The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

Pathway Bifurcation in the (4 + 3)/(5 + 2)-Cycloaddition of Butadiene and Oxidopyrylium Ylides: The Significance of Molecular Orbital Isosymmetry.

By drawing analogies from the dimerization of cyclopentadiene, a novel reaction pathway bifurcation is uncovered in the cycloaddition of oxidopyrylium ylides and butadiene. Analysis of the potential energy surface (at the M06-2X/6-311+G(d,p) level of theory) in combination with Born-Oppenheimer molecular dynamics simulations (M06-2X/6-31+G(d)) demonstrate that both the (4 + 3)- and (5 + 2)-cycloaddition products are accessed from the same transition state. Key indicators of a pathway bifurcation (asynchronous bond formation, and a second transition state for the interconversion of the products) are also observed. The absence of a post-transition state bifurcation in the related oxidopyridinium systems of Krenske and Harmata is rationalized. Finally, the isosymmetry of the oxidopyrylium and cyclopentadiene molecular orbitals as well as the presence of "secondary orbital interactions" are emphasized as the common source of nonstatistical behavior. Application of these principles will allow for the rapid identification of new reaction pathway bifurcations.

Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor.

D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure-activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.