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1.  Targeting receptor-mediated endocytotic pathways with nanoparticles: rationale and advances 
Advanced drug delivery reviews  2012;65(1):121-138.
Targeting of drugs and their carrier systems by using receptor-mediated endocytotic pathways was in its nascent stages 25 years ago. In the intervening years, an explosion of knowledge focused on design and synthesis of nanoparticulate delivery systems as well as elucidation of the cellular complexity of what was previously-termed receptor-mediated endocytosis has now created a situation when it has become possible to design and test the feasibility of delivery of highly specific nanoparticle drug carriers to specific cells and tissue. This review outlines the mechanisms governing the major modes of receptor-mediated endocytosis used in drug delivery and highlights recent approaches using these as targets for in vivo drug delivery of nanoparticles. The review also discusses some of the inherent complexity associated with the simple shift from a ligand-drug conjugate versus a ligand-nanoparticle conjugate, in terms of ligand valency and its relationship to the mode of receptor-mediated internalization.
doi:10.1016/j.addr.2012.09.041
PMCID: PMC3565049  PMID: 23026636
Endocytosis; Drug Delivery; Cellular Targeting; Multivalent Targeting
2.  Direct organocatalytic coupling of carboxylated piperazine-2,5-diones with indoles through conjugate addition of carbon nucleophiles to indolenine intermediates 
Tetrahedron letters  2010;51(4):609-612.
The indole–diketopiperazine bridge is an important structural feature of many bispyrrolidinoindoline and epipolythiodiketopiperazine fungal metabolites. Organocatalytic conjugate addition of diketopiperazines to indoles was achieved in good to excellent yields through electrophilic indolenine intermediates generated under mild conditions. Screening of catalysts and solvents at different temperatures was performed in order to achieve high product yields.
doi:10.1016/j.tetlet.2009.11.068
PMCID: PMC2805156  PMID: 20161551
4.  Direct Inhibition of Hypoxia-Inducible Transcription Factor Complex with Designed Dimeric Epidithiodiketopiperazine 
Journal of the American Chemical Society  2009;131(50):18078-18088.
Selective blockade of hypoxia-inducible gene expression by designed small molecules would prove valuable in suppressing tumor angiogenesis, metastasis and altered energy metabolism. We report the design, synthesis, and biological evaluation of dimeric epidithiodiketopiperazine (ETP) small molecule transcriptional antagonist targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1α. Our results indicate that disrupting this interaction results in rapid downregulation of hypoxia-inducible genes critical for cancer progression. The observed effects are compound-specific and dose-dependent. Controlling gene expression with designed small molecules targeting the transcription factor-coactivator interface may represent a new approach for arresting tumor growth.
doi:10.1021/ja807601b
PMCID: PMC2796602  PMID: 20000859
5.  Enantioselective organocatalytic α-sulfenylation of substituted diketopiperazines 
Tetrahedron, asymmetry  2009;20(23):2742-2750.
The asymmetric organocatalytic α-sulfenylation of substituted piperazine-2,5-diones is reported, with cinchona alkaloids as chiral Lewis bases and electrophilic sulfur transfer reagents. Catalyst loadings, the type of sulfur transfer reagent, temperature and solvent were investigated in order to optimize the reaction conditions. The effects of ring substitution and the type of catalyst on the yield and enantioselectivity of the reaction are reported.
doi:10.1016/j.tetasy.2009.10.037
PMCID: PMC2811878  PMID: 20161615
6.  Polymorphism and phase transition behavior of 6,6′-bis­(chloro­meth­yl)-1,1′,4,4′-tetra­methyl-3,3′-(p-phenyl­enedimethyl­ene)bis­(piperazine-2,5-dione) 
A crystallographic investigation of the title compound, C22H28Cl2N4O4, using crystals obtained under different crystallization conditions, revealed the presence of two distinct polymorphic forms. The mol­ecular conformation in the two polymorphs is very different: one adopts a ‘C’ shape, whereas the other adopts an ‘S’ shape. In the latter, the molecule lies across a crystallographic twofold axis. The ‘S’-shaped polymorph undergoes a reversible ortho­rhom­bic-to-monoclinic phase transition on cooling, whereas the structure of the ‘C’-shaped polymorph is temperature insensitive.
doi:10.1107/S0108270109024457
PMCID: PMC2720150  PMID: 19652319
7.  Efficient Organocatalytic α-Sulfenylation of Substituted Piperazine-2,5-diones 
Tetrahedron letters  2009;50(30):4310-4313.
Organocatalytic α-sulfenylation of substituted piperazine-2,5-diones is reported through the use of cinchona alkaloids as Lewis bases and electrophilic sulfur transfer reagents. 1-Phenylsulfanyl[1,2,4]triazole, a novel sulfur transfer reagent, gave excellent product yields with a number of substituted piperazine-2,5-diones under mild conditions. Catalyst loading, stoichiometry of sulfur electrophile, temperature and solvent were optimized to achieve high product yields.
doi:10.1016/j.tetlet.2009.05.031
PMCID: PMC2699310  PMID: 20161311
8.  Molecular Solids from Symmetrical Bis(piperazine-2,5-diones) with Open and Closed Monomer Conformations 
Crystal growth & design  2009;9(5):2191-2197.
