Biological Evaluation, Structure−Activity Relationships, and Three-Dimensional Quantitative Structure−Activity Relationship Studies of Dihydro-β-agarofuran Sesquiterpenes as Modulators of P-Glycoprotein-Dependent Multidrug Resistance

Abstract

Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.

Development of predictive in silico model for cyclosporine- and aureobasidin-based P-glycoprotein inhibitors employing receptor surface analysis

“…However, CsAs and AbAs are large and chemically complex molecules, which seems to have discouraged attempts to model their inhibitory structure-activity relationships. Accordingly, absence of published three-dimensional QSAR analyses specific to this group of Pgp inhibitors [23,[33][34][35][36][37][38] combined with the lack of useful Pgp 3D structural information prompted us to model a diverse set of cyclosporins and aureobasidins in order to probe their affinity interactions with their corresponding putative Pgp binding site. However, the sheer size and chemical complexity of these inhibitors restricted our modeling options.…”

Pharmacoinformatic Approaches to Design Natural Product Type Ligands of ABC-Transporters

“…Furthermore, they have shown clinical potential as anticancer drugs [21]. In a comprehensive study, 76 Dihydro--agarofuran derivatives were used to inhibit P-gp-mediated daunorubicin (DNR) efflux from intact cells [22] (Fig. (6)).…”

“…Structure-activity relationship studies [22] of compounds varied at the A-ring of sesquiterpenes suggest that an ester group at position C-2 seems essential for the inhibition of ABCB1. Sesquiterpenes with the OAc substituent at position C-3 were found to be more potent than the compounds with a hydroxyl or hydrogen group at the same position.…”

“…(7). Summary of the most prominent structural elements of ligands that are important for high P-gp activity obtained by 3D-QSAR/CoMFA (taken from [22]). …”

Advances in plant-based inhibitors of P-glycoprotein

“…It is noteworthy that, two features of terpenoids, the carbonyl groups at the C 2a , C 3 , C 8 positions (30, 31 and 35), and a hydrophobic substituent at the C 6 position (37), appear to be the key contributors for their P-gp inhibitory activity 119 . It is obvious that P-gp inhibitory effects of terpenoids depend on the chemical structure of the compound.…”