Synthesis and characterization of a novel Naphthalimide-Selenium based Temozolomide drug conjugate in glioma cells.

Temozolomide (TMZ) is the frontline chemotherapeutic drug against glioblastoma. As chemoresistance is a severe limitation of TMZ therapy, we aimed to synthesize a novel drug to improve its efficacy. This was achieved by conjugating TMZ with Naphthalimide (known DNA intercalator) via selenourea linkage (redox regulator).

Prospects of nano-theranostic approaches against breast and cervical cancer.

The bottleneck on therapeutics and diagnostics is removed by an alternate approach known as theranostics which combines both therapeutics and diagnostics within a single platform. Due to this "all in one" nature of theranostics, it is now extensively applied in the medicinal field mainly in cancer treatment over the conventional therapy. Recently, FDA approval of lutetium 177 (177Lu) DOTATATE and 177Lu-PSMA-based radionuclide theranostics are clinically used and very few theranostics specific to breast cancer are in clinical trials.

Neem leaf glycoprotein binding to Dectin-1 receptors on dendritic cell induces type-1 immunity through CARD9 mediated intracellular signal to NFκB.

Background: A water-soluble ingredient of mature leaves of the tropical mahogany 'Neem' (Azadirachta indica), was identified as glycoprotein, thus being named as 'Neem Leaf Glycoprotein' (NLGP). This non-toxic leaf-component regressed cancerous murine tumors (melanoma, carcinoma, sarcoma) recurrently in different experimental circumstances by boosting prime antitumor immune attributes. Such antitumor immunomodulation, aid cytotoxic T cell (T)-based annihilation of tumor cells.

Engineered Artesunate-Naphthalimide Hybrid Dual Drug for Synergistic Multimodal Therapy against Experimental Murine Lymphoma.

Lymphoma can effectively be treated with a chemotherapy regimen that is associated with adverse side effects due to increasing drug resistance, so there is an emergent need for alternative small-molecule inhibitors to overcome the resistance that occurs in lymphoma management and overall increase the prognosis rate. A new series of substituted naphthalimide moieties conjugated via ester and amide linkages with artesunate were designed, synthesized, and characterized. In addition to the conjugates, to further achieve a theranostic molecule, FITC was incorporated via a multistep synthesis process.

Single Inhibitors versus Dual Inhibitors: Role of HDAC in Cancer.

Due to the multimodal character of cancer, inhibition of two targets simultaneously by a single molecule is a beneficial and effective approach against cancer. Histone deacetylase (HDAC) was widely investigated as a novel category of anticancer drug targets due to its crucial role in various biological processes like cell-proliferation, metastasis, and apoptosis. Numerous HDAC inhibitors such as vorinostat and panobinostat are clinically approved but have limited usage due to their low efficacy, nonselectivity, drug resistance, and toxicity.

γc cytokine-aided crosstalk between dendritic cells and natural killer cells together with doxorubicin induces a healer response in experimental lymphoma by downregulating FOXP3 and programmed cell death protein 1.

Background Aims: The stimulatory natural killer-dendritic cell axis in the tumor microenvironment could play a critical role in stimulating cytotoxic T cells and driving immune responses against cancer.

Methods: We established a novel treatment protocol by adroitly combining chemotherapy with doxorubicin and immunotherapy with dendritic cells and natural killer cells against a highly aggressive and malignant lymphoma called Dalton's lymphoma.

Results: Our data suggest that binary application of adoptive cell therapy and chemotherapy nearly cures (95%) early-stage experimental lymphoma.

Development of a PAMAM Dendrimer for Sustained Release of Temozolomide against Experimental Murine Lymphoma: Assessment of Therapeutic Efficacy.

Enhanced drug localization at the tumor sites with minimal toxicity was demonstrated using dendrimer-conjugated temozolomide for treating experimental lymphoma, developed as a solid tumor. Herein, we have constructed a polyamidoamine (PAMAM) dendrimer conjugated with temozolomide to enhance the stability of the active drug metabolites, derived from the prodrug temozolomide. Our results suggest that the active drug (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide) (MTIC) (derived from temozolomide) showed stable and sustained release from the dendrimer-temozolomide conjugate, suggesting the suitability of the construct for therapy.

A study of vegetable oil modified QCM sensor to detect β-pinene in Indian cardamom.

