Screen for Small-Molecule Modulators of Circadian Rhythms Reveals Phenazine as a Redox-State Modifying Clockwork Tuner.

A high-throughput cell-based screen identified redox-active small molecules that produce a period lengthening of the circadian rhythm. The strongest period lengthening phenotype was induced by a phenazine carboxamide (VU661). Comparison to two isomeric benzquinoline carboxamides (VU673 and VU164) shows the activity is associated with the redox modulating phenazine functionality. Furthermore, ex vivo cell analysis using optical redox ratio measurements shows the period lengthening phenotype to be associated with a shift to the NAD/FAD oxidation state of nicotinamide and flavine coenzymes.

An unexpected effect of acetal stereochemistry on the course of its reductive cleavage.

Alternate routes to the BC spirocycle of 'upenamide starting from Diels-Alder adduct 1 are described. Key to utilizing 1 in a synthesis of 'upenamide is the differentiation of three functionalized carbons by either oxidation or protection state. A surprising effect of acetal stereochemistry on reaction course was observed and rationalized.

A concise Diels-Alder strategy leading to congeners of the ABC ring system of the marine alkaloid 'upenamide.

A second-generation approach to the BC spirocycle of 'upenamide is reported. Central to the synthesis is an endo selective Diels-Alder reaction between 1-(t-butyldimethylsiloxy)-1,3-butadiene and bromomaleic anhydride followed by a radical mediated allylation of the ring fusion bromide. Functional group manipulation provides three (9-11) advanced synthetic intermediates ready for coupling with the remaining half (DE bicycle) of 'upenamide.