No abstract

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6 – 8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6 – 8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate.

Two new fluorescent probes of protein structure and dynamics have been prepared by concise asymmetric syntheses using the Schöllkopf chiral auxiliary. The site-specific incorporation of one probe into dihydrofolate reductase is reported. The utility of these tryptophan derivatives lies in their absorption and emission maxima which differ from those of tryptophan, as well as in their large Stokes shifts and high molar absorptivities.

The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis. Regrettably, the synthetic dolastatin 16 (1), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (1) or to a chemically undetected component isolated with the natural product.

An aza analogue (1) of the experimental neuroprotective drug idebenone has been prepared and evaluated. The compound quenches lipid peroxidation more effectively than R-tocopherol and potently suppresses reactive oxygen species in cells under oxidative stress. It is thought to do so via a catalytic cycle in which both forms of oxidative stress are suppressed simultaneously. Consequently, the compound effectively protects cultured CEM leukemia cells and Friedreich's ataxia fibroblasts from oxidative stress more effectively than idebenone or idebenol.

A family of six homoleptic [Cu (L )] (ClO ) and six heteroleptic [Cu (L )(PPh ) ] (ClO ) bimetallic complexes, in which L are bis-Schiff base ligands with alkyl spacers of variable length (n=2-7 -CH -), were prepared to evaluate the role of the spacer on the formation of helicates or mesocates. In the homoleptic series, spectroscopic and theoretical studies indicate that preferences for a conformation are based on energetic parameters, mainly, the establishment of noncovalent interactions. The odd-even nature of the spacers preconditions the superposition of the aromatic rings to allow the juxtaposition necessary for noncovalent interactions, whereas the increase of the length reduces the strength of such interactions. Consequently, complexes with even-spacers of short length were identified as helicates in solution, [Cu (L )] (n=2, 4). Complexes [Cu (L )] (n=3-7) dissociate in solution to produce the monometallic complexes in equilibrium, [Cu (L )] . The stability of the bimetallic species is discussed in terms of their conformations. The set of heteroleptic complexes was prepared to evaluate the reach of the "odd-even rule" in the solid, which is based on the "zig-zag" arrangements of the spacers. Based on crystallographic information, "S-" and "C"-type conformations of L are related to even and odd spacers, respectively. This trend is considered in addition to other factors to explain preferences for either a mesocate or helicate conformation in the homoleptic series.

A series of aza analogues (4−9) of the experimental neuroprotective drug idebenone (1) have been prepared and evaluated for their ability to attenuate oxidative stress induced by glutathione depletion and to compensate for the decrease in oxidative phosphorylation efficiency in cultured Friedreich's ataxia (FRDA) fibroblasts and lymphocytes and also coenzyme Q 10 -deficient lymphocytes. Modification of the redox core of the previously reported 3 improved its antioxidant and cytoprotective properties. Compounds 4−9, having the same redox core, exhibited a range of antioxidant activities, reflecting side chain differences. Compounds having side chains extending 14−16 atoms from the pyrimidinol ring (6, 7, and 9) were potent antioxidants. They were superior to idebenone and more active than 3, 4, 5, and 8. Optimized analogue 7 and its acetate (7a) are of interest in defining potential therapeutic agents capable of blocking oxidative stress, maintaining mitochondrial membrane integrity, and augmenting ATP levels. Compounds with such properties may find utility in treating mitochondrial and neurodegenerative diseases such as FRDA and Alzheimer's disease. KEYWORDS: Mitochondrial dysfunction, electron transport chain, lipid peroxidation, cytoprotection, adenosine triphosphate M itochondrial dysfunction is linked to numerous neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia.1−6 Mitochondria are vitally important organelles involved in many essential cellular functions, notably energy metabolism. They produce 90% of our cellular ATP through oxidative phosphorylation within the mitochondrial respiratory chain.7−11 Within mitochondria, the primary site of reactive oxygen species (ROS) generation is the electron transport chain; 12,13 normally, mitochondria have an extensive network of antioxidant and detoxification systems, ensuring that lipid peroxidation and levels of ROS are kept at physiologically acceptable levels.14,15 Defects in the mitochondrial respiratory chain can undoubtedly lead to increased electron leakage and consequently to increased ROS production, causing progressive oxidative damage and ultimately cell death. 2−5,10,16The antioxidant and bioenergetic effects of coenzyme Q (CoQ 10 ) are well-known, 17,18 but its clinical utility is limited by its extreme hydrophobicity, which results in low bioavaibility. 19,20 To facilitate the delivery of such molecules to the mitochondria of cells, we have designed antioxidants bearing smaller lipophilic side chains and having pyrimidinol 21 or pyridinol 22−26 redox cores, based on earlier studies. 27−30 We demonstrated that an aza analogue of idebenone (3, Figure 1), having the 1,4-benzoquinone core replaced with a pyrimidinol core, retained the ability to function within the mitochondria. 21Because these aza analogues function at a number of levels to suppress damage that would otherwise be caused by electron leakage from the electron transport chain, we have denoted them multifunct...

No abstract