Synthesis and conversion of primary and secondary 2-aminoestradiols into A-ring-integrated benzoxazolone hybrids and their in vitro anticancer activity

Abstract

Estradiol–benzoxazolone hybrids with a common aromatic moiety were efficiently synthesized via primary and secondary aminophenol intermediates, and their anticancer activities were investigated.

Synthesis and biological profile of benzoxazolone derivatives

“…The final compounds showed anticancer activity against HeLa, MCF-7 breast cancer cell lines, and DU145/PC-3 prostate cancer cell lines at a much lower dose as compared to the cisplatin. [115] F I G U R E 33 Benzoxazolinone-1,3,4-thiadiazole hybrids as TNF-α inhibitors. application of certain specific set of conditions, solvents, coupling agents, activating agents, and catalysts.…”

Efficient access to domain-integrated estradiol-flavone hybrids via the corresponding chalcones and their in vitro anticancer potential

“…As a continuation, the resulting chalcones were intended to be converted to flavones. Although a number of flavone syntheses are based on the base-catalyzed Baker-Venkataraman rearrangement of 2-acyloxyacetophenones to β-diketones and subsequent acid-induced cyclodehydration [27,28,35], these methods suffer from several drawbacks, such as the need for strong bases and acids, long reaction times or low yields of the desired products [36]. Some publications describe the applicability of I 2 /DMSO system for the oxidative cyclization accompanied by O-deallylation of 2-allyloxy-chalcones and 2-allyloxyα,β-dibromo-chalcones to flavones [37][38][39], while others report on the ICl/DMSO-catalyzed synthesis of flavones from 2-hydroxychalcones [40].…”

“…[22][23][24][25]. Interestingly, only few examples are to be found in the literature for the preparation and pharmacological study of 2-connected [26] and 2,3-fused heterocyclic estradiol derivatives [27,28]. In this regard, we have recently reported a high-yield synthetic procedure for the preparation of 2-pyrazolyl estradiols and estradiol-pyrazolocoumarin hybrids [29].…”

Substitutional Diversity-Oriented Synthesis and In Vitro Anticancer Activity of Framework-Integrated Estradiol-Benzisoxazole Chimeras

“…First, molecular hybridization of steroids with other potentially active compounds often modulates bioactivity and improves the selectivity and side effect profile of the individual compounds [ 16 , 17 ]. In addition, derivatization of estrogens at the C2–C3 position by the introduction of a fused heteroring while simultaneously eliminating the phenolic OH group makes it likely that the novel derivative will not be able to bind to the estrogen receptor, and will therefore be free of undesired hormonal effects [ 18 ]. Even estradiol (E2) derivatives substituted at C-2 with different functional groups, such as 2-methoxyestradiol (2-ME2) and its structural analogues [ 19 ], in which the phenolic OH group required for estrogen receptor binding is intact, do not have hormonal effects due to steric and electronic factors induced by the C-2 group [ 20 ].…”

“…As a continuation of our ongoing research for designing steroidal A-ring integrated chimeras with anticancer activity [ 18 , 23 , 24 , 25 , 26 ], a benzisoxazole scaffold containing different substituents at the C-3′ position of the heteroring was hybridized with the aromatic ring of E2. According to a comprehensive analysis of the chemical structure of marketed anticancer agents, the most abundant functional groups of these drugs are OH, COOH, COOR, NH 2 and F; moreover, 43.4% of them contain both aromatic and non-aromatic rings as part of their structure [ 27 ].…”