Novel Structurally Varied N-Alkyl 1,4-Dihydropyridines as ABCB1 Inhibitors: Structure-Activity Relationships, Biological Activity and First Bioanalytical Evaluation

Abstract

Series of structurally varied N-alkyl 1,4-dihydropyridines and novel benzo-annelated derivatives as 1,4- dihydroquinolines have been characterized as ABCB1 inhibitors. Structure-activity relationships (SARs) are discussed. Cytotoxic activities of selected compounds have been determined. A first bioanalysis of ABCB1 substrate properties has been carried out in a cell-based model. Compounds with highest ABCB1 inhibiting activities were no substrates of ABCB1 and not transported by the efflux pump, thus profiling the new ABCB1 inhibitors.

Epoxylathyrane Derivatives as MDR-Selective Compounds for Disabling Multidrug Resistance in Cancer

“…Therefore, the present work aimed at assessing the ability of the macrocyclic diterpene derivatives 1-16 (Figure 1) for their potential as collateral sensitizing compounds, using the human tumor gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) cell models (drug-sensitive and drug-resistant sublines), Abbreviations: ABC, ATP binding cassette; ABCB1, ATP-binding cassette, subfamily B; CS, collateral sensitivity; EPG85-257P, parental gastric cancer cells; EPG85-257RDB, gastric cancer cells selected against daunorubicin; EPG85-257RNOV, gastric cancer cells selected against mitoxantrone; EPP-181 RDB, pancreatic cancer cells selected against daunorubicin; EPP-181P, parental pancreatic cancer cells; EPP-181RNOV, pancreatic cancer cells selected against mitoxantrone; MDR, multidrug resistance; MDR1, multidrug resistance gene 1; RR, relative resistance; NB, Naïve Bayes; RT, random trees. well described for MDR (Table S2; Lage et al, 2010;Hilgeroth et al, 2013;Reis et al, 2014). Additionally, the MDR-selective antiproliferative activity mode of action of compounds 8, 15, and 16 was assessed towards apoptosis and caspase-3 activation, using the same cell lines.…”

Exploring Jolkinol D Derivatives To Overcome Multidrug Resistance in Cancer

“…The type of interaction with the ATPase function of ABCB1 was also investigated for the parent molecule ( 1 ) and the strongest modulator ( 1.3 ). The MDR-selective antiproliferative activity was assayed using the human tumor gastric (EPG85-257) and pancreatic (EPP85-181) cell models (drug-sensitive and drug-resistant sublines), well characterized for MDR. − The most promising derivatives ( 1.8 , 1.10 ), and jolkinoate L ( 3 ), were investigated for their potential as apoptosis inducers.…”

Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells

“…For each cancer cell model, one sensitive cell line and two resistant sublines, selected for resistance to RDB and to RNOV, were tested. The characteristics of these MDR cell lines are well known and the same cancer cell models were used with a similar purpose in other studies [15][16][17][25][26][27] The collateral sensitivity effect was assessed by determining the RR (calculated as the ratio of the IC 50 of a compound against a resistant line divided by the IC 50 against the corresponding parental line). Compounds with an RR < 1 kill MDR cells more effectively than parental cells, and when they exhibit an RR ≤ 0.50 they have a collateral sensitivity effect.…”

“…Compounds 1-10, namely, balsaminol A (1), balsaminol D (2), balsaminol F (3), balsaminagenin A (4), balsaminagenin B (5), balsaminosides A-C (6-8), cucurbalsaminol A (9), and karavilagenin C (10), were previously isolated from the methanol extract of M. balsamina as reported [12,[21][22][23]. Compound 10, isolated in a large amount, gave rise to 18 compounds, namely, karavoates A-R (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), by using several alkanoyl and aroyl acylating reagents, as described [12,24]. The purity of the compounds was more than 95 % by HPLC.…”