ABSTRACT
The natural product Rocaglamide (1), isolated from the tree Aglaia elliptifolia, is a compelling but also challenging lead structure for crop protection. In laboratory assays, the natural product shows highly interesting insecticidal activity against chewing pests and beetles, but also phytotoxicity on some crop plants. Multi-step syntheses with control of stereochemistry were required to probe the structure-activity relationship (SAR), and seek simplified analogues. After a significant research effort, just two areas of the molecule were identified which allow modification whilst maintaining activity, as will be highlighted in this paper.
Subject(s)
Benzofurans/pharmacology , Insecticides/pharmacology , Benzofurans/chemical synthesis , Benzofurans/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
[reaction: see text] A new total synthesis of (-)-agelastatin A (1) has been achieved from the chiral oxazolidinone (-)-3. Although enone transposition was problematic when the Michael ring closure of 2 was attempted with strong base, the desired cyclization could be effected with Hunig's base after the pyrrole nucleus was brominated. Subsequent reduction and monobromination afforded synthetic (-)-agelastatin A (1).
Subject(s)
Alkaloids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Oxazolidinones/chemical synthesis , Porifera/chemistry , Alkaloids/pharmacology , Animals , Antineoplastic Agents/pharmacology , Catalysis , Indicators and Reagents , Molecular Structure , Oxazolidinones/pharmacology , StereoisomerismABSTRACT
Four series of C-10 non-acetal dimers were prepared from key trioxane alcohol 10beta-(2-hydroxyethyl)deoxoartemisinin (9b). All of the dimers prepared displayed potent low nanomolar antimalarial activity versus the K1 and HB3 strains of Plasmodium falciparum. The most potent compound assayed was phosphate dimer 14a, which was greater than 50 times more potent than the parent drug artemisinin and about 15 times more potent than the clinically used acetal artemether. In contrast to their potent activity versus malaria parasites, virtually all of the dimers expressed poor anticancer activity apart from the trioxane phosphate ester dimers 14a and 14b, which expressed nanomolar growth inhibitory (GI50) values versus a range of cancer cell lines in the NCI 60 human cell line screen. Further detailed studies on these dimers in vitro in HL60 cells demonstrate that both phosphate ester dimers (14a and 14b) are more potent than the anticancer agent doxorubicin. Interestingly, phosphate ester monomers 9c and 9d, antimalarially active in the low nanomolar region versus P. falciparum, are inactive as anticancer agents even at concentrations in the millimolar region. This observation emphasizes the importance of two trioxane units for high antiproliferative activity, and we propose that the nature of the linker in dimers of this type plays a crucial role in imparting potent anticancer activity.
Subject(s)
Acetals/chemical synthesis , Antimalarials/chemical synthesis , Antineoplastic Agents/chemical synthesis , Artemisinins/chemical synthesis , Acetals/chemistry , Acetals/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Artemisinins/chemistry , Artemisinins/pharmacology , Cell Line, Tumor , Dimerization , Drug Resistance , Drug Screening Assays, Antitumor , Flow Cytometry , Humans , Plasmodium falciparum/drug effects , Structure-Activity RelationshipABSTRACT
[reaction: see text] An enantiospecific total synthesis of Weinreb's advanced intermediate 2 for (-)-agelastatin A has been achieved from the Hough-Richardson aziridine 8. Noteworthy reactions in our sequence include the highly regioselective trans-diaxial ring-opening of 8 with azide ion to set up the vicinal diamido functionality present within (-)-2 and the Grubbs-Hoveyda ring-closing metathesis (RCM) reaction that was used to construct its cyclopentene core.
