Synthesis, structure-activity relationship and in vitro pharmacodynamics of A-ring modified caged xanthones in a preclinical model of inflammatory breast cancer

Abstract

Inflammatory breast cancer (IBC) is a highly metastatic, lethal form of breast cancer that lacks targeted therapeutic strategies. Inspired by the promising cytotoxicity of gambogic acid and related caged xanthones in spheroids MARY-X , an in vitro preclinical IBC model, we constructed a library of synthetic analogs and performed structure-activity relationship studies. The studies revealed that functionalizing the Aring of the caged xanthone framework can significantly affect potency. Specifically, introduction of hydroxyl or fluorine groups at discrete positions of the A-ring leads to enhanced cytotoxicity at submicromolar concentrations. These compounds induce complete dissolution of spheroids MARY-X with subsequent apoptosis of both the peripherally-and centrally-located cells, proliferative and quiescentprone (e.g. hypoxic), respectively. These results highlight the structural flexibility and pharmacological potential of the caged xanthone motif for the design of IBC-targeting therapeutics.

An Update on the Anticancer Activity of Xanthone Derivatives: A Review

“…Quantitative structure-activity relationship (QSAR) is a computational approach to rationalize the relationship between the chemical structure of drugs with their biological activity [188]. A QSAR study on the anticancer activity of 33 haloxanthones against HepG2 and MCF-7 cells was performed in our previous study.…”

Recent advances in the synthesis of xanthones and azaxanthones

“…The classical Grover, Shah and Shah method 95,96 constitutes a suitable approach for the synthesis of hydroxyxanthones from easily available salicylic acid derivatives and phenols heated along with zinc chloride in phosphoryl chloride. 33,39,43,49,51,60,65,[97][98][99][100][101][102][103][104] For the reaction to proceed directly to the desired xanthone, the 2,2′-dihydroxybenzophenone intermediate must contain an additional hydroxyl moiety ortho to the carbonyl group. Usually phloroglucinol is used in order to overcome this limitation; however, when other phenol derivatives like resorcinol are used, the synthetic pathway stops at the benzophenone form.…”

“…Front., 2020, 7, 3027-3066 ities can be achieved like alkoxy, 19,23,24,33,97 which in certain situations can be converted into chlorosulfonyl 24 or amine, 33 ethylenedioxy, 100 and allyl. 39,115,138 Other transformations include the introduction of glycosyl, 55,110,132,135,229,230 ester, 17,62,227 amino, 151 and even prenyl 23,39,40,45,46,49,50,52,53,97,98,[111][112][113][114]117,130,133,221,[231][232][233] moieties, the latter being further used for the synthesis of caged xanthones 39,49,105,138,234 or pyranoxanthones. 40,45,…”

“…In the last decade, both natural and synthetic xanthones have been reported with diverse biological and pharmacological properties, 5,6,8,16 including antibacterial, 8,17-27 antifungal, 8,17,20,21,[28][29][30] antiviral, 31 antioxidant, [32][33][34][35][36][37] antiobesity, 38 anti-inflammatory, 5,17,[39][40][41] anticoagulant, 42 and antitumour. 36,[43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] Particularly, some xanthones' molecular targets have been disclosed, including clinically important enzymes such as α-glucosidase, [59][60][61][62][63] topoisomerase, 64,…”

Xanthones and Cancer: from Natural Sources to Mechanisms of Action

“…From salicylic acid and phenol in phosphorus pentoxide-methanesulfonic acid [144,170] Benzoxanthone FeCl 3 -Catalyzed, three-components, one-pot [171] Caged xanthones Regioselective Claisen/DielsÀ Alder cascade reaction [151,[172][173][174]175] Haloxanthones From 2-bromofluorobenzenes and salicylaldehydes via palladium-catalyzed acylation-SNAr [167,176,177] Hydroxyxanthone Classical one-step synthesis starting from two aryls induced by Mannich reaction and Eaton's reagents. [167,[178][179][180][181][182] Pyranoxanthones From 1,3-dihydroxyxanthone with different reagents [180] Pyridyl xanthones Ag 2 CO 3 mediated oxidative cyclization [183] Sulfonamides xanthones Eaton's reagent and chlorosulfonic acid [184] Thioxanthones Heteropoly acid, catalytic, under microwave [176,185,186] Toxyloxanthones Regioselective aryne addition and Claisen rearrangement [187] Triazole xanthone…”