Novel Multidrug Resistance Reversal Agents

Abstract

A series of 59 alpha-aryl-alpha-thioether-alkyl, -alkanenitrile, and -alkanecarboxylic acid methyl ester tetrahydroisoquinoline and isoindoline derivatives (15a-48) were synthesized and evaluated as multidrug resistance (MDR) reversal agents. The compounds were tested on S1-B1-20 human colon carcinoma cells selected for resistance to bisantrene. Both the cytotoxicity of the reversal agents and their ability to resensitize the cells to bisantrene were determined. All but two of these compounds (15q, 40) were more effective MDR reversal agents in vitro than verapamil (VRP), a calcium channel antagonist which also has been shown to possess MDR modulating activity. Several showed good activity in this assay (IC50's < 0.5 microM), the most potent being isoindolines 44 (IC50 0.26 microM) and 46 (IC50 0.26 microM) and tetrahydroisoquinolines 47 (IC50 0.29 microM) and 15m (IC50 0.30 microM). A number of compounds were evaluated in vivo against vincristine (VCR)-resistant murine P388 leukemia, as well as against human epidermoid carcinoma KB/8.5 implanted sc in athymic mice. The reversal agents which consistently showed the highest activity, together with low toxicity, were alpha-aryl-alpha-thiotolylalkanenitrile tetrahydroisoquinoline derivatives with electron-rich alkoxy substituents on the aromatic rings. Of the tested compounds, the most effective reversal agents for both tumor lines were 15h (33% increased life span at 12.5 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 59% relative tumor growth at 50 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model) and 39a (48% increased life span at 50 mg/kg, 0.2 mg/kg VCR versus VCR alone in the VCR-resistant P388 leukemia model and 46% relative tumor growth at 25 mg/kg, 8 mg/kg doxorubicin versus doxorubicin alone in the KB/8.5 model). The mechanism of action of these compounds is believed to involve blocking the drug efflux pump, P-glycoprotein.

Quantitative Analysis of the Relative Transcript Levels of ABC Transporter Atr Genes in Aspergillus nidulans by Real-Time Reverse Transcription-PCR Assay

“…The lack of structural similarity to mammalian P-glycoproteins may be exploited in designing specific inhibitors of the fungal efflux pumps (14). In addition, combined therapy of an antifungal drug associated with a drug that blocks the drug efflux pump (for instance, a multiple drug resistance reversal agent or modulator [4,26]) might decrease the deleterious effects of these important pathogens.…”

DNA topoisomerases as targets for anticancer drugs

“…A number of chemicals have been developed to reverse the effect of MDR phenotype (85, 86). Some of these MDR antagonists act by binding to P170 and thereby cause intracellular accumulation of drug.…”

Anthrapyridones, a novel group of antitumour non‐cross resistant anthraquinone analogues. Synthesis and molecular basis of the cytotoxic activity towards K562/DOX cells

“…Current strategies to reverse MDR are based: (i) on the synthesis of new non‐cross resistant cytostatics (Antonini et al ., 1995; Bassan et al ., 1997; Kubota et al ., 1998; Stefańska et al ., 1999); (ii) on the identification of effective and more selective MDR reversing agents (chemosensitizers) (Raderer & Scheithaner, 1993; Pereira et al ., 1994; Mankhetkorn & Garnier‐Suillerot, 1996; Pascaud et al ., 1998; Berger et al ., 1999; Teodori et al ., 1999); (iii) on the selective inhibition of gene expression encoding ATP‐dependent export pump using antisense oligonucleotides (Alahari et al ., 1996; Stewart et al ., 1996; Garcia‐Chaumont et al ., 2000) or ribozymes (Palfner et al ., 1995).…”