A quartz crystal microbalance (QCM) sensor was developed in this study with the vegetable oil from olive (OLV-QCM) to detect an important volatile organic compound, β-pinene in Indian cardamom. Hydrophobic vegetable oil from olive, which contains oleic acid and omega-9, a monounsaturated fatty acid was found to be suitable for binding β-pinene through non-covalent bonds. The fabricated QCM sensor coating was examined with the field emission scanning electron microscope (FESEM) and Fourier-transform infrared spectroscopy (FTIR) to determine its surface morphology and chemical compositions.

Arsenic level in bladder tumor of patients from an exposed population: association with progression and prognosis.

To elucidate the impact of arsenic on progression and prognosis of bladder cancer. Total arsenic in 145 tumors (80 non-muscle-invasive [NMIBC] and 65 muscle-invasive bladder cancer [MIBC]) was measured and associated with Ki67 expression, tumor-clinicopathological parameters and patient outcome. Tumor arsenic concentration was higher in exposed than unexposed patients (256 μg/kg vs 77 μg/kg; p < 0.

Dendrimer-conjugated podophyllotoxin suppresses DENA-induced HCC progression by modulation of inflammatory and fibrogenic factors.

Podophyllotoxin has been explored as an anticancer, antiviral, and antibacterial agent; however, its low water solubility and toxicity limit its use. In this study, the efficacy of a more soluble and less toxic polyamidoamine (PAMAM) dendrimer-conjugated podophyllotoxin (DPODO) was evaluated against chemically induced hepatocellular carcinoma (HCC) in mice. HCC was induced by giving 0.

Design and synthesis of coumarin-based organoselenium as a new hit for myeloprotection and synergistic therapeutic efficacy in adjuvant therapy.

A newly designed organoselenium compound, methyl substituted umbelliferone selenocyanate (MUS), was synthesized as a primary hit against the myelotoxic activity of carboplatin. MUS was administered at 6 mg/kg b.wt, p.

Dendrimer conjugated estramustine nanocrystalline 'Dendot': An effective inhibitor of DMBA-TPA induced papilloma formation in mouse.

Clinically approved anticancer drug estramustine mediates its function by impairing microtubule polymerization. However, the low aqueous solubility and high toxicity limit its anticancer activity via the oral route. Previously, efforts have been made to develop an enhanced water soluble form of estramustine as estramustine phosphate (EM) but acidic gastrointestinal pH breaks the phosphate derivative via oral administration.

Design, synthesis, and identification of a novel napthalamide-isoselenocyanate compound NISC-6 as a dual Topoisomerase-IIα and Akt pathway inhibitor, and evaluation of its anti-melanoma activity.

Synthesis and anti-melanoma activity of novel naphthalimide isoselenocyanate (NISC) and naphthalimide selenourea (NSU) analogs are described. The novel agents were screened for growth inhibition of different human melanoma cell lines including those having BRAF mutation (UACC903, 1205Lu, and A375M) and BRAF (CHL-1). In general, the NISC analogs (4a-d) were more effective in inhibiting the cell viability than the NSU analogs (7a-b).

Dendrimers for theranostic applications.

Recently, there have been tremendous advances in the development of various nanotechnology-based platforms for diagnosis and therapy. These nanoplatforms, which include liposomes, micelles, polymers, and dendrimers, comprise highly integrated nanoparticles that provide multiple functions, such as targeting, imaging, and therapy. This review focuses on dendrimer-based nanocarriers that have recently been developed for 'theranostics (or theragnosis)', a combination of therapy and diagnostics.

Dual stimuli-sensitive dendrimers: Photothermogenic gold nanoparticle-loaded thermo-responsive elastin-mimetic dendrimers.

Dendrimers are synthetic macromolecules with unique structures that can work as nanoplatforms for both photothermogenic gold nanoparticles (AuNPs) and thermosensitive elastin-like peptides (ELPs) with valine-proline-glycine-valine-glycine (VPGVG) repeats. In this study, photothermogenic AuNPs were loaded into thermo-responsive elastin-mimetic dendrimers (dendrimers conjugating ELPs at their periphery) to produce dual stimuli-sensitive nanoparticles. Polyamidoamine G4 dendrimers were modified with acetylated VPGVG and (VPGVG)2, and the resulting materials were named ELP1-den and ELP2-den, respectively.

Comparative study of microtubule inhibitors--estramustine and natural podophyllotoxin conjugated PAMAM dendrimer on glioma cell proliferation.

