Substituted Chromones as Highly Potent Nontoxic Inhibitors, Specific for the Breast Cancer Resistance Protein

Abstract

A series of 13 disubstituted chromones was synthesized. Two types of substituents, on each side of the scaffold, contributed to both the potency of ABCG2 inhibition and the cytotoxicity. The best compound, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one (6g), displayed high-affinity inhibition and low cytotoxicity, giving a markedly high therapeutic index. The chromone derivative specifically inhibited ABCG2 versus other multidrug ABC transporters and was not transported. It constitutes a highly promising candidate for in vivo chemosensitization of ABCG2-expressing tumors.

Synthesis and Transformation of Halochromones

“…Suzuki coupling of 3-iodo-2-methylthiochromone with phenylboronic acid under PdCl 2 (PPh 3 ) 2 , K 2 CO 3 and DMF/H 2 O reaction conditions afforded 3-iodo-2-methylthioisoflavone in an excellent yield (94%) [164]. The cross-coupling of halogenated 3-iodochromones with substituted phenylboronic acids in the presence of Pd(PPh 3 ) 4 and Na 2 CO 3 in benzene afforded the corresponding halogenated isoflavones in moderate to high yields [75,165]. The reaction of 3-bromoflavone with phenylboronic acid in the presence of Pd(PPh 3 ) 4 and K 3 PO 4 under microwave irradiation conditions afforded the 2,3-diphenylchromone in good yield (86%) [98].…”

“…3-Iodochromones 125 are efficiently converted to the air-stable and crystallisable 3-(trimethylstannyl)chromones 126 by using Pd(PPh 3 ) 4 and hexamethylditin in dioxane. The Stille reaction of 3-(trimethylstannyl)chromones 126 with 4-iodonitrobenzene afforded ring A substituted 4'-nitroisoflavones 127 (Scheme 42) [165].…”

“…The Stille reaction of 3-(trimethylstannyl)chromones 126 with 4-iodonitrobenzene afforded ring A substituted 4'-nitroisoflavones 127 (Scheme 42) [165]. Stille reaction of 3-bromo-5,7-di-O-methylchrysin with allyltributyltin in the presence of a catalytic amount of Pd(PPh 3 ) 4 in anhydrous DMF prompted the synthesis of 3-allyl-5,7-di-Omethylchrysin [171].…”

“…Under Heck conditions, 3-bromo-2-styrylchromones 131 were coupled with styrenes 132 in the presence of Pd(PPh 3 ) 4 and triphenylphosphine as catalyst and using triethylamine as base, mainly leading to the initially unexpected formation of 2,3-diarylxanthone derivatives 134-136. The structural assignment of the minor products, 2,3-diaryl-3,4-dihydroxanthones 135, demystified the reaction mechanism indicating the initial formation of the expected 2,3-distyrylchromones 133 products, which suffer thermal electrocyclization, due to the high temperature conditions, and oxidation leading to the final obtained compounds.…”

“…Chromone-type compounds are well-known for their variety of biological properties, that include antitumor [4][5][6][7][8][9][10][11][12][13][14][15], hepatoprotective [16], antioxidant [17][18][19][20][21], anti-inflammatory [22][23][24][25], cardioprotective [26], antimicrobial [27,28] and antiviral activities [29,30]. The vast range of biological effects associated with these structural skeletons has led to substantial research devoted to the isolation from natural resources, synthesis and transformation of chromone derivatives and also to biological evaluation with emphasis on their potential medicinal applications.…”