Design, synthesis and evaluation of acridone-2-carbohydrazide derivatives as p-AKT Ser kinase inhibitors.

A series of benzylidene- and phenylethylidene-substituted acridone-2-carbohydrazide derivatives were designed, synthesized and evaluated for their cytotoxicity and response to p-AKT Ser. The structures of the synthesized compounds were confirmed by spectroscopic techniques and evaluated for AKT enzyme inhibition activities. Molecular docking and absorption, distribution, metabolism, elimination and toxicity studies were also performed.

Evaluation of -substituted acridone-based derivatives as AKT inhibitors against breast cancer cells: in vitro and molecular docking studies.

Unlabelled: A series of -substituted acridone-2-carboxamide derivatives were synthesized and evaluated for their potent anti-cancer agents targeting AKT kinase. In vitro cytotoxicity activity of the target compounds was tested against breast cancer cell lines (MCF-7 and MDA-MB-231). Among the tested compounds, four compounds (, , , and ) exhibited promising anti-cancer activity against both cancer cell lines.

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure-Activity Relationship.

Epidermal growth factor receptor (EGFR) belongs to the family of tyrosine kinase that is activated when a specific ligand binds to it. The EGFR plays a vital role in the cellular proliferation process, differentiation, and apoptosis. In the case of cancer, EGFR undergoes uncontrolled auto-phosphorylation that results in increased cellular proliferation and decreased apoptosis, causing cancer promotion.

A comprehensive review on acridone based derivatives as future anti-cancer agents and their structure activity relationships.

The development of drug resistance and severe side-effects has reduced the clinical efficacy of the existing anti-cancer drugs available in the market. Thus, there is always a constant need to develop newer anti-cancer drugs with minimal adverse effects. Researchers all over the world have been focusing on various alternative strategies to discover novel, potent, and target specific molecules for cancer therapy.

Design of experiment-based LC-MS/MS method development for simultaneous estimation of nateglinide and metformin hydrochloride in rat plasma.

This research aims to develop and validate a bioanalytical method for simultaneous estimation of an antidiabetic combination using LC-MS/MS in rat plasma. Nateglinide and metformin hydrochloride are commonly used combination for clinical management of Type 2 diabetes. Hence, simultaneous determination in plasma is essential for the rapid analysis of samples from the pharmacokinetic studies.

Design, synthesis, modelling studies and biological evaluation of 1,3,4-oxadiazole derivatives as potent anticancer agents targeting thymidine phosphorylase enzyme.

A series of novel 1,3,4-oxadiazole derivatives with substituted phenyl ring were designed and synthesized with an objective of discovering newer anti-cancer agents targeting thymidine phosphorylase enzyme (TP). The 1,3,4-oxadiazole derivatives were synthesized by simple and convenient methods in the lab. Chemical structure of the all the synthesized compounds were characterized by IR, H NMR and mass spectral methods and evaluated for cytotoxicity by MTT method against two breast cancer cell lines (MCF-7 and MDA-MB-231).

Study of Combinatorial Drug Synergy of Novel Acridone Derivatives With Temozolomide Using and Methods in the Treatment of Drug-Resistant Glioma.

Drug resistance is one of the critical challenges faced in the treatment of Glioma. There are only limited drugs available in the treatment of Glioma and among them Temozolomide (TMZ) has shown some effectiveness in treating Glioma patients, however, the rate of recovery remains poor due to the inability of this drug to act on the drug resistant tumor sub-populations. Hence, in this study three novel Acridone derivative drugs AC2, AC7, and AC26 have been proposed.

Targeting telomerase for its advent in cancer therapeutics.

Telomerase has emerged as an important primary target in anticancer therapy. It is a distinctive reverse transcriptase enzyme, which extends the length of telomere at the 3' chromosomal end, and uses telomerase reverse transcriptase (TERT) and telomerase RNA template-containing domains. Telomerase has a vital role and is a contributing factor in human health, mainly affecting cell aging and cell proliferation.

Cancer cell fusion: a potential target to tackle drug-resistant and metastatic cancer cells.

Cell fusion is an integral, established phenomenon underlying various physiological processes in the cell cycle. Although research in cancer metastasis has hypothesised numerous molecular mechanisms and signalling pathways responsible for invasion and metastasis, the origin and progression of metastatic cells within primary tumours remains unclear. Recently, the role of cancer cell fusion in cancer metastasis and development of multidrug resistance (MDR) in tumours has gained prominence.

Synthesis of novel gefitinib-based derivatives and their anticancer activity.