The synthetic estramustine (EM) and natural podophyllotoxin (PODO) anti-mitotic agents that inhibit tubulin polymerization are known anticancer agents. As low bioavailability limits their anticancer properties, we investigated whether conjugation with PAMAM dendrimer (D) could enhance the activity of D-EM and D-PODO by altering their release pattern. Release kinetics indicated synthesized conjugates to be stable against hydrolytic cleavage and showed sustained release characteristics.

Enhancing the efficacy of Ara-C through conjugation with PAMAM dendrimer and linear PEG: a comparative study.

1β-d-Arabinofuranosylcytosine (Cytarabine, Ara-C) is a key drug in the treatment of acute myeloid leukemia. Ara-C has a number of limitations such as a rapid deactivation by cytidine deaminase leading to the formation of a biologically inactive metabolite, Ara-U (1β-d-arabinofuranosyluracil), a low lipophilicity, and fast clearance from the body. To address these problems, we developed a conjugate in which hydroxyl-terminated PAMAM dendrimer, G4-OH ["D"] and PEG were used as carriers for the drug (Ara-C).

Development of novel naphthalimide derivatives and their evaluation as potential melanoma therapeutics.

Synthesis and anti-melanoma activity of various naphthalimide analogs, rationally modified by introducing isothiocyanate (ITC) and thiourea (TU) functionalities, found in well-known anti-cancer agents, is described. The structure-activity relationship comparison of the novel agents in inhibiting cancer cell growth was evaluated in various melanoma cell lines. Both ITC and TU analogs effectively inhibited cell viability and induced apoptosis in various human melanoma cells.

Development of a sphingosine kinase 1 specific small-molecule inhibitor.

The sphingolipid metabolic pathway represents a potential source of new therapeutic targets for numerous hyperproliferative/inflammatory diseases. Targets such as the sphingosine kinases (SphKs) have been extensively studied and numerous strategies have been employed to develop inhibitors against these enzymes. Herein, we report on the optimization of our novel small-molecule inhibitor SKI-I (N'-[(2-hydroxy-1-naphthyl)methylene]-3-(2-naphthyl)-1H-pyrazole-5-carbohydrazide) and the identification of a SphK1-specific analog, SKI-178, that is active in vitro and in vivo.

Naphthalimide based novel organoselenocyanates: finding less toxic forms of selenium that would retain protective efficacy.

A series of naphthalimide based organoselenocyanates were synthesized and screened for their toxicity as well as their ability to modulate several detoxifying/antioxidative enzyme levels at a primary screening dose of 3 mg/kg b.w. in normal Swiss albino mice for 30 days.

Amelioration of cisplatin-induced nephrotoxicity in mice by oral administration of diphenylmethyl selenocyanate.

Cisplatin is one of the most potent and active cytotoxic drug in the treatment of cancer. However, side-effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the promising efficacy of cisplatin. The present study was designed to ascertain the possible in vivo protective potential of a synthetic organoselenium compound diphenylmethyl selenocyanate (3 mg/kg.

Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs.

Sphingosine kinase (SphK) is a lipid kinase with oncogenic activity, and SphK inhibitors (SKIs) are known for their anti-cancer activity. Here, we report highly efficient syntheses of SKIs and their aspirinyl (Asp) analogs. Both SKIs and their Asp analogs were highly cytotoxic towards multiple human cancer cell lines; in several cases the Asp analogs were up to three times more effective.

Synthesis of isosteric selenium analog of the PPARbeta/delta agonist GW501516 and comparison of biological activity.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. Herein, we describe an efficient synthesis of a novel isosteric selenium analog of the highly specific PPARbeta/delta ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (GW501516; 1). The study examined the efficiency of the novel selenium analog 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-selenazol-5-yl)-methylsulfanyl)phenoxy-acetic acid (2) to activate PPARbeta/delta and the effect of ligand activation of PPARbeta/delta on cell proliferation and target gene expression in human HaCaT keratinocytes.

Cellular and pharmacological selectivity of the peroxisome proliferator-activated receptor-beta/delta antagonist GSK3787.

The availability of high-affinity agonists for peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) has led to significant advances in our understanding of the functional role of PPARbeta/delta. In this study, a new PPARbeta/delta antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), was characterized using in vivo and in vitro models. Orally administered GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (GW0742)-induced up-regulation of Angptl4 and Adrp mRNA expression in wild-type mouse colon but not in Pparbeta/delta-null mouse colon.