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Drugs exert desired and undesired effects based on theirbindinginteractions with protein target(s) and off-target(s), providing evidencefor drug efficacy and toxicity. Pioglitazone and rosiglitazone possessa common functional core, glitazone, which is considered a privilegedscaffold upon which to build a drug selective for a given targetinthis case, PPARγ. Herein, we report a retrospective analysisof two variants of the glitazone scaffold, pioglitazone and rosiglitazone,in an effort to identify off-target binding events in the rat heartto explain recently reported cardiovascular risk associated with thesedrugs. Our results suggest that glitazone has affinity for dehydrogenases,consistent with known binding preferences for related rhodanine cores.Both drugs bound ion channels and modulators, with implications incongestive heart failure, arrhythmia, and peripheral edema. Additionalproteins involved in glucose homeostasis, synaptic transduction, andmitochondrial energy production were detected and potentially contributeto drug efficacy and cardiotoxicity. [ABSTRACT FROM AUTHOR] more...

To gauge the feasibility of carbenoid eliminative cross-coupling for the synthesis of polyfunctional alkenes, a P-glycoprotein inhibitor containing an ( E )-configured 4-chromanylidene-type trisubstituted olefin was prepared as well as its previously undescribed ( Z )-isomer. Stereospecific alkene synthesis required generation of functionalized enantioenriched α-metalated carbamates [R 1 R 2 CM(O 2 CN i -Pr 2 ), M = Li or Bneo], and problems associated with incorrect lithiation regioselectivity and unexpected organolithium configurational lability were encountered. Solutions to these difficulties are described together with a method for ee determination of α-carbamoyloxyboronates. more...