No abstract

Novel O-alkylated quinoline and N-alkylated 4-quinolone derivatives attached to the ferrocene moiety through 4,1-(7a-d, 8a-d and 12a-d) and 1,4-disubstituted (9a, 9b, 10a and 10b) 1,2,3-triazole moiety were synthesized. The observed regioselectivity of O-vs. N-alkylation was explored by the use of NMR and computational techniques. Among the N-alkylated derivatives, the quinolone-ferrocene conjugate 9a displayed marked activities against chronic myeloid leukemia in blast crisis (K562) and Burkitt lymphoma (Raji). The 6-chloroquinolone-ferrocene conjugate 12c, with selective inhibitory activity on Raji cells and no cytostatic effect on normal MDCK1 cells was highlighted as the most promising anticancer organometallic complex in a group of O-alkylated quinolines.

Diverse natural coumarin-based compounds linked to aryl via a 1,2,3-triazole spacer with antiproliferative activity against K562 cells, radical scavenging activity and a decrease of ROS production were provided.

Notch pathway was found to be activated in most glioblastomas (GBMs), underlining the importance of Notch in formation and recurrence of GBM. In this study, a Notch inhibitory peptide, dominant negative MAML (dnMAML), was conjugated to elastin-like polypeptide (ELP) for tumor targeted delivery. ELP is a thermally responsive polypeptide that can be actively and passively targeted to the tumor site by localized application of hyperthermia. This complex was further modified with the addition of a cell penetrating peptide, SynB1, for improved cellular uptake and blood-brain barrier penetration. The SynB1-ELP1-dnMAML was examined for its cellular uptake, cytotoxicity, apoptosis, cell cycle inhibition and the inhibition of target genes' expression. SynB1-ELP1-dnMAML inhibited the growth of D54 and U251 cells by inducing apoptosis and cell cycle arrest, especially in the presence of hyperthermia. Hyperthermia increased overall uptake of the polypeptide by the cells and enhanced the resulting pharmacological effects of dnMAML, showing the inhibition of targets of Notch pathway such as Hes-1 and Hey-L. These results confirm that dnMAML is an effective Notch inhibitor and combination with ELP may allow thermal targeting of the SynB1-ELP1-dnMAML complex in cancer cells while avoiding the dangers of systemic Notch inhibition.

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a chloride and bicarbonate channel in secretory epithelia with a critical role in maintaining fluid homeostasis. Mutations in CFTR are associated with Cystic Fibrosis (CF), the most common lethal autosomal recessive disorder in Caucasians. While remarkable treatment advances have been made recently in the form of modulator drugs directly rescuing CFTR dysfunction, there is still considerable scope for improvement of therapeutic effectiveness. Here, we report the application of a high-throughput screening variant of the Mammalian Membrane Two-Hybrid (MaMTH-HTS) to map the protein-protein interactions of wild-type (wt) and mutant CFTR (F508del), in an effort to better understand CF cellular effects and identify new drug targets for patient-specific treatments. Combined with functional validation in multiple disease models, we have uncovered candidate proteins with potential roles in CFTR function/CF pathophysiology, including Fibrinogen Like 2 (FGL2), which we demonstrate in patient-derived intestinal organoids has a significant effect on CFTR functional expression.