Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers

The phytochemical study of Euphorbia pedroi led to the isolation of a new tetracyclic triterpenoid with an unusual spiro scaffold, spiropedroxodiol (1), along with seven known terpenoids (2–8). Aiming at obtaining compounds with improved multidrug-resistance (MDR) reversal activity, compound 8, Read more ›

Optimizing the flavanone core toward new selective nitrogen-containing modulators of ABC transporters

Aim: Naringenin (1), isolated in large amount from the aerial parts of Euphorbia pedroi, was chemically derivatized to yield 18 imine derivatives (2–19) and three alkylated derivatives through a Mannich-type reaction (20–22) that were tested as multidrug resistance (MDR) reversers Read more ›

Discovery of a small-molecule protein kinase Cδ-selective activator with promising application in colon cancer therapy

Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, Read more ›

Structure-function relationships in ABCG2: insights from molecular dynamics simulations and molecular docking studies

Efflux pumps of the ATP-binding cassette transporters superfamily (ABC transporters) are frequently involved in the multidrug-resistance (MDR) phenomenon in cancer cells. Herein, we describe a new atomistic model for the MDR-related ABCG2 efflux pump, also named breast cancer resistance protein Read more ›

About P-glycoprotein: a new drugable domain is emerging from structural data

P-glycoprotein (P-gp) has been considered an important molecular target in the reversal of multidrug resistance (MDR). As such, the development of P-gp modulators able to restore drug sensitivity in resistant cells is still considered one of the most promising strategies Read more ›

Indolo[3,2-c]quinoline G-Quadruplex Stabilizers: a Structural Analysis of Binding to the Human Telomeric G-Quadruplex

A library of 5-methylindolo[3,2-c]quinolones (IQc) with various substitution patterns of alkyldiamine side chains were evaluated for G-quadruplex (G4) binding mode and efficiency. Fluorescence resonance energy transfer melting assays showed that IQcs with a positive charge in the heteroaromatic nucleus and Read more ›

Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies

One of the greatest threats to cancer treatment is the development, by some tumors, of resistance to the pharmacological action of several structurally unrelated cytotoxic agents—multidrug resistance (MDR). As P-glycoprotein (P-gp) is one of the most studied ATP-dependent efflux pumps Read more ›

Flavones as isosteres of 4(1H)-quinolones: Discovery of ligand efficient and dual stage antimalarial lead compounds

Malaria is responsible for nearly one million deaths annually, and the increasing prevalence of multi-resistant strains of Plasmodium falciparum poses a great challenge to controlling the disease. A diverse set of flavones, isosteric to 4(1H)-quinolones, were prepared and profiled for Read more ›

Synthesis, G-Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2-b]quinolines with One, Two, or Three Basic Side Chains

G-quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined Read more ›

Molecular Docking Characterizes Substrate-Binding Sites and Efflux Modulation Mechanisms within P-Glycoprotein

P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype overexpressed by several cancer cell lines. Experimental studies contributed to important knowledge concerning substrate polyspecificity, efflux mechanism, and drug-binding sites. This information is, however, Read more ›

Exploring the Molecular Basis of Qo bc1 Complex Inhibitors Activity to Find Novel Antimalarials Hits

Cytochrome bc1 complex is a crucial element in the mitochondrial respiratory chain, being indispensable for the survival of several species of Plasmodia that cause malaria and, Qo bc1 Complex Inhibitorstherefore, it is a promising target for antimalarial drug development. We Read more ›

Colon Adenocarcinoma Multidrug Resistance Reverted by Euphorbia Diterpenes: Structure-Activity Relationships and Pharmacophore Modeling

Multidrug resistance (MDR) is a limiting step on the success of cancer chemotherapy. The drug efflux mediated by P-gp (P- glycoprotein) is one of the best studied mechanisms of MDR. This paper focuses on the inhibitory P-gp efflux activity, pharmacophore Read more ›

A quantum mechanical study of novel potential inhibitors of cytochrome bc1 as antimalarial compounds

Cytochrome bc1 is a validated drug target of Plasmodium falciparum, the parasite that causes the most lethal form of malaria. The inhibition of cytochrome bc1 leads to the shutdown of the mitochondrial metabolism and the consequent arrest of pyrimidine biosynthesis Read more ›

Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure–activity study

The first structure–activity relationship study of vinyl sulfones as caspase-3 inhibitors is reported. A series of 12 vinyl sulfones was synthesized and evaluated for two downstream caspases (caspases-3 and -7). Dipeptidyl derivatives were significantly superior to their counterparts containing only Asp Read more ›

Design, synthesis and structure–activity relationships of (1H-pyridin-4-ylidene)amines as potential antimalarials

(1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were prepared as potential clopidol isosteres in the development of antimalarials. Their antiplasmodial activity was evaluated in vitro against the Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains. The most Read more ›