Effect of substituents at the C3´, C3´N, C10 and C2-meta-benzoate positions of taxane derivatives on their activity against resistant cancer cells.

We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells.

Exercise attenuates neuronal degeneration in Parkinson's disease rat model by regulating the level of adenosine 2A receptor.

Parkinson's disease occurs due to loss of dopaminergic neurons, which alters the behavioural changes. The present study evaluates the effect of exercise on neurodegeneration against Parkinson's disease (PD) rat model and postulates its effect on novel molecular pathway. Rotenone was administered at 1 mg/kg s.

Amplicon Contains Cyclic AMP Response Element-Driven Gene in Taxane-Resistant MCF-7 Breast Cancer Sublines.

A limited number of studies are devoted to regulating expression in cancer. Hence, we aimed to unveil the regulation of expression in MCF-7 breast cancer cells (with high expression) and taxane-resistant MCF-7 sublines (manifesting even higher expression). We found that transcription is regulated primarily by the cyclic AMP response element (CRE) in hypomethylated proximal promoters in both taxane-sensitive and taxane-resistant MCF-7 cells.

SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins.

Fatty acid binding proteins (FABPs) serve as critical modulators of endocannabinoid signaling by facilitating the intracellular transport of anandamide and whose inhibition potentiates anandamide signaling. Our previous work has identified a novel small-molecule FABP inhibitor, α-truxillic acid 1-naphthyl monoester (SB-FI-26, 3) that has shown efficacy as an antinociceptive and anti-inflammatory agent in rodent models. In the present work, we have performed an extensive SAR study on a series of 3-analogs as novel FABP inhibitors based on computer-aided inhibitor drug design and docking analysis, chemical synthesis and biological evaluations.

Design, Synthesis, and Biological Evaluations of Asymmetric Bow-Tie PAMAM Dendrimer-Based Conjugates for Tumor-Targeted Drug Delivery.

A unique asymmetric bow-tie poly(amidoamine) (PAMAM) dendrimer (ABTD) scaffold was designed and developed as a well-defined macromolecular carrier for tumor-targeted drug delivery. The ABTD scaffold in this study consists of a G3-half-dendron (G3-HD) unit and a G1-half-dendron (G1-HD) unit, bearing thiol moiety in each unit and a bis(maleimide) linker unit, which undergo sequential thiol-maleimide coupling to assemble the scaffold. This assembly methodology is applicable to all other combinations of different generations of PAMAM dendrimers.

Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel.

We tested the role of substituents at the C3' and C3'N positions of the taxane molecule to identify taxane derivatives capable of overcoming acquired resistance to paclitaxel. Paclitaxel-resistant sublines SK-BR-3/PacR and MCF-7/PacR as well as the original paclitaxel-sensitive breast cancer cell lines SK-BR-3 and MCF-7 were used for testing. Increased expression of the ABCB1 transporter was found to be involved in the acquired resistance.

Strategic incorporation of fluorine in the drug discovery of new-generation antitubercular agents targeting bacterial cell division protein FtsZ.

This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds.

Design, Synthesis and Application of Fluorine-Labeled Taxoids as F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems.

Novel tumor-targeting drug conjugates, BLT-F () and BLT-S-F (), bearing a fluorotaxoid as the warhead, a mechanism-based self-immolative disulfide linker, and biotin as the tumor-targeting module, were designed and synthesized as F NMR probes. Fluorine atoms and CF groups were strategically incorporated into the conjugates to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time monitoring with F NMR. Time-resolved F NMR study on probe disclosed a stepwise mechanism for release of a fluorotaxoid, which might not have been detected by other analytical methods.