Lisa M. Pérez

Gold–Silane and Gold–Stannane Complexes: Saturated Molecules as σ‐Acceptor Ligands

The discovery that saturated molecules may form s complexes by side-on coordination of a s bond to a transition metal represents a major breakthrough in transition-metal chemistry. Over the years, considerable progress has been made in the understanding of this bonding situation. The coordination and activation of s bonds involving Group 14 elements (E = C, Si, Ge, Sn, Pb) is at the forefront of developments in this area. An increasing variety of complexes A and B 7] (Scheme 1) featuring side-on coordinated s(E H) and s(E E) bonds have been isolated, and the key factors governing the delicate balance between dissociation and oxidative addition have been progressively identified. The common feature and believed prerequisite for the coordination of saturated molecules free of lone pairs to transition metals is the superposition of ligand!metal donation (from a filled s orbital of the ligand to an empty d orbital of the metal) and metal!ligand back-donation (from a filled d orbital of the metal to an empty s* orbital of the ligand). Aiming at identifying new types of metal–ligand interactions, and stimulated by our work on Group 13 Lewis acids as acceptor ligands, we recently became interested in complexes of type C, in which a saturated Group 14 element could behave as an end-on, s-acceptor ligand toward a transition metal. Heavier Group 14 elements such as silicon and tin are known to readily form hypervalent compounds through donor!acceptor interactions with organic Lewis bases. A related situation is envisioned in complexes C, with a transition metal acting as a Lewis base. Such donor! acceptor interactions between transition metals and silanes or stannanes have been invoked in a few highly strained complexes on the basis of relatively short M E distances. Furthermore, the presence of a Pd!Sn dative bond was recently evidenced structurally and theoretically in a palladastannatrane cage complex supported by four methimazolyl groups. Herein, we report the straightforward synthesis and complete characterization of three gold complexes supported by diphosphino silane and stannane ligands. The presence of metal!silane and metal!stannane interactions in these complexes has been substantiated spectroscopically, structurally, and theoretically, thus providing unambiguous evidence for the existence of complexes of type C. From our previous studies on Group 13 Lewis acids, the use of two phosphine buttresses ligated by ortho-phenylene spacers was considered as a good compromise in order to support, but not impose, the coordination of the Group 14 element. We thus targeted the two complexes [o{(iPr2P)C6H4}2E(Ph)FAuCl] 2 (E = Si) and 4 (E = Sn). The Scheme 1. Complexes A–C featuring Group 14 saturated molecules coordinated to transition metals (E= C, Si, Ge, Sn, Pb).

Pyrrolinone-pyrrolidine oligomers as universal peptidomimetics.

Peptidomimetics 1-3 were prepared from amino acid-derived tetramic acids 7 as the key starting materials. Calculations show that preferred conformations of 1 can align their side-chain vectors with amino acids in common secondary structures more effectively than conformations of 3. A good fit was found for a preferred conformation of 2 (an extended derivative of 1) with a sheet/β-turn/sheet motif.

Thermal Decomposition Pathways of Hydroxylamine: Theoretical Investigation on the Initial Steps

Hydroxylamine (NH(2)OH) is an unstable compound at room temperature, and it has been involved in two tragic industrial incidents. Although experimental studies have been carried out to study the thermal stability of hydroxylamine, the detailed decomposition mechanism is still in debate. In this work, several density functional and ab initio methods were used in conjunction with several basis sets to investigate the initial thermal decomposition steps of hydroxylamine, including both unimolecular and bimolecular reaction pathways. The theoretical investigation shows that simple bond dissociations and unimolecular reactions are unlikely to occur. The energetically favorable initial step of decomposition pathways was determined as a bimolecular isomerization of hydroxylamine into ammonia oxide with an activation barrier of approximately 25 kcal/mol at the MPW1K level of theory. Because hydroxylamine is available only in aqueous solutions, solvent effects on the initial decomposition pathways were also studied using water cluster methods and the polarizable continuum model (PCM). In water, the activation barrier of the bimolecular isomerization reaction decreases to approximately 16 kcal/mol. The results indicate that the bimolecular isomerization pathway of hydroxylamine is more favorable in aqueous solutions. However, the bimolecular nature of this reaction means that more dilute aqueous solution will be more stable.

