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Background: Search for new antiviral and anticancer agents are essential because of the emergence of drug resistance in recent years. In continuation of our efforts in identifying the new small molecule antiviral and anticancer agents, we identified chalcones as potent antiviral and anticancer agents., Objective: With the aim of identifying the broad acting antiviral and anticancer agents, we discovered substituted aryl/heteroaryl derived thienyl chalcones as antiviral and anticancer agents., Method: A focused set of thienyl chalcone derivaties II-VI was screened for selected viruses Hepatitis B virus (HBV), Herpes simplex virus 1 (HSV-1), Human cytomegalovirus (HCMV), Dengue virus 2 (DENV2), Influenza A (H1N1) virus, MERS coronavirus, Poliovirus 1 (PV 1), Rift Valley fever (RVF), Tacaribe virus (TCRV), Venezuelan equine encephalitis virus (VEE) and Zika virus (ZIKV) using the National Institute of Allergy and Infectious Diseases (NIAID)'s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. Additionally, a cyclopropylquinoline derivative IV has been screened for 60 human cancer cell lines using the Development Therapeutics Program (DTP) of NCI., Results: All thienyl chalcone derivatives II-VI displayed moderate to excellent antiviral activity towards several viruses tested. Compounds V and VI were turned out be active compounds towards human cytomegalovirus for both normal strain (AD169) as well as resistant isolate (GDGr K17). Particularly, cyano derivative V showed very high potency (EC50: <0.05 µM) towards AD169 strain of HCMV compared to standard drug Ganciclovir (EC50: 0.12 µM). Additionally, it showed moderate activity in the secondary assay (AD169; EC50: 2.30 µM). The cyclopropylquinoline derivative IV displayed high potency towards Rift Valley fever virus (RVFV) and Tacaribe virus (TCRV) towards Rift Valley fever virus (RVFV). The cyclopropylquinoline derivative IV is nearly 28 times more potent in our initial in vitro visual assay (EC50: 0.39 µg/ml) and nearly 17 times more potent in neutral red assay (EC50: 0.71 μg/ml) compared to the standard drug Ribavirin (EC50: 11 µg/ml; visual assay and EC50: 12 µg/ml; neutral red assay). It is nearly 12 times more potent in our initial in vitro visual assay (EC50: >1 µg/ml) and nearly 8 times more potent in neutral red assay (EC50: >1.3 µg/ml) compared to the standard drug Ribavirin (EC50: 12 µg/ml; visual assay and EC50: 9.9 µg/ml; neutral red assay) towards Tacaribe virus (TCRV). Additionally, cyclopropylquinoline derivative IV has shown strong growth inhibitory activity towards three major cancers (colon, breast, and leukemia) cell lines and moderate growth inhibition shown towards other cancer cell lines screened., Conclusion: Compounds V and VI were demonstrated viral inhibition towards Human cytomegalovirus, whereas cyclopropylquinoline derivative IV towards Rift Valley fever virus and Tacaribe virus. Additionally, cyclopropylquinoline derivative IV has displayed very good cytotoxicity against colon, breast and leukemia cell lines in vitro., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Indanone is one of the privileged structures in medicinal chemistry and it's commonly associated with various pharmacologically active compounds. The indanone moiety is found in several natural compounds and also, it can be used as intermediate in the synthesis of many different types of medicinally important molecules. Among the medicinally important indanones, the most significant drug probably is donepezil (IV), an acetylcholinesterase (AChE) inhibitor, which has been approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Along with donepezil, the indanone moiety can be seen in a number of other pre-clinical and clinical candidates which belong to different categories with diverse therapeutic activities. In summary, the present review article encompasses the recent biological applications such as antialzheimer, anticancer, antimicrobial and antiviral activity of various indanone derivatives., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative ( V ) as an initial hit from a similarity search using four known V-ATPase inhibitors ( I - IV ). Based on the initial hit ( V ), we designed and synthesized a focused set of novel bisbenzimidazole analogs ( 2a - e ). All newly prepared compounds have been screened for selected human breast cancer (MDA-MB-468, MDA-MB-231, and MCF7) and ovarian cancer (A2780, Cis-A2780, and PA-1) cell lines, along with the normal breast epithelial cell line, MCF10A. The bisbenzimidazole derivative ( 2e ) is active against all cell lines tested. Remarkably, it demonstrated high cytotoxicity against the triple-negative breast cancer (TNBC) cell line, MDA-MB-468 (IC 50 = 0.04 ± 0.02 μM). Additionally, it has been shown to inhibit the V-ATPase pump that is mainly responsible for acidification. To the best of our knowledge the bisbenzimidazole pharmacophore has been identified as the first V-ATPase inhibitor in its class. These results strongly suggest that the compound 2e could be further developed as a potential anticancer V-ATPase inhibitor for breast cancer treatment., Competing Interests: The authors declare no conflict of interest.

Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults. GBM tumors are also notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR at different levels were used. Simultaneous knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment also markedly reduced the expression of programmed death-ligand 1 (PD-L1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused deactivation of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which may suppress the activity of key cellular kinases. Inhibition of either target was associated with downregulation of the other target as well, which may underlie the increased efficacy of the dual nanobioconjugate that is directed against both CK2 and EGFR. Importantly, the single nanodrugs, and especially the dual nanodrug, markedly suppressed the expression of the cancer stem cell markers c-Myc, CD133, and nestin, which could contribute to the efficacy of the treatments. In both tumor models, the nanobioconjugates significantly increased (up to 2-fold) animal survival compared with the PBS-treated control group. The versatile nanobioconjugates developed in this study, with the abilities of anti-cancer drug delivery across biobarriers and the inhibition of key tumor regulators, offer a promising nanotherapeutic approach to treat GBMs, and to potentially prevent drug resistance and retard the recurrence of brain tumors., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Discovery of new indole-based tubulin polymerization inhibitors will continue to dominate the synthetic efforts of many medicinal chemists working in the field. The indole ring system is an essential part of several tubulin inhibitors identified in the recent years. The present review article will update the synthesis, anticancer and tubulin inhibition activities of several important new indole classes such as 2-phenylindoles (28, 29 & 30), oxindoles (35 & 38), indole-3-acrylamides (44), indolines (46), aroylindoles (49), carbozoles (75, 76 & 82), azacarbolines (87) and annulated indoles (100-105).

Cancer remains one of the unsolved diseases of today's advanced drug discovery world even though it is known to humans for centuries. There is continued effort to discover new chemotherapeutic agents to improve the outcome of cancer patients. Small-molecule agonists at tolllike receptor 7 and 8 (TLR7/8) have recently generated renewed interest in cancer research owing to their profound antitumoral activity. TLR-7/8 agonist imidazoquinolines (Imiquimod, and Resiquimod) and dual inhibitor of phosphoinositide 3-kinase and mammalian target of rapamycin (NVP-BEZ235) have emerged as clinically important candidates for treating cancers. This article reviews briefly the synthesis, structure-activity relationship (SAR) and biological activities of clinically studied imidazoquinolines along with novel emerging preclinical imidazoquinolines for the anticancer activity.

Chromenes constitute chemically important class of heterocyclic compounds having diverse biological and chemical importance. Development of environmentally benign, efficient and economical methods for the synthesis of chromenes remains a significant challenge in synthetic chemistry. The synthesis of chromenes, therefore, has attracted enormous attention from medicinal and organic chemists. Researchers have embraced the concepts of microwave (high speed) synthesis to produce biologically and chemically important chromenes in a time sensitive manner. This review will summarize the recent biological applications such as anticancer, antimicrobial, neurodegenerative and insecticidal activity of new chromenes prepared via microwave irradiation. The development of new methodologies for the synthesis of chromenes including green chemistry processes has also been discussed.

The search for newer cytotoxic agents has taken many paths in the recent years and in fact some of these efforts led to the discovery of some potent cytotoxic agents. Though the vast number of targets of tumor progression has been identified recently, kinases remained key targets in drug design. It is well established that inhibition of JNK1, a serine/threonine protein kinase delays tumor formation. Poly hydroxylated chromenone analog, quescetagetin, inhibits JNK1. As a part of design of coumarin based JNK1 inhibitors, docking studies and 4D QSAR studies were carried out. 3- pyrazolyl substituted coumarin derivatives were chosen for these studies. Docking studies revealed that 3-pyrazolyl substituted coumarins make key interactions with residues at active site of JNK1. In order to investigate the structural features required in these inhibitors, 4D QSAR studies using LQTAgrid module were carried out. The 4D QSAR model built with PLS regression on the matrix of variables specific for interaction energies at each grid point around the molecular dynamics generated conformations of individual compounds shows good predictive abilities. The squared correlation coefficient, R(2) for the model is 0.785, R(2) cross-validated (Q(2)) is 0.698, R(2) predicted is 0.701. Most of the descriptors contributing to 4D QSAR model are Coulombic potential energy based descriptors which highlight the importance of specific atoms in coumarin derivatives in generating these electrostatic potential at specific grid points with the -NH3 probe. We rationalize that solvent accessible van der Waals surface area around such compounds is good measure of this Coulombic potential energy and can be exploited in designing more active compounds.

Late transition metal complexes that bear N-heterocyclic carbene (NHC) ligands have seen a speedy growth in their use as both, metal-based drug candidates and potentially active homogeneous catalysts in a plethora of C-C and C-N bond forming reactions. This review article focuses on the recent developments and advances in preparation and characterization of NHC-metal complexes (metal: silver, gold, copper, palladium, nickel and ruthenium) and their biomedical applications. Their design, syntheses and characterization have been reviewed and correlated to their antimicrobial and anticancer efficacies. All these initial discoveries help validate the great potential of NHC-metal derivatives as a class of effective antimicrobial and anticancer agents.