Drug latentiation is a process of modifying a drug molecule structurally to improve its binding affinity as well as increasing the drug-receptor interactions and potentiate its therapeutic potential. In the quest for discovering more potent epidermal growth factor receptor (EGFR) inhibitors, gefitinib-based derivatives were designed by simple structural modification at the secondary amine of gefitinib by N-alkylation. Three gefitinib derivatives (gefitinib-NB, -NP, and -NIP) were synthesized by N-alkylation and phase transfer catalysis.

E-drug delivery: a futuristic approach.

Drug delivery systems are undergoing technology changes to enhance patient comfort and compliance. Electronic drug delivery (E-drug delivery) systems are being developed to regulate drug dose delivery by easy monitoring of doses, especially in chronic and age-related diseases. E-drug delivery can monitor the correct dose of anesthesia, could be used in GI tracking by E-capsules, in epilepsy, insulin drug delivery, cardiac ailments and cancer therapy.

Ligand based design and synthesis of pyrazole based derivatives as selective COX-2 inhibitors.

The design and synthesis of novel pyrazole based derivatives has been carried out using the ligand based approach like pharmacophore and QSAR modelling of reported pyrazoles from the available literature to investigate the chemical features that are essential for the design of selective and potent COX-2 inhibitors. Both pharmacophore and QSAR models with good statistical parameters were selected for the design of the lead molecule. Also by exploiting the chemical structures of selective and marketed COX-2 inhibitors, celecoxib and SC-558 were used in designing the molecules which are used in the treatment of inflammation and related disorders.

An overview of tramadol and its usage in pain management and future perspective.

Patients with chronic non-malignant pain report impairment of physical and social life along with psychological state affecting their overall quality of life. The purpose of managing pain is to reduce the trauma and improve the patient comfort with better quality of life. Tramadol is a centrally acting weak μ-opioid receptor analgesic and is a racemic mixture of (+)-tramadol and (-)-tramadol enantiomers.

Acridone-pyrimidine hybrids- design, synthesis, cytotoxicity studies in resistant and sensitive cancer cells and molecular docking studies.

Hybrid systems of acridones with substituted pyrimidines were designed with an objective of discovering next generation anticancer agents targeting multiple mechanisms in the cancer cell. Hybrid compounds were synthesized by simple and convenient methods in the lab, characterized by NMR and Mass spectral methods and screened for cytotoxicity against A549 (lung), Hela (cervical), MCF7 (breast) and MDA-MB-231 (breast) cancer cell lines respectively. Evaluation of compounds for cell proliferation identified active compounds 11b, 11d and 11h against MCF7, MDA-MB-231 and A549 cell lines.

Design, synthesis, biological evaluation, molecular docking and QSAR studies of 2,4-dimethylacridones as anticancer agents.

Drug resistance in cancer is an unmet medical challenge and a major drawback for the failure of many chemotherapeutic drugs. Search for targeted, effective drug with minimum toxicity is an urgent need. Acridone which is an alkaloid derivative has been attributed as molecule in reversing drug resistance in cancer cells for a long time now.

Chemosensitizing acridones: in vitro calmodulin dependent cAMP phosphodiesterase inhibition, docking, pharmacophore modeling and 3D QSAR studies.

Calmodulin inhibitors have proved to play a significant role in sensitizing MDR cancer cells by interfering with cellular drug accumulation. The present investigation focuses on the evaluation of in vitro inhibitory efficacy of chloro acridones against calmodulin dependent cAMP phosphodiesterase (PDE1c). Moreover, molecular docking of acridones was performed with PDE1c in order to identify the possible protein ligand interactions and results thus obtained were compared with in vitro data.

In-vitro cytotoxicity and cell cycle analysis of two novel bis-1,2, 4-triazole derivatives: 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio-4-(p-tolyl)-1,2,4-triazol-3-yl]-butane (MNP-14) and 1,4-bis[5-(carbethoxy-methyl)-thio-4-(p-ethoxy phenyl)-1,2,4-triazol-3-yl]-butane (MNP-16).

In the present study, we have tested the cytotoxic and DNA damage activity of two novel bis-1,2,4 triazole derivatives, namely 1,4-bis[5-(5-mercapto-1,3,4-oxadiazol-2-yl-methyl)-thio-4-(p-tolyl)-1,2,4-triazol-3-yl]-butane (MNP-14) and 1,4-bis[5-(carbethoxy-methyl)-thio-4-(p-ethoxy phenyl) -1,2,4-triazol-3-yl]-butane (MNP-16). The effect of these molecules on cellular apoptosis was also determined. The in-vitro cytotoxicity was evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay as well as Trypan blue dye exclusion methods against human acute lymphoblastic leukemia (MOLT4) and lung cancer cells (A549).

Cytotoxicity studies of some novel fluoro acridone derivatives against sensitive and resistant cancer cell lines and their mechanistic studies.

