1519-23-9Relevant articles and documents
Optimization by Molecular Fine Tuning of Dihydro-β-agarofuran Sesquiterpenoids as Reversers of P-Glycoprotein-Mediated Multidrug Resistance
Callies, Oliver,Sánchez-Ca?ete, María P.,Gamarro, Francisco,Jiménez, Ignacio A.,Castanys, Santiago,Bazzocchi, Isabel L.
supporting information, p. 1880 - 1890 (2016/03/22)
P-glycoprotein (P-gp) plays a crucial role in the development of multidrug resistance (MDR), a major obstacle for successful chemotherapy in cancer. Herein, we report on the development of a natural-product-based library of 81 dihydro-β-agarofuran sesquiterpenes (2-82) by optimization of the lead compound 1. The compound library was evaluated for its ability to inhibit P-gp-mediated daunomycin efflux in MDR cells. Selected analogues were further analyzed for their P-gp inhibition constant, intrinsic toxicity, and potency to reverse daunomycin and vinblastine resistances. Analogues 6, 24, 28, 59, and 66 were identified as having higher potency than compound 1 and verapamil, a first-generation P-gp modulator. SAR analysis revealed the size of the aliphatic chains and presence of nitrogen atoms are important structural characteristics to modulate reversal activity. The present study highlights the potential of these analogues as modulators of P-gp mediated MDR in cancer cells.
Synthesis of Analogues of the Carboxyl Protease Inhibitor Pepstatin. Effect of Structure in Subsite P3 on Inhibition of Pepsin
Rich, Daniel H.,Bernartowicz, Michael S.
, p. 791 - 795 (2007/10/02)
A series of pepstatin analogues having minimum structural requirements for tight-binding inhibition has been synthesized and tested on porcine pepsin.Subtle changes in the geometry and size of side chains at the valine-1 position of pepstatin were found to dramatically affect inhibitor potency as well as the type of kinetic behavior observed.The inhibitors reported here can be grouped into two categories: the more potent inhibitors are slow-binding inhibitors, i.e., exhibit slow, time-dependent inhibition; the weaker inhibitors, with Ki values greater than 10-8M, are not time-dependent inhibitors.A minimum kinetic mechanism is proposed to account for the observed kinetic behavior.