Glioblastoma Multiforme (GBM) continues to demand improved chemotherapeutic solutions. In order to discover novel chemotherapeutic agents for GBM, we identified novel tetrahydroisoquinoline (THI) analogs as antiglioma agents. The present study reports the design, synthesis and in vitro evaluation of new THI derivatives in four established human glioma cell lines (T98, U87, LN18 and A172). Our structure activity relationship (SAR) studies revealed that the important modification of the carbon linker between the biphenyl and THI ring yielded EDL-360 (12) as a potent antiglioma agent (LN18; IC50: 5.42 ± 0.06 μM) and is considered to be our new lead drug candidate for further preclinical studies.

Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient's treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-L-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconjugate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin™ family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future.

To further develop therapeutic strategies targeting the proteasome system, we studied the antitumor activity and mechanisms of action of MLN2238, a reversible proteasome inhibitor, in preclinical lymphoma models. Experiments were conducted in rituximab-chemotherapy-sensitive cell lines, rituximab-chemotherapy-resistant cell lines (RRCL), and primary B-cell lymphoma cells. Cells were exposed to MLN2238 or caspase-dependent inhibitors, and differences in cell viability, alterations in apoptotic protein levels, effects on cell cycle, and the possibility of synergy when combined with chemotherapeutic agents were evaluated. MLN2238 showed more potent dose-dependent and time-dependent cytotoxicity and inhibition of cell proliferation in lymphoma cells than bortezomib. Our data suggest that MLN2238 can induce caspase-independent cell death in RRCL. MLN2238 (and to a much lesser degree bortezomib) reduced RRCL S phase and induced cell cycle arrest in the G2/M phase. Exposure of rituximab-chemotherapy-sensitive cell lines and RRCL to MLN2238 potentiated the cytotoxic effects of gemcitabine, doxorubicin, and paclitaxel and overcame resistance to chemotherapy in RRCL. MLN2238 is a potent proteasome inhibitor active in rituximab-chemotherapy-sensitive and rituximab-chemotherapy-resistant cell models and potentiates the antitumor activity of chemotherapy agents and has the potential of becoming an effective therapeutic agent in the treatment of therapy-resistant B-cell lymphoma.

Introduction: Gliomas are considered the most malignant form of brain tumors, and ranked among the most aggressive human cancers. Despite advance standard therapy the prognosis for patients with gliomas remains poor. Chemotherapy has played an important role as an adjuvant in treating gliomas. The efficacy of the chemotherapeutic drug is limited due to poor drug delivery and the inherent chemo- and radio-resistance. Challenges of the brain cancer therapy in clinical settings are; i) to overcome the chemo- and radio-resistance, ii) to improve drug delivery to tumors and iii) the development of effective drug screening procedures., Areas Covered: In this review, the authors discuss clinically important chemotherapeutic agents used for treating malignant gliomas along with novel drug design approaches. The authors, furthermore, discuss the in vitro and in vivo drug screening procedures for the development of novel drug candidates., Expert Opinion: The development of novel and highly potent chemotherapeutic agents for both glioma and glioma stem cells (GSCs) is highly important for future brain cancer research. Thus, research efforts should be directed towards developing innovative molecularly targeted antiglioma agents in order to reduce the toxicity and drug resistance which are associated with current forms of therapy. Development of novel pre-clinical drug screening procedures is also very critical for the overall success of brain cancer therapies in clinical settings.

Autotaxin (ATX), a lysophospholipase D, plays an important role in cancer invasion, metastasis, tumor progression, tumorigenesis, neuropathic pain, fibrotic diseases, cholestatic pruritus, lymphocyte homing, and thrombotic diseases by producing the lipid mediator lysophosphatidic acid (LPA). A high-throughput screen of ATX inhibition using the lysophosphatidylcholine-like substrate fluorogenic substrate 3 (FS-3) and ∼10,000 compounds from the University of Cincinnati Drug Discovery Center identified several small-molecule inhibitors with IC₅₀ vales ranging from nanomolar to low micromolar. The pharmacology of the three most potent compounds: 918013 (1; 2,4-dichloro-N-(3-fluorophenyl)-5-(4-morpholinylsulfonyl) benzamide), 931126 (2; 4-oxo-4-{2-[(5-phenoxy-1H-indol-2-yl)carbonyl]hydrazino}-N-(4-phenylbutan-2-yl)butanamide), and 966791 (3; N-(2,6-dimethylphenyl)-2-[N-(2-furylmethyl)(4-(1,2,3,4-tetraazolyl)phenyl)carbonylamino]-2-(4-hydroxy-3-methoxyphenyl) acetamide), were further characterized in enzyme, cellular, and whole animal models. Compounds 1 and 2 were competitive inhibitors of ATX-mediated hydrolysis of the lysophospholipase substrate FS-3. In contrast, compound 3 was a competitive inhibitor of both FS-3 and the phosphodiesterase substrate p-nitrophenyl thymidine 5'-monophosphate. Computational docking and mutagenesis suggested that compounds 1 and 2 target the hydrophobic pocket, thereby blocking access to the active site of ATX. The potencies of compounds 1-3 were comparable to each other in each of the assays. All of these compounds significantly reduced invasion of A2058 human melanoma cells in vitro and the colonization of lung metastases by B16-F10 murine melanoma cells in C57BL/6 mice. The compounds had no agonist or antagonist effects on select LPA or sphingosine 1-phosphate receptors, nor did they inhibit nucleotide pyrophosphatase/phosphodiesterase (NPP) enzymes NPP6 and NPP7. These results identify the molecular surface of the hydrophobic pocket of ATX as a target-binding site for inhibitors of enzymatic activity.