A series of novel N(10)-substituted acridone derivatives bearing alkyl side-chain with tertiary amine groups at the terminal position were evaluated for their in vitro cytotoxic effects against drug sensitive and resistant cancer cell lines. All the molecules were designed on the basis of hydrogen bond acceptors, carbonyl, fluoro groups with precise spatial separation and structural features of lipophilicity, positive charge at neutral pH and presence of aromatic rings. The in vitro cytotoxic effects in comparison with reference drugs doxorubicin (DX) and C(1311) against cancer cell lines SW 1573, SW 1573 2R 160 (Pg-P expressing) which are non-small cell lung cancer cells, human embryo kidney cells HEK 293, HEK 293 MRP4, HEK 293 MRP5i, human promyelocytic leukemia sensitive cell line HL-60, including its multidrug cross-resistant of two main (P-gp and MRP) phenotype sublines vincristine resistant HL-60/VINC and doxorubicin resistant HL-60/DX cancer cell lines are presented.

Synthesis of 2-fluoro N(10)-substituted acridones and their cytotoxicity studies in sensitive and resistant cancer cell lines and their DNA intercalation studies.

A series of 2-fluoro N(10)-substituted acridone derivatives with varying alkyl side chain length with propyl, butyl substitution, and a tertiary amine group at the terminal end of the alkyl side chain were synthesized and screened against cancer cell lines SW 1573, SW 1573 2R 160 (P-gp substrate) which are non-small lung cancer cell lines, MCF-7, MCF-7/MR (BCRP substrate) are breast cancer cell lines, 2008 WT, 2008MRP1, 2008MRP2, 2008MRP3 are ovarian cancer cell lines, and human embryo kidney cell lines like HEK293, HEK293 MRP4, and HEK293 MRP5i. The propyl-series compounds showed lipophilicity in the range of 1.93 to 4.

Design of new drug molecules to be used in reversing multidrug resistance in cancer cells.

Over the past two decades, a number of chemical entities have been investigated in the continuing quest to reverse P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in cancer cells and some have undergone clinical trials, but currently none are in clinical use. Unfortunately, most of these agents suffer clinically from their intrinsic toxicity or from undesired effects on the pharmacokinetics of the accompanying anti-cancer drugs. An acridonecarboxamide (GF120918), Imidazo acridone (C(1311)) and timethylene acridone derivative 1,3-bis(9-oxoacridin-10-yl)-propane (PBA) have already been shown to be among the group of compounds known to modify P-gp mediated MDR in cancer.

Synthesis of 2-methyl N10-substituted acridones as selective inhibitors of multidrug resistance (MDR) associated protein in cancer cells.

A series of N10-substituted-2-methyl acridone derivatives are synthesized and are examined for its ability to reverse P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in breast cancer cell lines MCF-7 and MCF-7/Adr. The structural requirement of in-vitro anti-cancer and reversal of drug resistance are studied. The results showed that compound 16 with four carbon spacer exhibited promising in-vitro anti-cancer and reversal of drug resistance in comparison to the other analogues.

Chloro acridone derivatives as cytotoxic agents active on multidrug-resistant cell lines and their duplex DNA complex studies by electrospray ionization mass spectrometry.

We report herein in vitro anti-proliferative activity and duplex DNA complex studies of a series of N10-substituted acridone derivatives. All the molecules have been designed on the basis of the presence of specific recognition patterns consisting of hydrogen bond acceptors (or electron donors), carbonyl, chloro groups with precise spatial separation and structural features (lipophilicity, positive charge at neutral pH and presence of aromatic rings). The in vitro cytotoxic effects have been demonstrated against human promyelocytic leukemia sensitive cell line (HL-60), including its multidrug cross-resistance of two main (P-gp and MRP) phenotype sublines vincristine-resistant (HL-60/VINC) and doxorubicin-resistant (HL-60/DX) cancer cell lines.

Targeting calmodulin in reversing multi drug resistance in cancer cells.

Calmodulin is a Ca2+ binding protein found in many eukaryotic cells. It is one of the most important intracellular mediators of Ca2+-dependant signaling in eukaryotic cells. It regulates diverse processes including mitosis, muscle contraction and nucleotide metabolism by modulating the activity of at least 30 different target enzymes in a calcium-dependant manner.

Sensitization of multidrug resistant (MDR) cancer cells to vinblastine by novel acridones: correlation between anti-calmodulin activity and anti-MDR activity.

Multidrug resistance (MDR) of cancer cells remains to be an important cause of chemotherapy failure. Search for the new MDR reversal agents is still an unceasing challenge for the scientists. In an attempt to find clinically useful modulators of MDR, a series of 19 N(10)-substituted-2-bromoacridones has been synthesized.