Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereo-chemistry in this class of compounds has a major effect on their binding affinities to MDM2; with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.

Despite four additional electron‐withdrawing substituents, the octahalogenated porphyrins 2 are more easily oxidized than their tetra‐halogenated counterparts 1. This apparent paradox can be explained by the structures of the molecules: porphyrins 2 are almost planar, whereas in 1 steric interactions are minimized by a saddle conformation, which makes these porphyrins easier to oxidize.

This study evaluates the impact of the extension of the π-conjugated system of pyridiniums on their various properties. The molecular scaffold of aryl-substituted expanded pyridiniums (referred to as branched species) can be photochemically bis-cyclized into the corresponding fused polycyclic derivatives (referred to as pericondensed species). The representative 1,2,4,6-tetraphenylpyridinium (1(H)) and 1,2,3,5,6-pentaphenyl-4-(p-tolyl)pyridinium (2(Me)) tetra- and hexa-branched pyridiniums are herein compared with their corresponding pericondensed derivatives, the fully fused 9-phenylbenzo[1,2]quinolizino[3,4,5,6-def]phenanthridinium (1(H)f) and the hitherto unknown hemifused 9-methyl-1,2,3-triphenylbenzo[h]phenanthro[9,10,1-def]isoquinolinium (2(Me)f). Combined solid-state X-ray crystallography and solution NMR experiments showed that stacking interactions are barely efficient when the pericondensed pyridiniums are not appropriately substituted. The electrochemical study revealed that the first reduction process of all the expanded pyridiniums occurs at around -1 V vs. SCE, which indicates that the lowest unoccupied molecular orbital (LUMO) remains essentially localized on the pyridinium core regardless of pericondensation. In contrast, the electronic and photophysical properties are significantly affected on going from branched to pericondensed pyridiniums. Typically, the number of absorption bands increases with extended activity towards the visible region (down to ca. 450 nm in MeCN), whereas emission quantum yields are increased by three orders of magnitude (at ca. 0.25 on average). A relationship is established between the observed differential impact of the pericondensation and the importance of the localized LUMO on the properties considered: predominant for the first reduction process compared with secondary for the optical and photophysical properties.

A new class of triarylpyridinio-derivatized [4'-(p-phenyl)(n)]terpyridyl ligands, R(1)(2)R(2)TP(+)-(p)(n)tpy, was designed as a novel category of electron-acceptor (A)-substituted proto-photosensitizing molecules. The first elements of this versatile family of ligands (i.e., n = 0, 1 and R(1) = R(2) = H), H(3)TP(+)-tpy and H(3)TP(+)-ptpy, were synthesized as well as their Ru(II) and Os(II) complexes to form the related acceptor-functionalized M(tpy)(2)(2+) and M(ptpy)(2)(2+) photosensitizer components denoted P0 and P1, respectively. Within the P1 series of compounds, an electron-donor (D)-substituted ligand, Me(2)N-ptpy, was also involved and associated with H(3)TP(+)-ptpy, giving rise to various combinations (up to 10 polyad systems). The two resulting series of nanometer-scale rigid rod-like photosensitized supramolecular architectures are of potential interest for long-range photoinduced electron transfer purposes. The main structural features of such supermolecules were determined by comparing the results obtained from (i) single-crystal X-ray analysis of the two free ligands together with that of the P0A/Ru and P1A(2)/Ru complexes and (ii) a detailed solution (1)H NMR study of the P0 series and, more specifically, of the P0A/Ru dyad (ROESY experiment). It is shown that the pseudoperpendicular conformation of the covalently linked A and P subunits found in the solid state is persistent in fluid medium; i.e., A is not conjugated with P (P0 and P1). The first insights regarding the consequences upon intercomponent couplings of combined substituent effects and conjugation (case of D-based polyads)-or absence of conjugation-are discussed in the light of ground-state electronic properties of the compounds.

An unprecedented solid‐state reaction of a fullerene monoadduct leads to the antipodal fullerene bisadduct 1. This regiospecific transfer of anthracene appears to be driven by an increase in entropy.

As an alternative to conventional charge-separation functional molecular models based on long-range ET within redox cascades, a "compact approach" has been examined. To this end, spacer elements usually inserted between main redox-active units within polyad systems have been removed, allowing extended rigidity but at the expense of enhanced intercomponent electronic communication. The molecular assemblies investigated here are of the P-(theta (1))-A type, where the theta (1) twist angle is related to the degree of conjugation between the photosensitizer (P, of {Ru(bpy)(3)}(2+) type) and the electron-acceptor (A). 4-N- and 4-N-,4'-N-(2,4,6-triphenylpyridinio)-2,2'-bipyridine ligands (A(1)-bpy and A(2)-bpy, respectively) have been synthesized to give complexes with Ru(II), 1-bpy and 2-bpy, respectively. Combined solid-state analysis (X-ray crystallography), solution studies ((1)H NMR, cyclic voltammetry) and computational structural optimization allowed verifying that theta (1) angle approaches 90 degrees within 1-bpy and 2-bpy in solution. Also, anticipated existence of strong intercomponent electronic coupling has been confirmed by investigating electronic absorption properties and electrochemical behavior of the compounds. The capability of 1-bpy and 2-bpy to undergo PET process was evaluated by carrying out their photophysical study (steady state emission and time-resolved spectroscopy at both 293 and 77 K). The conformational dependence of photoinduced processes within P-(theta (1))-A systems has been established by comparing the photophysical properties of 1-bpy (and 2-bpy) with those of an affiliated species reported in the literature, 1-phen. A complementary theoretical analysis (DFT) of the change of spin density distribution within model [1-bpy(theta (1))](-) mono-reduced species as a function of theta (1) has been undertaken and the possibility of conformationally switching emission properties of P was derived.

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Carbon monoxide and nitrobenzene react under Pd catalysis, for example, with Pd(OAc)2/o‐phenanthroline, to give phenylisocyanate, which forms very stable palladacycles such as 1 with catalytic intermediates. The results provide insight into the mechanism of this important catalytic reaction.