Cancer is a major devastating disease, and is a leading cause of death worldwide. Despite the progress in cancer treatment, cancer mortality rate remains high. Therefore, the discovery and development of improved anticancer drugs to treat cancer are needed. 4H-chromenes have strong cytotoxicity against a panel of human cancer cell lines involving pathways that include microtubule depolarization and tumor vasculature disruption. A chromene analog, Crolibulin™ (EPC2407) is currently in Phase I/II clinical trials for the treatment of advanced solid tumors. This article reviews the general synthesis, biological activities and structure-activity relatinships of different classes of chromenes.

Agents that interfere with tubulin function have a broad anti-tumor spectrum and they represent one of the most significant classes of anticancer agents. In the past few years, several small synthetic molecules that have an indole nucleus as a core structure have been identified as tubulin inhibitors. Among these, several aroylindoles, arylthioindoles, diarylindoles and indolylglyoxyamides have shown good inhibition towards the tubulin polymerization. This article reviews the synthesis, biological activities and SARs of these main classes of indoles. Brief mention has also been made about the fused indole analogs as tubulin inhibitors.

Purpose: Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer., Methods: CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined., Results: CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells, IC(50) for CBDIV17 was ≈ 12 μM and ≈ 21 μM in LNCaP and C4-2 cells, respectively, whereas bicalutamide had IC(50) of ≈ 46 μM in LNCaP cells and minimal effect in C4-2 cells. CBDIV17 induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser(81). These hydrophobic drugs were solubilized using micelles prepared with polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-LA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo., Conclusions: Our results demonstrated that CBDIV17 in combination with embelin can potentially treat advanced prostate cancer.

As a continuation of our efforts to discover and develop small molecules as anticancer agents, we identified GRI-394837 as an initial hit from similarity search on RGD and its analogs. Based on GRI-394837, we designed and synthesized a focused set of novel chromenes (4a-e) in a single step using microwave method. All five compounds showed activity in the nanomolar range (IC(50): 7.4-640 nM) in two melanoma, three prostate and four glioma cancer cell lines. The chromene 4e is active against all the cell lines and particularly against the A172 human glioma cell line (IC(50): 7.4 nM). Interestingly, in vitro tubulin polymerization assay shows 4e to be a weak tubulin polymerization inhibitor but it shows very strong cytotoxicity in cellular assays, therefore there must be additional unknown mechanism(s) for the anticancer activity. Additionally, the strong antiproliferative activity was verified by one of the selected chromene (4a) by the NCI 60 cell line screen. These results strongly suggest that the novel chromenes could be further developed as a potential therapeutic agent for a variety of aggressive cancers., (Copyright © 2012. Published by Elsevier Ltd.)

To investigate the effectiveness of EDL-291, a 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-1,2,3,4-tetrahydroisoquinoline dihydrochloride compound, in inhibiting the survival of glioblastoma in vitro and in vivo. Dose-response curves were generated to determine the EC50 in rat and human glioblastoma cell lines by treatment with different dilutions of EDL-291. To evaluate the architecture of the glioblastoma cells after treatment with EDL-291, the rat and human glioblastoma cells were stained with Mito Tracker Green FM. To determine whether autophagy was induced in EDL-291-treated glioblastoma cells, both rat and human glioblastoma cell lines were stained with acridine orange and light chain-3 immunoblots were performed. The efficacy of EDL-291 was monitored in vivo using a rat glioblastoma model. Rat glioblastoma cells were transplanted into an intracranial rat model, followed by infusions of saline, a low dose of EDL-291 (20 mg/kg for the first half hour, followed by 40 mg/kg EDL-291 in saline for 4 h), or a high dose of EDL-291 (60 mg/kg for the first half hour, followed by 90 mg/kg EDL-291 for 4 h). EDL-291 inhibits glioblastoma in vitro by destroying the mitochondria as shown with Mito Tracker Green FM. Acridine orange staining and light chain-3 immunoblots suggest that autophagy is induced when glioblastoma cells are treated with EDL-291. In vivo, a low dosage of EDL-291 is sufficient and effective in reducing glioblastoma tumor size. EDL-291 selectively induces cell death in rat and human glioblastoma cell lines by the induction of autophagy. EDL-291 exhibits antiglioblastoma effects both in vitro and in vivo.

