Tariquidar-Related Chalcones and Ketones as ABCG2 Modulators

Abstract

ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse anticancer drugs. In order to investigate their role in resistance, potent and selective ABCG2 modulators have been described in the literature. A leading class of modulators are the tariquidar analogues; however, their susceptibility to hydrolysis limits their applicable use. To overcome this, we synthesized a novel series of chalcone- and ketone-based compounds inspired by reported tariquidar analogues. Compounds were characterized and evaluated for their ABCG2 modulatory activity and ABC transporter selectivity. When compared to transporters ABCB1 and ABCC1, the chalcone-based compounds exhibited selectivity for ABCG2, while the ketone-based compounds showed only a slight preference for ABCG2. From the former series, chalcone (UR-DP48) displayed similar activity to the reference fumitremorgin C, both producing comparable maximal effects. The compound exhibited marked antiproliferative activity, while cytotoxicity was less pronounced for the most active compound from the ketone series. Chalcone-containing tariquidar analogues are promising modulators to aid in functional investigations of ABCG2 transporters.

Chalcone Derivatives: Role in Anticancer Therapy

“…In addition to the aforementioned chalcone hybrids, other hybrids, such as chalcone–ferrocene [ 95 , 96 , 97 ], chalcone–furan/thiophene hybrids [ 98 , 99 , 100 , 101 ], chalcone–pyridine/pyrimidine hybrids [ 102 , 103 , 104 , 105 , 106 ], chalcone–quinoline/quinolone hybrids [ 107 , 108 , 109 , 110 , 111 ], chalcone–quinoxaline/quinazolinone hybrids [ 112 , 113 , 114 ], chalcone-quinone hybrids [ 115 , 116 , 117 ], chalcone–triazine hybrids [ 118 , 119 ], and chalcone–dithiocarbamate hybrids [ 120 , 121 ] also showed certain anticancer activity.…”

“…The best derivative ( 75 ) was selective for ABCG2 over P-glycoprotein and MRP1 and stimulated ABCG2 basal ATPase activity [ 183 ]. Peña-Solórzano et al found that tariquidar-related chalcones ( 76 ) exhibited selectivity for ABCG2 to a greater extent than the transporters ABCB1 and ABCC1 [ 109 ]. Notably, novel quinolone chalcones ( 77 ) synthesized by Lindamulage et al could overcome multidrug resistance by impeding MRP1 function while maintaining strong inhibition of microtubule activity [ 111 ].…”

Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

“…Structure-activity relationship studies suggested that the presence of a 4-tert-butylphenyl moiety on the inverted amide (compound 92), conferred the best P-gp inhibitory activity (IC 50 = 1. In search for more stable analogues, Peña-Solórzano et al [163] prepared a series of tariquidar analogues with chalcone and ketone moieties, according to a bioisosteric approach [ Figure 16]. These compounds were investigated for their inhibitory activity and selectivity toward BCRP.…”

“…In search for more stable analogues, Peña-Solórzano et al [ 163 ] prepared a series of tariquidar analogues with chalcone and ketone moieties, according to a bioisosteric approach [Figure 16] . These compounds were investigated for their inhibitory activity and selectivity toward BCRP.…”

Síntese, avaliação biológica e modelagem molecular de potenciais antitumorais análogos da sanguinarina planejados por simplificação molecular

“…Proteínas transportadoras de efluxo ABC, como ABCB1 e ABCG2, estão relacionadas à resistência de glioblastoma frente à quimioterapia e menor sobrevida do paciente (EMERY et al, 2017;MUNOZ et al, 2014;SCHAICH et al, 2009;WIJAYA;FUKUDA;SCHUETZ, 2017 (FALLACARA et al, 2019;PERAZZOLI et al, 2015). Adicionalmente, inibidores de transportadores de efluxo podem ser empregados como adjuvantes na terapia antitumoral, proporcionando maior eficácia do tratamento (PEÑA-SOLÓRZANO et al, 2018;SAEED et al, 2018).…”