The design, synthesis and solid state structures of a new class of xylylene-linked bis(1,4- piperazine-2,5-diones) are reported in an effort to extend the molecular framework of piperazine-2,5-diones. These compounds were derived from piperazine-2,5-dione as the core structure, synthesized via a new efficient route, and their crystal structures were determined. We examined the effects of side chain substitution on conformations of the linked bis-DKPs. Crystallization of 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(hydroxymethyl)-1,4-dimethylpiperazine-2,5-dione] yielded molecular solids with an unusual network of “C”-shaped monomers held together by four intermolecular hydrogen bonds per asymmetric unit. Similarly, intermolecular interactions between the iodomethyl groups in 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(iodomethyl)-1,4-dimethyl-piperazine-2,5-dione] result in the monomers adopting a “C”-shape in the solid state. Assembly of the monomers with side chains converted to methyl groups or tert-butyldimethylsilyl ethers, thereby lacking these stabilizing intermolecular interactions, results in an infinite array of “S”-shaped conformations. These results suggest that the interplay between the attractive intermolecular interactions and repulsive steric interactions of the substituents at the C6 and C6' positions of the diketopiperazine rings is important in determining the solid-state conformations of xylylene-linked bis(piperazine-2,5-diones).
doi:10.1021/cg800902u
PMCID: PMC2699313  PMID: 20161254
9.  Diethyl trans-2,5-bis­(4-methoxy­benzyl­sulfan­yl)-1,4-dimethyl-3,6-dioxopiperazine-2,5-carboxyl­ate 
The title compound, C28H34N2O8S2, was synthesized as part of a project to develop synthetic routes to analogues of sporidesmins, a class of secondary metabolite produced by the filamentous fungi Chaetomium and Pithomyces sp. The complete molecule is generated by crystallographic inversion symmetry: the methoxy group is essentially coplanar with the benzene ring to which it is bonded, a mean plane fitted through the non-H atoms of the aromatic ring and the meth­oxy group having an r.m.s. deviation of 0.0140 Å. Similarly, the ester group is also essentially planar (r.m.s. deviation of a plane fitted through all non-H atoms is 0.0101 Å). There is only one independent C—H⋯O inter­action, which links together adjacent mol­ecules into a two-dimensional sheet in the bc plane.
doi:10.1107/S1600536809022211
PMCID: PMC2969498  PMID: 21582859
10.  Completion of a Programmable DNA-Binding Small Molecule Library 
Tetrahedron  2007;63(27):6146-6151.
Hairpin pyrrole-imidazole (Py-Im) polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells and downregulate endogenous gene expression. We complete here a library of 27 hairpin Py-Im polyamides which bind 7-base-pair sequences of the general form 5′-WWGNNNW-3′ (where W = A or T, N = W, G, or C). Their equilibrium association constants (Ka) range from Ka = 1×108 M−1 to 4×1010 M−1 with good sequence specificity. A table of binding affinities and sequence contexts for this completed 27-member library has been assembled for the benefit of the chemical biology community interested in molecular control of transcription.
doi:10.1016/j.tet.2007.03.041
PMCID: PMC2151752  PMID: 18596841
molecular recognition; gene regulation; polyamide; small molecule-nucleic acid interaction
11.  Influence of structural variation on nuclear localization of DNA-binding polyamide-fluorophore conjugates 
Nucleic Acids Research  2004;32(9):2802-2818.
A pivotal step forward in chemical approaches to controlling gene expression is the development of sequence-specific DNA-binding molecules that can enter live cells and traffic to nuclei unaided. DNA-binding polyamides are a class of programmable, sequence-specific small molecules that have been shown to influence a wide variety of protein–DNA interactions. We have synthesized over 100 polyamide-fluorophore conjugates and assayed their nuclear uptake profiles in 13 mammalian cell lines. The compiled dataset, comprising 1300 entries, establishes a benchmark for the nuclear localization of polyamide-dye conjugates. Compounds in this series were chosen to provide systematic variation in several structural variables, including dye composition and placement, molecular weight, charge, ordering of the aromatic and aliphatic amino-acid building blocks and overall shape. Nuclear uptake does not appear to be correlated with polyamide molecular weight or with the number of imidazole residues, although the positions of imidazole residues affect nuclear access properties significantly. Generally negative determinants for nuclear access include the presence of a β-Ala-tail residue and the lack of a cationic alkyl amine moiety, whereas the presence of an acetylated 2,4-diaminobutyric acid-turn is a positive factor for nuclear localization. We discuss implications of these data on the design of polyamide-dye conjugates for use in biological systems.
doi:10.1093/nar/gkh609
PMCID: PMC419610  PMID: 15155849

Results 1-11 (11)