PMLA nanoparticles with diameters of 150-250 nm are prepared, and their hydrolytic degradation is studied under physiological conditions. Degradation occurs by hydrolysis of the side chain methyl ester followed by cleavage of the main-chain ester group with methanol and L-malic acid as the final degradation products. No alteration of the cell viability is found after 1 h of incubation, but toxicity increases significantly after 3 d, probably due to the noxious effect of the released methanol. Anticancer drugs temozolomide and doxorubicin are encapsulated in the NPs with 20-40% efficiency, and their release is monitored using in vitro essays. Temozolomide is fully liberated within several hours, whereas doxorubicin is steadily released from the particles over a period of 1 month., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D activity, which leads to generation of the growth-factor-like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy-resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4-tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4-substituted benzylphosphonic acid and 6-substituted naphthalen-2-ylmethylphosphonic acid analogues block ATX activity with K(i) values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed-mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30 b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose-dependent manner. The average terminal half-life for compound 22 is 10±5.4 h and it causes a long-lasting decrease in plasma LPA levels. Compounds 22 and 30 b significantly decrease lung metastasis of B16-F10 syngeneic mouse melanoma in a post-inoculation treatment paradigm. The 4-substituted benzylphosphonic acids and 6-substituted naphthalen-2-ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX-LPA-LPAR axis both in vitro and in vivo., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1-100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law-healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: Temozolomide (TMZ) is a pro-drug releasing a DNA alkylating agent that is the most effective drug to treat glial tumors when combined with radiation. TMZ is toxic, and therapeutic dosages are limited by severe side effects. Targeted delivery is thus needed to improve efficiency and reduce non-tumor tissue toxicity., Methods: Multifunctional targetable nanoconjugates of TMZ hydrazide were synthesized using poly(β-L-malic acid) platform, which contained a targeting monoclonal antibody to transferrin receptor (TfR), trileucine (LLL), for pH-dependent endosomal membrane disruption, and PEG for protection., Results: The water-soluble TMZ nanoconjugates had hydrodynamic diameters in the range of 6.5 to 14.8 nm and ζ potentials in the range of -6.3 to -17.7 mV. Fifty percent degradation in human plasma was observed in 40 h at 37°C. TMZ conjugated with polymer had a half-life of 5-7 h, compared with 1.8 h for free TMZ. The strongest reduction of human brain and breast cancer cell viability was obtained by versions of TMZ nanoconjugates containing LLL and anti-TfR antibody. TMZ-resistant cancer cell lines were sensitive to TMZ nanoconjugate treatment., Conclusions: TMZ-polymer nanoconjugates entered the tumor cells by receptor-mediated endocytosis, effectively reduced cancer cell viability, and can potentially be used for targeted tumor treatment.

PURPOSE. To investigate the effectiveness of a novel isoquinoline derivative, EDL-155, in killing retinoblastoma in vitro and in vivo. METHODS. Dose-response curves were generated in which Y79 retinoblastoma cells tagged with luciferase (Y79-Luc) were treated with serial concentrations of EDL-155. Electron microscopy was used to evaluate the ultrastructural morphology of EDL-155-treated Y79 cells. To determine whether autophagy was induced in EDL-155-treated Y79-Luc cells, staining with acridine orange and LC-3 immunoblot analysis was performed. To evaluate the efficacy of EDL-155 in vivo, Y79-Luc retinoblastoma cells were injected into the vitreous cavity of newborn rats, followed by periocular injections of EDL-155 (20 mg/kg/day) or an equivalent dosage of saline. RESULTS. EDL-155 appeared to destroy the retinoblastoma cells in vitro with an EC(50) of 9.1 micriM. EDL-155-treated retinoblastoma cells displayed a lack of viable mitochondria and the presence of autophagosomes wrapped in the characteristic double membranes. Acridine orange staining of EDL-155-treated retinoblastoma cells demonstrated the accumulation of vacuoles, and the immunoblots displayed a shift in molecular weight of LC-3, indicative of incorporation into autophagosome vesicles. In the retinoblastoma animal model, four doses of EDL-155 were delivered over 4 days, which was sufficient to see a significant decrease (P = 0.01) in viable intraocular tumors. Seven of the 25 rats treated with EDL-155 had no detectable living tumor. No significant decrease in viable tumor was observed in control animals. CONCLUSIONS. EDL-155 appears to eliminate retinoblastoma cells by disrupting mitochondria and inducing autophagy. Local delivery of EDL-155 may be an effective therapy for some types of ocular cancers.

