Small P-gp modulating molecules: SAR studies on tetrahydroisoquinoline derivatives.
نویسندگان
چکیده
The development of small molecules as P-gp modulating agents and SAR studies on these ligands represented the aim of the present work. A series of 6,7-dimethoxytetrahydroisoquinoline derivatives was prepared and their ability to inhibit P-gp activity has been evaluated. The basic nucleus of these compounds, common to the best P-gp inhibitors such as Tariquidar and Elacridar, has been functionalized with no-basic moiety from our studied sigma receptor ligands displaying potent P-gp inhibition. The best results were obtained for compounds 3c and 3a (EC(50)=1.64 and 4.86 microM, respectively) and these results were remarkable because Elacridar showed in the same biological evaluation similar inhibitory activity (EC(50)=2 microM). SAR studies displayed that the removal of double bond on the spacer or its shifting into tetraline ring decreased the P-gp inhibiting activity. Moreover, the P-gp inhibition mechanism of tested compounds was investigated by three selected biological experiments. The results displayed that only compound 3c was P-gp inhibitor as Elacridar, while compound 3a and reference compounds Cyclosporin A and Verapamil modulated P-gp activity saturating the efflux pump as substrates. Flow cytometry studies carried out in Doxorubicin resistant breast cancer cell line (MCF7/Adr) confirmed that compound 3c increased Doxorubicin cell accumulation 5.7-fold. In addition, in MCF7/Adr, antiproliferative effect of 5 microM Doxorubicin shifted from 5% to 95% when co-administered with compound 3c (20 microM). The present study suggested a new class of small molecules displaying P-gp inhibitor activity differing from reference compounds Elacridar and Tariquidar for a simplified, and in the meantime, efficacious no-basic moiety.
منابع مشابه
Synthesis and multidrug resistance reversal activity of 1,2-disubstituted tetrahydroisoquinoline derivatives.
BACKGROUND Cancer treatment often fails due to multidrug resistance (MDR) of the tumor cells. One of the major causes is overexpression of P-glycoprotein (P-gp). MATERIALS AND METHODS By N-substitution reactions of diamine, amino acid and amino alcohol derivatives with 1-substituted tetrahydroisoquinoline skeleton, structurally diverse 1,2-disubstituted 1,2,3,4-tetrahydroisoquinolines were sy...
متن کاملApplication of the statistical methods in systematic structure-activity relationship analysis of thiazole, benzothiazole and tetrahydroisoquinoline derivatives with biological activity.
The procedure of initial studies to evaluate usefulness of the collected data for performing efficient QSAR analysis of any group of pharmacologically active substances was worked out. Structure-Activity Relationship (SAR) study on the thiazole derivatives with H1-antihistamine activity, the benzothiazole derivatives with H3-antihistamine activity and tetrahydroisoquinoline (TIQ) derivatives wi...
متن کاملCapillary electrophoretic study of small, highly sulfated, non-sugar molecules interacting with antithrombin.
Affinity CE (ACE) was used to study interactions of small, highly sulfated, aromatic molecules with antithrombin (AT). The high charge density of the small molecules induces differential migration of the complex resulting in a versatile method of assessing binding affinities, nature of interactions and site of binding on the inhibitor. Scatchard analysis of the interaction of three tetrahydrois...
متن کاملSynthesis of some novel 11b-substituted pyrimido[6,1-a]-isoquinoline derivatives.
A series of novel 11b-substituted 1,6,7,11b-tetrahydropyrimido[6,1-a]- isoquinoline-2,4-diones and 4-thioxo-1,3,4,6,7,11b-hexahydropyrimido[6,1-a]isoquinolin-2- ones were synthesized, utilizing two alternative strategies for ring closure of tetrahydroisoquinoline intermediates obtained from N-phenethyl enaminones.
متن کاملA class of promising acaricidal tetrahydroisoquinoline derivatives: synthesis, biological evaluation and structure-activity relationships.
As part of our continuing research on isoquinoline acaricidal drugs, this paper reports the preparation of a series of the 2-aryl-1-cyano-1,2,3,4-tetrahydroisoquinolines with various substituents on the N-phenyl ring, their in vitro acaricidal activities against Psoroptes cuniculi, a mange mite, and discusses their SAR as well. The structures of all compounds, including 12 new ones, were elucid...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Bioorganic & medicinal chemistry
دوره 16 1 شماره
صفحات -
تاریخ انتشار 2008