10.1021/jm960384x
The research focuses on the structure-activity relationship (SAR) studies of benzofuran analogs of propafenone-type modulators aimed at reversing multidrug resistance in tumor cells. The purpose of the study was to understand the structural features required for effective inhibition of P-glycoprotein (PGP), a membrane-bound efflux pump associated with multidrug resistance. The researchers synthesized a series of benzofurylethanolamine analogs and evaluated their activity in vitro using rhodamine-123 efflux studies and daunomycin cytotoxicity assays. The conclusions drawn from the study indicated that there is an excellent correlation between the calculated lipophilicity of the compounds and their multidrug resistance-reversing activity, with the benzofuran analogs generally having lower activity/lipophilicity ratios compared to propafenones. The study also found that the incorporation of the ether oxygen of propafenone into a benzofuran moiety led to a decrease in activity, which could be partially compensated by increasing lipophilicity.
10.1081/SCC-120030758
The study presents a facile total synthesis of idarubicinone-7-β-D-glucuronide, an anthracycline antibiotic analog, using a series of carboxylic acid derivatives as key intermediates. The researchers employed polyphosphoric acid (PPA) and AlCl3 as catalysts to cyclize dimethoxybenzene with various carboxylic acid derivatives, yielding naphthalenones, which were further transformed into (+)-idarubicinone 3b. Esterification with (S)-(+)-O-acetylmandelic acid and subsequent separation and deprotection steps led to the isolation of (+)-3b and (2)-3b. These compounds were then glycosylated with acetobromo-α-D-glucuronic acid methyl ester, using ZnBr2 as a catalyst, to produce two kinds of idarubicinone-7-β-D-glucuronide (20 and 21). The synthesized compounds were intended to enhance drug efficacy, potentially improving the pharmacological profile of idarubicinone by attaching glucuronic acid moieties. The study also detailed the synthetic method for an AB-ring synthon necessary for the synthesis of the aglycone and provided a comprehensive analysis of the synthesized compounds using various analytical techniques.
10.1021/jm00157a027
The research aimed to synthesize and evaluate the antitumor properties of the 9-aza analogue of N-(trifluoroacetyl)-4-demethoxydaunomycin, a derivative of the anthracycline antibiotics doxorubicin and daunomycin. The study hypothesized that the bioisosteric replacement of carbon with nitrogen in the alicyclic A ring of the glycosides could potentially enhance antitumor activity. The synthesis involved a series of chemical reactions, including Pomeranz-Fritsch condensation, borohydride reduction, acid-catalyzed cyclization, selective N-acetylation, Friedel-Crafts acylation, epoxidation, and glycosidation with N,O-bis(trifluoroacetyl)daunosamine bromide and silver trifluoromethanesulfonate. The resulting diastereoisomers were separated and their structures confirmed using CD and NMR spectroscopy. However, the study concluded that both diastereoisomers were inactive in mice carrying the P388 tumor, suggesting that the side-chain keto moiety could not be replaced by an aliphatic amide group without losing antitumor activity. The chemicals used in the process included 2,5-dimethoxy-benzaldehyde, 2-aminoacetaldehyde dimethyl acetal, sodium borohydride, phthalic anhydride, and various reagents for protection and deprotection of functional groups, as well as for the final glycosidation step.