Our group has used the tetrahydroisoquinoline derivative EDL-155 to treat glioblastoma in animal models and it is currently being evaluated in the treatment of ocular cancers. The purpose of this study was to develop a rapid and sensitive liquid chromatography and tandem mass spectrometry (LC-MS/MS) method to study the plasma and vitreous humor disposition of EDL-155 in rats. Animals received a single periocular injection of EDL-155 (20 mg/kg). Animals were sacrificed at specified times (5, 60, 120, 240 and 360 min) and plasma and vitreous humor samples were obtained. EDL-155 was isolated by protein precipitation and the extracts were analyzed by reversed-phase high-pressure liquid chromatography (HPLC) with MS/MS detection. A structurally similar analog was used as internal standard (IS). The chromatographic run time was 3.5 min per injection. The mass spectrometer was operated in positive-ion, multiple reaction monitoring (MRM) mode. The mass transitions monitored were m/z332.2 --> 167.2 (EDL-155) and m/z391.2 --> 200.2 (IS). The lower limit of quantification (LLOQ) was 0.1 ng/ml in both vitreous humor and plasma. The method was validated for selectivity, linearity, accuracy and precision in rat vitreous humor and partially validated for accuracy and precision in rat plasma. The ion suppression, recovery and stability of the analyte in the biological matrix were also tested. The assay was rapid, sensitive and robust enough to support EDL-155 ocular penetration studies in a rodent model of intraocular cancer. Application of this method revealed that EDL-155 was rapidly passed into the vitreous humor following periocular administration. Further, vitreous humor exposure exceeded systemic exposure by approximately sevenfold. High local concentrations coupled with minimal systemic exposure supports further testing of EDL-155 as localized therapy for intraocular cancers., (2009 John Wiley & Sons, Ltd.)

The effects of 1-(biphenyl-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol (EDL-155) on the growth of glioma was tested in vitro and in vivo. Normal cultured rat astrocytes and C6 rat glioma were used as a differential screen to test the effects of EDL-155. The compound was preferentially cytotoxic for C6 glioma (EC50=1.5 micromol/l) relative to cultured neonatal astrocytes (EC50=27.4 micromol/l). When compared with a standard chemotherapeutic agent, carmustine (1,3-bis[2-chloroethyl]-1-nitrosourea), or temozolomide, EDL-155 was more selective and more potent in our differential tissue culture assay. The effect of EDL-155 was also tested in an animal model in which C6 glioma was transplanted into the brains of Sprague-Dawley rats. EDL-155 was delivered directly onto the tumor by an osmotic minipump directly into the brain or by intraperitoneal injection. Animals treated with EDL-155 had significantly smaller tumors than did control animals treated with carrier solution. We observed anatomical changes in cultured glioma cells treated with EDL-155 that were consistent with selective destruction of mitochondria and the induction of autophagy. These changes were not observed in normal astrocytes cultured from rat pups. The selective killing of glioma in tissue culture and in the rat brain models indicates that EDL-155 has potential therapeutic value in treating this type of brain cancer.

Purpose: Tetrahydroisoquinolines (THIs) have demonstrated anti-cancer activity in rodent models of glioma, a form of brain cancer refractory to therapeutic intervention. In this study, peripheral and cerebrospinal fluid (CSF) pharmacokinetics in rats were determined to assess the drug developability of the novel THI EDL-155 for the treatment of glioma., Methods: Serial blood and CSF samples were collected from rats following intravenous bolus administration of EDL-155 (10-20 mg/kg). Samples were analyzed by LC/MS/MS. Pharmacokinetic analyses using compartmental and noncompartmental methods were performed using the computer program WinNonlin. Plasma protein binding was measured using the charcoal adsorption method. The in vivo efficacy of EDL-155 (i.p. 20 mg/kg twice daily for 7 days) was assessed in rats with stereotactically implanted C6 glioma cells into the caudate., Results: EDL-155 plasma concentration data were described by a one-compartment model. EDL-155 demonstrated rapid clearance (342.5+/-49.9 ml/min/kg), high volume of distribution (13.0+/-1.2 l/kg) and a terminal half-life of 23.7+/-1.5 min. Dose-normalized CSF area under the curve (AUC(CSF)) as a percentage of peripheral exposure (AUC(Plasma)) was 1.4%. EDL-155 was highly bound to plasma proteins (>93%). Intracranial tumor volume at 7 days post-implantation was approximately 30% smaller in animals treated with EDL-155 when compared to vehicle control animals (13.2+/-5.3 mm(3) vs. 18.7+/-6.3 mm(3); P=0.04)., Conclusion: High clearance and extensive protein binding limit the brain availability of EDL-155 following systemic administration. EDL-155 treatment resulted in reduced tumor size despite limited blood brain barrier penetrability, which suggests that analogs with increased metabolic stability and brain penetrability may provide a therapeutic option for primary central nervous system tumors such as glioma. On-going studies are focused on the design, synthesis, and testing of novel analogs based upon these findings.

