administered along with DOX to prevent or more likely to reduce cardiovascular toxicity, their use is often limited by additional side effects. Recently, attention has been drawn to natural compounds that prevent DOX cardiotoxicity. This review focuses on some of the natural bioactive compounds with potential therapeutic efficacy against DOX-induced cardiotoxicity (DIC). SUMMARY: Some natural compounds, especially flavonols, flavonoids and proanthocyanidins, have the most protective effects against DIC by forming stable radicals and preventing the assembly of the NOX subunits.

Anti-Proliferative Potential of Fluorinated Curcumin Analogues: Experimental and Computational Analysis and Review of the Literature.

BACKGROUND: Curcuminoids, flavoring, and coloring agents in food have potent antioxidant, anti-tumor activity, and anti-inflammatory effects. However, they are rapidly metabolized to lesser active metabolites. Therefore, various studies have been conducted to synthesize new and stable curcumin analogues with enhanced therapeutic activity. METHODS: Fluorinated curcumin compounds (2a-2f) were synthesized by Knoevenagel condensation between fluorobenzaldehydes (1a-1f) with curcumin. Fluorinated demethoxycurcumin (3a) was synthesized by condensation between demethoxycurcumin and 3,4-difluorobenzaldehyde (1f). The structures of these compounds were confirmed by FTIR, 1H-NMR, 13C-NMR, 19FNMR, and mass spectroscopy. Antiproliferative activities of these synthetic compounds were evaluated against breast cancer cells (4T1), melanoma cancer cells (B16F10), and normal cell lines (NIH 3T3) using MTT assay. The interaction of curcumin, 2f and 3a with several proteins (1HCL, 2ZOQ, 3D94, 5EW3, 4WA9, 1XKK, 6CCY) was investigated. The structural preservation of the epidermal growth factor receptor (EGFR) was investigated by molecular dynamics simulation. RESULTS: The spectroscopic data obtained confirmed the proposed structure of fluorinated analogues. The results showed that compounds 2f and 3a inhibited cancer cells proliferation significantly more than other compounds. Compounds 2f and 3a showed the highest affinity and lowest binding energy with EGFR. The binding energies were -7.8, -10, and - 9.8 kcal/mol for curcumin, 2f and 3a with EGFR, respectively. The molecular docking results demonstrated that compounds 2f and 3a were firmly bound in a complex with EGFR via the formation of a hydrogen bond. CONCLUSION: In summary, we found that fluorinated demethoxycurcumin and fluorinated curcumin induces cancer cell death and binds to EGFR with high affinity.

3D-QSAR Studies of 1,2,4-Oxadiazole Derivatives as Sortase A Inhibitors.

Sortase A (SrtA) is an enzyme that catalyzes the attachment of proteins to the cell wall of Gram-positive bacterial membrane, preventing the spread of pathogenic bacterial strains. Here, one class of oxadiazole compounds was distinguished as an efficient inhibitor of SrtA via the "S. aureus Sortase A" substrate-based virtual screening. The current study on 3D-QSAR was done by utilizing preparation of the structure in the Schrödinger software suite and an assessment of 120 derivatives with the crystal structure of 1,2,4-oxadiazole which was extracted from the PDB data bank. The docking operation of the best compound in terms of pMIC (pMIC = 2.77) was done to determine the drug likeliness and binding form of 1,2,4-oxadiazole derivatives as antibiotics in the active site. Using the kNN-MFA way, seven models of 3D-QSAR were created and amongst them, and one model was selected as the best. The chosen model based on q 2 (pred_r 2) and R 2 values related to the sixth factor of PLS illustrates better and more acceptable external and internal predictions. Values of crossvalidation (pred_r 2), validation (q 2), and F were observed 0.5479, 0.6319, and 179.0, respectively, for a test group including 24 molecules and the training group including 96 molecules. The external reliability outcomes showed that the acceptable and the selective 3D-QSAR model had a high predictive potential (R 2 = 0.9235) which was confirmed by the Y-randomization test. Besides, the model applicability domain was described successfully to validate the estimation of the model.

Design and synthesis of targeted star-shaped micelle for guided delivery of camptothecin: In vitro and in vivo evaluation.