Triazine Dendrimers for Drug Delivery: Evaluation of Solubilization Properties, Activity in Cell Culture, and In Vivo Toxicity of a Candidate Vehicle

Three criteria are evaluated to assess the potential of a dendrimer based on triazines, 1, for use as a vehicle for drug delivery. These criteria are: (1) its ability to solubilize small hydrophobic guests as measured spectrophotometrically; (2) its ability to deliver a drug in vitro as evaluated using a gene reporter assay; and (3) its in vivo toxicity in mice as determined by autopsy and screens of liver and kidney function. Vehicle 1 solubilizes pyrene to a similar extent to dendrimers based on poly(arylether)s, 4, encapsulating approximately 0.2 molecules of pyrene per dendrimer. This activity is approximately 10-fold greater than that of the more polar poly(propyleneimine) and poly(amidoamine) dendrimers, 2 and 3. Gas-phase computational models reveal that both 1 and 4 have cores that are accessible to solvent, suggesting that these dendrimers can occupy much greater volumes than 2 and 3 whose cores are confined toward the interior of the structure. Electrostatic potential maps can be used to rationalize differences in solubilization between 1 and 4. Precipitation results from mixing cationic 1 with the anionic indomethacin, but not with methotrexate, suggesting that the composition of the drug may dictate the scope of delivery applications. Dendrimer 1 solubilizes 10-hydroxycamptothecin and a novel bisindolemethane; approximately four and five molecules of drug per dendrimer are solubilized, respectively. In cell-culture experiments using a luciferase reporter gene assay, the dendrimer:bisindolemethane conjugate shows comparable activity to the bisindolemethane delivered in aqueous DMSO, suggesting that the dendrimer does not preclude delivery of the molecule to an intracellular target. Preliminary toxicology studies of 1 in mice show that this molecule has no adverse toxicity to the kidneys or the liver in single doses delivered intraperitoneally up to 10 mg/kg.

Synthesis of Odd Generation Triazine Dendrimers Using a Divergent, Macromonomer Approach

Using a macromonomer, first, third, and fifth generation triazine dendrimers can be prepared using a divergent approach. The nine-step process to the fifth generation target relies on an iterative two-reactions-per-generation strategy to yield the desired material in approximately 48% overall yield. This target displays 96 surface groups. NMR spectroscopy and mass spectrometry show that exceptionally narrow polydispersity is achieved using this strategy.

Synthesis, structures, and properties of mixed dithiolene-carbonyl and dithiolene-phosphine complexes of tungsten.

A new, high yield synthesis of [Ni(S(2)C(2)Me(2))(2)] (3) is described using 4,5-dimethyl-1,3-dithiol-2-one, Me(2)C(2)S(2)CO (1), as dithiolene ligand precursor. Reaction of (Me(2)C(2)S(2))Sn(n)Bu(2), 2, with WCl(6) produces tris(dithiolene) [W(S(2)C(2)Me(2))(3)] (6) and demonstrates the potential synthetic utility of this compound in metallodithiolene synthesis. The series of compounds [W(S(2)C(2)Me(2))(x)(CO)(6-2x)] (x = 1-3), obtained as a mixture via the reaction of [Ni(S(2)C(2)Me(2))(2)] with [W(MeCN)(3)(CO)(3)], has been characterized structurally. A trigonal prismatic geometry is observed for [W(S(2)C(2)Me(2))(CO)(4)] (4) and confirmed by a DFT geometry optimization to be lower in energy than an octahedron by 5.1 kcal/mol. The tris(dithiolene) compound [W(S(2)C(2)Me(2))(3)] crystallizes in disordered fashion upon a 2-fold axis in C2/c, a different space group than that observed for its molybdenum homologue (P1), which is attributed to a slightly smaller chelate fold angle, alpha, in the former. The reactivity of 4 and [W(S(2)C(2)Me(2))(2)(CO)(2)] (5) toward PMe(3) has been examined. Compound 4 yields only [W(S(2)C(2)Me(2))(CO)(2)(PMe(3))(2)] (7), while 5 produces either [W(S(2)C(2)Me(2))(2)(CO)(PMe(3))] (8) or [W(S(2)C(2)Me(2))(2)(PMe(3))(2)] (9) depending upon reaction conditions. Crystallographic characterization of 5, 8, and 9 reveals a trend toward greater reduction of the dithiolene ligand (i.e., more ene-1,2-dithiolate character) across the series, as manifested by C-C and C-S bond lengths. These structural data indicate a profound effect exerted by the pi-acidic CO ligands upon the apparent state of reduction of the dithiolene ligand in compounds with ostensibly the same oxidation state.