Cultured rat astrocytes and C6 rat glioma were used as a differential screen for a variety of 1,2,3,4-tetrahydroisoquinoline (THI) derivatives. Compound 1 [1-(biphenyl-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydrochloride] selectively blocked the growth of C6 glioma leaving normal astrocytes relatively unaffected. The potential for clinical utility of 1 was further substantiated in human gliomas and other tumor cell lines. Preliminary SAR of this activity was characterized by synthesis and testing of several THI and conformationally flexible variants.

The aim of this study was to screen the in vitro antimicrobial, antioxidant and cytotoxicity effect of Curkolin®, a combination of curcumin and C. forskolin in the ratio 4:1. Curcuma longa L. is the source of curcumin while C. forskohlii has been used in traditional ayurvedic medicine for curing various disorders and therefore the forskolin is the source of the diterpenoids. The medicinal properties of plants are investigated throughout the world for scientific advancement for their important pharmacological activities, user convenient, economically viable with low toxicity. The antioxidant property of Curkolin® was determined to be 55.42 µg/ml using (Diphenyl picryl hydrazine) DPPH assay and was then compared with standard Butylated hydroxytoluene (BHT). The antimicrobial activity was assessed by calculating the MIC and MBC using microplate serial dilution technique. It exhibited 250 µg/ml, the least MIC value of Bacillus cereus as compared to the rest Gram-positive (Streptococcus mutans and Staphylococcus aureus) and Gram-negative (Escherichia coli and Salmonella typhi) bacteria. Further, it was analyzed for cytotoxic screening on MCF-7 breast cancer cell line by MTT assay, which has shown a strong anti-proliferative activity. The IC50 values of Curkolin® were found 135.8 μg/ml. Together these results suggest the combination to be an effective antioxidant, antimicrobial and cytotoxic agent. [ABSTRACT FROM AUTHOR]

Melphalan dimer is an impurity from the synthesis of Melphalan (M216900) which is an antineoplastic agent. In this article, a new route for the synthesis of Melphalan dimer impurity G has been discussed. The new research provides the first high-yield, high-purity synthesis of this impurity. The impurity has been confirmed for purity using HPLC, and its structure has been identified using MS, ¹H and 13C NMR. [ABSTRACT FROM AUTHOR]