This study aimed to synthesize a star-shaped micelle using 3-azido-2,2-bis(azidomethyl)propan-1-ol (pentaerythritol triazide) core, as an initiator for the synthesis of three-arm polylactic acid (PLA) block. Then, the ends of the PLA arms were converted to PLA triazide followed by conjugation to the three alkyne-PEG-maleamide through click reaction. The maleamide ends were available for coupling with sulfhydryl-modified DNA aptamer against epithelial cell adhesion molecule in order to offer targeted delivery of encapsulated drug, camptothecin to the site of action. The successful synthesis of the star-shaped polymers was confirmed via1HNMR. Hydrophobic anti-cancer drug, camptothecin was encapsulated into the micelles core implementing solvent switching method providing loading content (LC%) and encapsulation efficiency (EE%) of 3.7 ± 0.4 and 73.7 ± 8.2, respectively. The size of both non-targeted and aptamer-targeted micelles was determined to be 154 and 192 nm, respectively with polydispersity index below 0.3. In vitro drug release evaluation at 37 °C, pH 7.4 showed a controlled release pattern for camptothecin during 72 h. In vitro cytotoxicity of the prepared non-targeted and targeted micelles was carried out on human colorectal adenocarcinoma (HT29) and mouse colon carcinoma (C26) as EpCAM positive cell lines and Chinese hamster ovary (CHO) as EpCAM negative cell line. The results verified significantly higher cytotoxicity of the targeted micelles on HT29 and C26 cell lines, while no obvious difference was observed between targeted and non-targeted formulation on CHO cell line. The in vivo therapeutic efficiency investigation on BALB/c C26 tumor-bearing mice showed superior capability of the targeted formulation on tumor suppression and survival rate of the treated mice. The developed platform exhibited excellent characteristics to diminish camptothecin drawbacks and its adverse effects while considerably increasing its therapeutic index.

Synthesis and biological evaluation of novel quinoline analogs of ketoprofen as multidrug resistance protein 2 (MRP2) inhibitors.

OBJECTIVES: A new series of quinoline analogs of ketoprofen was designed and synthesized as multidrug resistance protein 2 (MRP2) inhibitors using ketoprofen as the lead compounds. MATERIALS AND METHODS: The cytotoxic activity of the compounds was evaluated againt two cancer cell lines including A2780/RCIS (MRP2-overexpressing ovarian carcinoma), A2780, drug-sensitive ovarian carcinoma using MTT assay. Compounds showing low toxicity in MTT test were selected to investigate their MRP inhibition activity. MRP2 inhibitory potency was evaluated by determination of the uptake amount of fluorescent 5-carboxy fluorescein diacetate (5-CFDA) substrate, by A2780/RCIS in the presence of the selected compounds. Mode of interaction between synthesized ligands and homology modeled MRP2 was investigated by MOE software. RESULTS: Compound 6d, a 4-carboxy quinoline possessing dimethoxy phenyl in position 2 of quinoline ring, showed the most MRP2 inhibition activity among all the quinolines and more than the reference drug ketoprofen. MRP2 inhibition activity of compound 7d was less in comparison to that of compound 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2. Docking studies showed that compound 7d methyl ester of 6d, interacted less compared to its parent 6d, which is consistent with biological results. CONCLUSION: This study indicates that 6- or 8-benzoyl-2-arylquinoline is a suitable scaffold to design MRP2 inhibitors. The position of benzoyl in quinoline ring is important in inhibition of MRP2. Generally, MRP2 inhibition activity of compound 7d was less in comparison to that of 6d, indicating that carboxyl group in position 4 of quinoline may interact with MRP2.

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for Identification of Tubulin Inhibitors with Potential Anticancer Activity.

In this study, we aimed to develop a pharmacophore-based three-dimensional quantitative structure activity relationship (3D-QSAR) for a set including sixty-two cytotoxic quinolines (1-62) as anticancer agents with tubulin inhibitory activity. A total of 279 pharmacophore hypotheses were generated based on the survival score to build QSAR models. A six-point pharmacophore model (AAARRR.1061) was identified as the best model which consisted of three hydrogen bond acceptors (A) and three aromatic ring (R) features. The model showed a high correlation coefficient (R 2 = 0.865), cross-validation coefficient (Q 2 = 0.718), and F value (72.3). The best pharmacophore model was then validated by the Y-Randomization test and ROC-AUC analysis. The generated 3D contour maps were used to reveal the structure activity relationship of the compounds. The IBScreen database was screened against AAARRR.1061, and after calculating ADMET properties, 10 compounds were selected for further docking study. Molecular docking analysis showed that compound STOCK2S-23597 with the highest docking score (-10.948 kcal/mol) had hydrophobic interactions and can form four hydrogen bonds with active site residues.