6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline amides and corresponding ester isosteres as multidrug resistance reversers

Abstract

Aiming to deepen the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.

Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

“…Although several compounds showed potent and selective efficacy for the P-gp transporter, only four compounds (14, 87 The mechanism of MDR modulation of all of the abovementioned compounds was due to an inhibition of P-gp-mediated drug efflux. 84,85,87,89 In addition, 16 inhibited P-gp ATPase activity without affecting P-gp expression. 84 In silico analyses, such as molecular docking and dynamic stimulation, indicated that 16 formed a long-lasting interaction with P-gp via hydrophobic interactions and hydrogen bond contacts.…”

“…Moreover, the removal of the 6,7‐dimethoxy group or the replacement of the tetrahydroisoquinoline with tetrahydroquinoline significantly decreased the potency. Although several compounds showed potent and selective efficacy for the P‐gp transporter, only four compounds ( 14 , 87 15 , 85 16 , 84 and 17 , 89 Figure 4B) were found to reverse P‐gp‐mediated MDR in cancer cells. Specifically, 14 restored DOX efficacy in P‐gp‐overexpressing DOX‐resistant glioblastoma and malignant pleural mesothelioma stem cells 90,91 at nanomolar concentrations.…”

“…The 6,7-dimethoxylated tetrahydroisoquinoline scaffold was the important pharmacophore that was nearly Apart from the tariquidar analogs, a series of tetrahydroisoquinoline-based P-gp inhibitors, with relatively simplified structures, have been reported 57,60,61,[84][85][86][87][88][89] and the general structure was characterized by connecting the important pharmacophore 6,7-dimethoxy-tetrahydroisoquinoline to an aromatic moiety by a flexible linker ( Figure 4A). After determining the P-gp inhibitory efficacy of these compounds in vitro, the general SAR studies of these compounds ( Figure 4A) indicated that the aromatic moiety is flexible and appropriate substitution on the aromatic ring could increase the efficacy.…”

“…15,85 16,84 and 17,89 Figure 4B) were found to reverse P-gp-mediated MDR in cancer cells. Specifically, -gp inhibitor, elacridar 53.…”

Multienzyme One‐Pot Cascades Incorporating Methyltransferases for the Strategic Diversification of Tetrahydroisoquinoline Alkaloids

“…Alongside their applications as analgesics and antitussives,[ 1 , 2 , 3 , 4 ] THIQs show promise as therapeutics towards cancer, neuropathologies and multi‐drug resistant bacteria. [ 3 , 5 , 6 , 7 , 8 ] However, supply of these compounds for studies and clinical use is limited. Natural THIQs can be harvested from mixtures from certain plants, but their chemical syntheses are complicated by the presence of chiral centres and the density of functional groups.…”