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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 ›

Assessing the Stabilization of P-Glycoprotein’s Nucleotide- Binding Domains by the Linker, Using Molecular Dynamics

This paper focuses on the importance of the intermediate linker sequence for the stabilization of the cytoplasmic portion of murine P-glycoprotein, an ABC transporter involved in Multidrug Resistance (MDR) in cancer. Three putative protein-protein interaction areas were predicted to exist, Read more ›

Enhancing Macrocyclic Diterpenes as Multidrug-Resistance Reversers: Structure–Activity Studies on Jolkinol D Derivatives

The phytochemical study of Euphorbia piscatoria yielded jolkinol D (1) in a large amount, whose derivatization gave rise to 12 ester derivatives (2–13) and hydrolysis to compound 14. The in vitro modulation of P-gp of compounds 1–14 was evaluated through Read more ›

Insights on P-Glycoprotein’s Efflux Mechanism Obtained by Molecular Dynamics Simulations

P-Glycoprotein (P-gp) is often involved in multidrug resistance (MDR) to the pharmacological action of a wide number of anticancer agents. In this article, a series of molecular dynamics simulations of murine’s P-gp were developed, elucidating the importance of the lipid 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 ›

Identification of new antimalarial leads by use of virtual screening against cytochrome bc1

Cytochrome bc1 is a validated drug target in malaria parasites. The spread of Plasmodium falciparum strains resistant to multiple antimalarials emphasizes the urgent need for new Identification of new antimalarial leads by use of virtual screening against cytochrome bc1drugs. We Read more ›

Toward a Better Pharmacophore Description of P-Glycoprotein Modulators, Based on Macrocyclic Diterpenes from Euphorbia Species

Multidrug resistance related to the increased expression of P-glycoprotein (P-gp) by cancer cells is the major contributor for the failure of chemotherapeutic treatments. Starting from pharmacophores and data already published and in macrocyclic diterpenes isolated from Euphorbia species, a comprehensive Read more ›

Properties and behaviour of tetracyclic allopsoralen derivatives inside a DPPC lipid bilayer model

Allopsoralens are angular psoralen derivatives presenting advantages over the parent compound because of monofunctional DNA-photobinding and consequent lower toxicity. Allopsoralen molecules with three different substituents and different protonation states were studied using the molecular dynamics technique. The location of these 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 ›

Incorporation of Basic Side Chains into Cryptolepine Scaffold: Structure−Antimalarial Activity Relationships and Mechanistic Studies

The synthesis of cryptolepine derivatives containing basic side-chains at the C-11 position and their evaluations for antiplasmodial and cytotoxicity properties are reported. Propyl, butyl, and cycloalkyl diamine side chains significantly increased activity against chloroquine-resistant Plasmodium falciparum strains while reducing cytotoxicity 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 ›

Properties and Permeability of Hypericin and Brominated Hypericin in Lipid Membranes

The promising photosensitizing properties of hypericin, a substituted phenanthroperylene quinone naturally found in Saint John’s wort, has led to the proposal that it can be utilized in photodynamic therapy. Structurally modified derivatives are at the present time being investigated to 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 ›