Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.
Herein, we report the development of an anti-filoviral screening system, based on a pseudotyping strategy, and its application in the discovery of a novel group of small molecules that selectively inhibit the Ebola and Marburg glycoprotein (GP)-mediated infection of human cells. Using Ebola Zaire GP-pseudotyped HIV particles bearing a luciferase reporter gene and 293T cells, a library of 237 small molecules was screened for inhibition of GP-mediated viral entry. From this assay, lead compound 8a was identified as a selective inhibitor of filoviral entry with an IC 50 of 30 μM. In order to analyze functional group requirements for efficacy, a structure-activity relationship analysis of this 3,5-disubstituted isoxazole was then conducted with 56 isoxazole and triazole derivatives prepared using "click" chemistry. This study revealed that while the isoxazole ring can be replaced by a triazole system, the 5-(diethylamino)acetamido substituent found in 8a is required for inhibition of viral-cell entry. Variation of the 3-aryl substituent provided a number of more potent anti-viral agents with IC 50 values ranging to 2.5 μM. Lead compound 8a and three of its derivatives were also found to block the Marburg glycoprotein (GP)-mediated infection of human cells.
The reduction of carbon-carbon multiple bonds in alkynes and olefins supported on a polystyrene resin has been investigated. Homogeneous catalysis by titanocene reagents is effective for the stereoselective preparation of cis-olefins from diarylacetylenes, while the use of copper(I) hydride reagents is effective for the reduction of alpha,beta-unsaturated ketones.
The embodiment of lactam rings within a wealth of physiologically active natural products and pharmaceutical agents ensures that the development of synthetic methods, which facilitate the preparation of these saturated N-heterocycles, is of critical importance. Herein the development of a versatile method for the synthesis of 4 to 8-membered α-vinyl and α-(2-silylvinyl) lactams involving the iodine(III)-mediated oxidative cyclization of unsaturated O-alkyl hydroxamates, which encompass an allylsilane, is reported. Importantly, the outcome of this transformation can be effectively controlled through variation of the substitution pattern at the silicon center. While allyltrimethylsilanes undergo ring closure with desilylation to form α-vinyl lactams, the corresponding triisopropyl and triphenylsilanes cyclize without loss of the larger silyl group to form E-vinylsilanes with excellent stereoselectivity. From a mechanistic standpoint, it is proposed that this reaction proceeds via concerted alkene addition of a singlet nitrenium ion (or its equivalent) to form a bicyclic N-acyl-N-alkoxyaziridinium ion, which undergoes eliminative ring opening.
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