Multidrug resistance (MDR) against standard therapies poses a serious challenge in cancer treatment, and there is a clinical need for new anticancer agents that would selectively target MDR malignancies. Our previous studies have identified a 4H-chromene system, CXL017 (4) as an example, that can preferentially kill MDR cancer cells. To further improve its potency, we have performed detailed structure-activity relationship (SAR) studies at the 3, 4, and 6 positions of the 4H-chromene system. The results reveal that the 3 and 4 positions prefer rigid and hydrophobic functional groups while the 6 position prefers a meta or para-substituted aryl functional group and the substituent should be small and hydrophilic. We have also identified and characterized nine MDR cancer cells that acquire MDR through different mechanisms and demonstrated the scope of our new lead, 9g, to selectively target different MDR cancers, which holds promise to help manage MDR in cancer treatment.
Acting as in situ sources of triflyl nitrate (TfONO(2)) and trifluoroacetyl nitrate (CF(3)COONO(2)), the EAN/Tf(2)O and EAN/TFAA systems, generated via metathesis in the readily available ethylammonium nitrate (EAN) ionic liquid as solvent, are powerful electrophilic nitrating reagents for a wide variety of aromatic and heteroaromatic compounds. Comparative nitration experiments indicate that EAN/Tf(2)O is superior to EAN/TFAA for nitration of strongly deactivated systems. Both systems exhibit low substrate selectivity (K(T)/K(B) = 5-10) in between values reported for covalent nitrates and preformed nitronium salts.
Abstract1‐Aryl/alkyl‐1H‐1,2,3,4‐tetrazoles can conveniently be synthesized in one‐pot reactions from the corresponding amines by reaction with TMSN3 and CH(OEt)3 using the readily available, recyclable, Brønsted acidic ionic liquids [EtNH3][NO3] IL‐1 and [PMIM(SO3 H)][OTf] IL‐2 under mild conditions in high yields. Based on comparative reactions, whereas both ILs are excellent promoters, reactions are completed with shorter reaction times and in higher yields with IL‐2. Among 24 examples provided, identical products were obtained via the two ILs, except in the case of 2‐aminobenzoic acid where tetrazole was formed with IL‐2 and 2‐ethylquinazolin‐4(3H)‐one was formed with IL‐1. By leaving out TMS‐N3 from the reaction, the in‐situ formed CH(OEt)2+ and EtC(OEt)2+ (via their corresponding orthoesters) react under sonication with o‐phenylenediamine bearing various substituents, o‐aminothiophenol and o‐aminophenol to form a wide array of benzazoles (benzimidazole, benzothiazole and benzoxazole) and quinazolin‐4(3H)‐one in high yields (18 examples). The two ILs reacted differently in reaction with 2‐aminobenzamide, whereas quinazolin‐4(3H)one was formed with IL‐2/CH(OEt)3, the “unexpected” N‐ethylquinazolin‐4(3H)one was isolated with IL‐1/CH(OEt)3. The latter was also formed from 2‐aminobenzoic acid in IL‐1/CH(OEt)3. Mechanistic implications are addressed. The reported protocols enable rapid assembly of a host of heterocyclic systems in high yields with the added advantage of recycling and re‐use of the ILs.
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