ABSTRACT
A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2', C-3' and C-11' positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Streptonigrin/analogs & derivatives , Antineoplastic Agents/metabolism , Antineoplastic Agents/toxicity , Cell Line, Tumor , Humans , NAD(P)H Dehydrogenase (Quinone)/chemistry , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Streptonigrin/chemistry , Streptonigrin/metabolism , Streptonigrin/toxicity , Structure-Activity RelationshipABSTRACT
1,1-Dimethylallyl (DMA) esters of various N-protected amino acids have been synthesized using prenyldimethylsulfonium tetrafluroborate, a reagent that can be readily made and stored, in conjunction with catalytic CuBr. These reactions were complete within several hours and afforded DMA esters in high yields. As has been previously shown in our group, DMA esters represent a palladium-labile proctecting group for carboxylic acids that resists nucleophilic attack as a tert-butyl ester would.
Subject(s)
Carboxylic Acids/chemistry , Esters , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray IonizationABSTRACT
[reaction: see text] Carboxylic acids were converted in high yield to their 1,1-dimethylallyl (DMA) esters in two steps. Palladium-catalyzed deprotection of DMA esters was shown to be compatible with tert-butyl, benzyl, and Fmoc protecting groups, and Fmoc deprotection could be carried out selectively in the presence of DMA esters. DMA esters were also shown to be resistant to nucleophilic attack, suggesting that they will serve as alternatives to tert-butyl esters when acidic deprotection conditions need to be avoided.
