No abstract

Over the past decade, surface-modified, water soluble fullerenes have been shown by many different investigators to exhibit strong antioxidant activity against reactive oxygen species (ROS) in vitro and to protect cells and tissues from oxidative injury and cell death in vivo. Nevertheless, progress in developing fullerenes as bona fide drug candidates has been hampered by three development issues: 1) lack of methods for scalable synthesis; 2) inability to produce highly purified, single-species regioisomers compatible with pharmaceutical applications; and 3) inadequate understanding of structure-function relationships with respect to various surface modifications (e.g., anionic versus cationic versus charge-neutral polarity). To address these challenges, we have designed and synthesized more than a dozen novel water soluble fullerenes that can be purified as single isomers and which we believe can be manufactured to scale at reasonable cost. These compounds differ in addition pattern, lipophilicity and number and type of charge and were examined for their water solubility, antioxidant activity against superoxide anions and binding of cytochrome C. Our results indicate that dendritic water soluble fullerene[60] monoadducts exhibit the highest degree of antioxidant activity against superoxide anions in vitro as compared with trismalonate-derived anionic fullerenes as well as cationic fullerenes of similar overall structure. Among the higher adducts, anionic derivatives have a higher antioxidant activity than comparable cationic compounds. To achieve sufficient water solubility without the aid of a surfactant or co-solvent at least three charges on the addends are required. Significantly, anionic in contrast to cationic fullerene adducts bind with high affinity to cytochrome C.

The stereochemistry and secondary isotope effects of the [2 + 2] photocycloaddition of trans, trans- (7), cis,cis- (8), and cis,trans-2,4-hexadiene (9), 2,5-dimethyl-2,4-hexadiene (1), and its deuterated analogues 1- d 1 , 1- d 6 , and trans -1- d 3 to C60 have been investigated. A loss of stereochemistry in the cyclobutane ring for photocycloaddition of all three 2,4-hexadiene isomers 7, 8, and 9 to C60 was observed (the trans stereochemistry in the cyclobutane ring predominates in all cases), while the unreactive double bond retained its stereochemical integrity in the adducts. The cis double bond of 9 is 1.5 times more reactive than the trans. The [2 + 2] photocycloaddition of (E)-2,4-dimethyl-2,4-hexadiene (10) to C60 is regiospecific, affording two diastereomeric adducts, 10a and 10b, by addition on the methyl monosubstituted terminal double bond. These results, when taken in conjunction with the small inverse intramolecular secondary isotope effect (k H/k D = 0.90 ± 0.05) in the [2 + 2] photocycloaddition of 1- d 6 to C60, favor the formation of an open biradical intermediate in the rate-determining step.

The dynamic adaptability of tetragonal prismatic nanocapsule 1 8+ in the selective separation of fullerenes and endohedral metallofullerenes (EMFs) remains unexplored. Therefore, the essential molecular details of the fullerene recognition and binding process into the coordination capsule and the origins of fullerene selectivity remain elusive. In this work, the key steps of fullerene recognition and binding processes have been deciphered by designing a protocol which combines 1 H− 1 H exchange spectroscopy (2D-EXSY) NMR experiments, long time-scale Molecular Dynamics (MD) and accelerated Molecular Dynamics (aMD) simulations, which are combined to completely reconstruct the spontaneous binding and unbinding pathways from nanosecond to second timerange. On one hand, binding (k′ on ) and unbinding (k off ) rate constants were extracted from 1 H− 1 H exchange spectroscopy (EXSY) NMR experiments for both C 60 and C 70 . On the other hand, MD and aMD allowed monitoring the molecular basis of the encapsulation and guest competition processes at a very early stage under nonequilibrium conditions. The receptor capsule displays dynamical adaptability features similar to those observed in the process of biomolecular recognition in proteins. In addition, the encapsulation of bis-aza[60]fullerene (C 59 N) 2 within a supramolecular coordination capsule has been studied for the first time, showcasing the pros and cons of the dumbbell-shaped guest in the dynamics of the encapsulation process and in the stability of the final bound adduct. The powerful combination of NMR, MD, and aMD methodologies allows to obtain a precise picture of the subtle events directing the encapsulation and is thus a predictive tool for understanding host−guest encapsulation and interactions in numerous supramolecular systems.

The synthesis and flash column chromatographic separation of enantiomerically pure tris-adducts of C60 with an e,e,e-addition pattern is achieved via cyclopropanation with chiral D3-symmetrical cyclo-tris(malonate) tethers.