Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides.

The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.

Site-Selective Aliphatic C-H Chlorination Using N-Chloroamides Enables a Synthesis of Chlorolissoclimide.

Methods for the practical, intermolecular functionalization of aliphatic C-H bonds remain a paramount goal of organic synthesis. Free radical alkane chlorination is an important industrial process for the production of small molecule chloroalkanes from simple hydrocarbons, yet applications to fine chemical synthesis are rare. Herein, we report a site-selective chlorination of aliphatic C-H bonds using readily available N-chloroamides and apply this transformation to a synthesis of chlorolissoclimide, a potently cytotoxic labdane diterpenoid. These reactions deliver alkyl chlorides in useful chemical yields with substrate as the limiting reagent. Notably, this approach tolerates substrate unsaturation that normally poses major challenges in chemoselective, aliphatic C-H functionalization. The sterically and electronically dictated site selectivities of the C-H chlorination are among the most selective alkane functionalizations known, providing a unique tool for chemical synthesis. The short synthesis of chlorolissoclimide features a high yielding, gram-scale radical C-H chlorination of sclareolide and a three-step/two-pot process for the introduction of the ß-hydroxysuccinimide that is salient to all the lissoclimides and haterumaimides. Preliminary assays indicate that chlorolissoclimide and analogues are moderately active against aggressive melanoma and prostate cancer cell lines.

Progress towards a DNA-based model system for the study of electron spin-spin interactions.

A DNA-based model system is described for studying electron spin-spin interactions between a paramagnetic metal ion and a nitroxide spin label. The modified base deoxythymidine-EDTA (dT-EDTA) chelates the divalent or trivalent metal ion and produces a new feature in the circular dichroism (CD) spectra that makes it possible to monitor local DNA melting. Based on the results of optical and electron paramagnetic resonance (EPR) experiments, we find that the terminus of the DNA duplex that incorporates dT-EDTA and the spin-label melts at a higher temperature than the rest of the DNA duplex. EPR microwave progressive power saturation experiments performed at 77 K are consistent with the specific binding of Dy(III) at the EDTA site and an intramolecular dipole-dipole interaction between the nitroxide spin-label and the chelated Dy(III). This model system should be suitable for studying the relaxation properties of metal ions by saturation-recovery EPR.