Background Hormone and Growth Factor Receptors (HR) such as ER, PR, HER2 and AR are involved in the pathogenesis of various cancers and are commonly targeted in treatment regimens. HR antagonists Standard of Care (SoC) are often administered as monotherapy or as combinations with selected cytotoxic or targeted agents. In the SHIVA trial, monotherapy with HR antagonists based on molecular profiling was reported with dismal outcomes. We hypothesized that Encyclopedic Tumor Analysis (ETA)-informed novel combinations of HR and synergistic cytotoxic or targeted agents could be efficacious in multiple cancers. Methods Molecular Profiling (MP) of patients' fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify molecular targets of approved anticancer agents in a label-agnostic manner. Immunohistochemistry (IHC) identified hormone receptors (HR) that could be targeted with endocrine agents. Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified functional vulnerabilities of the tumor against a panel of systemic anticancer agents. Molecular indications linked to ER, PR, HER2 and AR as well as IHC findings were linked to selection of HR antagonists. Synergistic integration of MP, IHC and CRR data (i.e. ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scans to determine treatment response. Results 37 patients underwent ETA from the study sponsor and received ETA-guided combination treatments of HR antagonists with other agents. PR was seen in 17 patients (ORR = 45.9%). 32 patients showed PR or SD at most recent follow-up (DCR = 86.5%) and progression was seen in 5 patients. Median PFS was 147 days (range 31 to 410). No significant therapy related adverse events were observed in any of these patients. Most patients reported stable to improved Quality of Life (QoL). Conclusions ETA-guided combination treatment regimens with HR antagonists offer a viable and efficient strategy in advanced refractory malignancies and outperform monotherapy options. Legal entity responsible for the study The Authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. S. Schuster: Full / Part-time employment: Datar Cancer Genetics Limited. C. Sims: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Though mTOR inhibition is considered an attractive strategy for cancer management, anti-mTOR monotherapies have not shown meaningful benefits. We hypothesized that an Encyclopedic Tumor Analysis (ETA) can identify vulnerabilities in the tumor in addition to mTOR activation. We further hypothesized that tandem synergistic targeting of these vulnerabilities using combination of mTOR inhibitors and other systemic anticancer agents in a label- and organ-agnostic manner can improve outcomes in refractory solid organ cancers as compared to mTOR inhibition monotherapy alone. Methods Molecular Profiling (MP) of patients' fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify druggable molecular targets in a label-agnostic manner. Immunohistochemistry (IHC) identified targetable hormone receptors (HR). Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified vulnerabilities of the tumor against a panel of systemic anticancer agents. Molecular indications linked to PIK3CA, mTOR, PTEN or TP53 genes were used for selection of mTOR inhibitors. Synergistic integration of MP, IHC and CRR datasets (i.e. ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scan to determine treatment response. Results Among 41 patients who received combination treatments, 23 patients showed PR (ORR = 56.1%), 16 showed SD (DCR = 95.1%) and progression was observed in 2 patients. One patient who received monotherapy progressed at 27 days. Median PFS was 110 days (range 27 to 592). In the SHIVA trial where patients with mTOR activation (n = 46) received monotherapy with mTOR inhibitor, median PFS of 72 days (range 57 to 100) was reported. No significant therapy–related adverse events were reported in any patient. Most patients reported stable to improved Quality of Life (QoL). Conclusions ETA-guided combination regimens with mTOR inhibitors offer a viable and efficient strategy in advanced refractory malignancies and outperform mTOR inhibitor monotherapy. Legal entity responsible for the study The authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Ghaisas: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. H. Singh: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Refractory cancers pose formidable management challenges. We hypothesized that such malignancies have unexplored vulnerabilities that can be identified using Encyclopedic Tumor Analysis (ETA) and effectively targeted using conventional agents in a label- and organ-agnostic manner to yield treatment benefit. The pan-cancer RESILIENT trial addressed patients with advanced refractory malignancies who were treated with ETA guided treatments regimens without any restrictive eligibility criteria. Methods Molecular Profiling (MP) of patients' fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify molecular targets of approved anticancer agents in a label-agnostic manner. Immunohistochemistry (IHC) identified hormone receptors (HR) that could be targeted with endocrine agents. Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified functional vulnerabilities of the tumor against a panel of systemic anticancer agents. Synergistic integration of MP, IHC and CRR datasets (i.e. ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scans to determine treatment response as well as Objective Response Rate (ORR), Disease Control Rate (DCR) and Progression Free Survival (PFS). Results Among the 200 patients who were screened, 110 patients received ETA-guided treatments and were evaluable for response per protocol. PR was observed in 47 patients (ORR = 42.7%) and 99 patients continued to exhibit PR or SD at study termination (DCR = 90%). Median PFS was 125 days. Median PFS rate at 90 days was 94.0%. No significant therapy related adverse events (AEs) were noted – there were no grade IV AEs or treatment related deaths. Most patients reported stable to improved Quality of Life (QoL) in terms of disease-related symptoms and functional status. Conclusions ETA-guided treatments offer meaningful survival benefits and outperformed available alternatives including checkpoint inhibitors in this heavily pretreated pan-cancer population. Legal entity responsible for the study The authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Ghaisas: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. H. Singh: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Innate and acquired chemoresistance to anticancer therapies are a well-known phenomenon in Esophageal Squamous Cell Carcinomas (ESCC). There are presently no viable approaches for real-time monitoring of resistance in ESCC. We used a novel method for chemo-interrogation (CI) by harvesting sufficient number of Circulating-Tumor Associated Cells (C-TACs) which are defined as apoptosis-resistant cells of tumorigenic origin and are positive for Epithelial Cell Adhesion Molecule (EpCAM) and pan-cytokeratins (pan-CK) irrespective of CD45 status. Methods Peripheral blood was collected from 80 patients with confirmed diagnosis of ESCC, among whom 52 were recently diagnosed therapy-naïve, while 28 were pretreated patients. Peripheral blood mononuclear cells (PBMCs) were harvested by centrifugation and treated with commercially available stabilizing agents, by a proprietary protocol, to stabilize apoptosis resistant C-TACs. Surviving C-TACs were confirmed by immunostaining for EpCAM, pan-CK and CD45. Harvested C-TACs were treated in vitro with a panel of conventional cytotoxic anticancer agents and fraction of surviving cells were estimated to determine resistance profiles. Results Among the 52 cases of recently diagnosed therapy naïve ESCC, innate chemoresistance was observed towards platinum agents in 40.8% samples (unique patient-drug combinations), taxanes in 34.6% samples, topoisomerase inhibitors in 42.9% samples and antimetabolites in 34.6% samples. Among the 28 cases of previously treated ESCC, resistance towards previously administered systemic agents was observed in 87% of all samples, which included resistance towards platinum agents in 87.5% samples, taxanes in 82.1% samples, topoisomerase inhibitors in 100% samples and antimetabolites in 85.7% samples, respectively. Conclusions We show for the first time that sufficient C-TACs can be harvested for meaningful CI in newly diagnosed treatment naïve ESCC as well as refractory ESCCs. Post-treatment chemoresistance being an order of magnitude higher than the untreated cohort, indicates that C-TACs in ESCC are resistance-educated by previous treatments and can guide treatment strategy in ESCC. Legal entity responsible for the study The authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. S. Schuster: Full / Part-time employment: Datar Cancer Genetics Limited. C. Sims: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Khan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. V. Mhase: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]