Factors that influence helical preferences for singly charged gas-phase peptide ions: the effects of multiple potential charge-carrying sites.

Ion mobility-mass spectrometry is used to investigate the structure(s) of a series of model peptide [M + H](+) ions to better understand how intrinsic properties affect structure in low dielectric environments. The influence of peptide length, amino acid sequence, and composition on gas-phase structure is examined for a series of model peptides that have been previously studied in solution. Collision cross sections for the [M + H](+) ions of Ac-(AAKAA)(n)Y-NH(2) (n = 3-6) and Ac-Y(AEAAKA)(n)F-NH(2) (n = 2-5) are reported and correlated with candidate structures generated using molecular modeling techniques. The [M + H](+) ions of the AAKAA peptide series each exhibit a single, dominant ion mobility arrival time distribution (ATD) which correlates to partial helical structures, whereas the [M + H](+) ions of the AEAAKA ion series are composed of ATDs which correlate to charge-solvated globules (i.e., the charge is coordinated or solvated by polar peptide functional groups). These data raise numerous questions concerning intrinsic properties (amino acid sequence and composition as well as charge location) that dictate gas-phase peptide ion structure, which may reflect trends for peptide ion structure in low dielectric environments, such as transmembrane segments.

The contributions of molecular framework to IMS collision cross-sections of gas-phase peptide ions.

Molecular dynamics (MD) is an essential tool for correlating collision cross-section data determined by ion mobility spectrometry (IMS) with candidate (calculated) structures. Conventional methods used for ion structure determination rely on comparing the measured cross-sections with the calculated collision cross-section for the lowest energy structure(s) taken from a large pool of candidate structures generated through multiple tiers of simulated annealing. We are developing methods to evaluate candidate structures from an ensemble of many conformations rather than the lowest energy structure. Here, we describe computational simulations and clustering methods to assign backbone conformations for singly-protonated ions of the model peptide (NH2-Met-Ile-Phe-Ala-Gly-Ile-Lys-COOH) formed by both MALDI and ESI, and compare the structures of MIFAGIK derivatives to test the ‘sensitivity’ of the cluster analysis method. Cluster analysis suggests that [MIFAGIK + H]+ ions formed by MALDI have a predominantly turn structure even though the low-energy ions prefer partial helical conformers. Although the ions formed by ESI have collision cross-sections that are different from those formed by MALDI, the results of cluster analysis indicate that the ions backbone structures are similar. Chemical modifications (N-acetyl, methylester as well as addition of Boc or Fmoc groups) to MIFAGIK alter the distribution of various conformers; the most dramatic changes are observed for the [M + Na]+ ion, which show a strong preference for random coil conformers owing to the strong solvation by the backbone amide groups.

A Multifaceted Secondary Structure Mimic Based On Piperidine‐piperidinones

Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus DLD-1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol(-1) above the minimum energy solution state.

Exploring Key Orientations at Protein-protein Interfaces with Small Molecule Probes

Small molecule probes that selectively perturb protein-protein interactions (PPIs) are pivotal to biomedical science, but their discovery is challenging. We hypothesized that conformational resemblance of semirigid scaffolds expressing amino acid side-chains to PPI-interface regions could guide this process. Consequently, a data mining algorithm was developed to sample huge numbers of PPIs to find ones that match preferred conformers of a selected semirigid scaffold. Conformations of one such chemotype (1aaa; all methyl side-chains) matched several biomedically significant PPIs, including the dimerization interface of HIV-1 protease. On the basis of these observations, four molecules 1 with side-chains corresponding to the matching HIV-1 dimerization interface regions were prepared; all four inhibited HIV-1 protease via perturbation of dimerization. These data indicate this approach may inspire design of small molecule interface probes to perturb PPIs.