ABSTRACT: Deciphering the significance of length, sequence, and stereochemistry in block copolymer self-assembly remains an ongoing challenge. A dearth of methods to access uniform block co-oligomers/polymers with precise stereochemical sequences has precluded such studies. Here, we develop iterative exponential growth methods for the synthesis of a small library of unimolecular stereoisomeric diblock 32-mers. X-ray scattering reveals that stereochemistry modulates the phase behavior of these polymers, which we rationalize based on simulations carried out on a theoretical model system. This work demonstrates that stereochemical sequence can play a crucial role in unimolecular polymer self-assembly.
Project description:Three stereoisomeric inhibitors of Pin1: (2R,5S)-, (2S,5R)- and (2S,5S)-Ac-pSer-?[(Z)CH = C]-pipecolyl(Pip)-2-(2-naphthyl)ethylamine 1, that mimic L-pSer-D-Pro, D-pSer-L-Pro, and D-pSer-D-Pro amides respectively, were synthesized by a 13-step route. The newly formed stereogenic centers in the pipecolyl ring were introduced by Luche reduction, followed by stereospecific [2,3]-Still-Wittig rearrangement. The (Z)- to (E)-alkene ratio in the rearrangements were consistently 5.5 to 1. The stereochemistry at the original Ser ?-carbon controlled the stereochemistry of the Luche reduction, but it did not affect the stereochemical outcome of the rearrangement, which consistently gave the (Z)-alkene. The epimerized by-product, (2S,5S)-10, resulting from the work-up after Na/NH3 debenzylation of (2S,5R)-9, was carried on to the (2S,5S)-1 isomer. Compound (2S,5S)-10 was resynthesized from the Luche reduction by-product, (2R,3R)-3, and the stereochemistry was confirmed by comparison of the optical rotations. The IC50 values for (2R,5S)-1, (2S,5R)-1 and (2S,5S)-1 Pin1 inhibition were: 52, 85, and 140 ?M, respectively.
Project description:Branched mannopentaoses were synthesized through two routes. While assembly from the nonreducing end to the reducing end was more convergent with fewer intermediate steps, two diastereomers were obtained. On the other hand, synthesis from the reducing end to the nonreducing end yielded the mannopentaose with the desired stereochemistry as a single isomer. Our results suggest that it is still challenging to reliably predict stereochemical outcome of a glycosylation reaction. It is necessary to thoroughly characterize anomeric configurations of newly formed glycosidic linkages in complex oligosaccharide synthesis.
Project description:Platinum-based chemotherapy has been widely used to treat cancers including ovarian cancer; however, it suffers from dose-limiting toxicity. Judiciously designed drug nanocarriers can enhance the anticancer efficacy of platinum-based chemotherapy while reducing its systemic toxicity. Herein the authors report a stable and water-soluble unimolecular nanoparticle constructed from a hydrophilic multi-arm star block copolymer poly(amidoamine)-b-poly(aspartic acid)-b-poly(ethylene glycol) (PAMAM-PAsp-PEG) conjugated with both cRGD (cyclo(Arg-Gly-Asp-D-Phe-Cys) peptide and cyanine5 (Cy5) fluorescent dye as a platinum-based drug nanocarrier for targeted ovarian cancer therapy. Carboplatin is complexed to the poly(aspartic acid) inner shell via pH-responsive ion-dipole interactions between carboplatin and the carboxylate groups of poly(aspartic acid). Based on flow cytometry and confocal laser scanning microscopy analyses, cRGD-conjugated unimolecular nanoparticles exhibit much higher cellular uptake by ovarian cancer cells overexpressing ?v ?3 integrin than nontargeted (i.e., cRGD-lacking) ones. Carboplatin-complexed cRGD-conjugated nanoparticles also exhibit higher cytotoxicity than nontargeted nanoparticles as well as free carboplatin, while empty unimolecular nanoparticles show no cytotoxicity. These results indicate that stable unimolecular nanoparticles made of individual hydrophilic multi-arm star block copolymer molecules conjugate with tumor-targeting ligands and dyes (i.e., PAMAM-PAsp-PEG-cRGD/Cy5) are promising nanocarriers for platinum-based anticancer drugs for targeted cancer therapy.
Project description:A unique pH/redox dual-sensitive cationic unimolecular nanoparticle (NP) enabling excellent endosomal/lysosomal escape and efficient siRNA decomplexation inside the target cells was developed for tumor-targeted delivery of siRNA. siRNA was complexed into the cationic core of the unimolecular NP through electrostatic interactions. The cationic core used for complexing siRNA contained reducible disulfide bonds that underwent intracellular reduction owing to the presence of high concentrations of reduced glutathione (GSH) inside the cells, thereby facilitating the decomplexation of siRNA from the unimolecular NPs. The cationic polymers were conjugated onto the hyperbranched core (H40) via a pH-sensitive bond, which further facilitated the decomplexation of siRNA from the NPs. In vitro studies on the siRNA release behaviors showed that dual stimuli (pH=5.3, 10mM GSH) induced the quickest release of siRNA from the NPs. In addition, the imidazole groups attached to the cationic polymer segments enhanced the endosomal/lysosomal escape of NPs via the proton sponge effect. Intracellular tracking studies revealed that siRNA delivered by unimolecular NPs was efficiently released to the cytosol. Moreover, the GE11 peptide, an anti-EGFR peptide, enhanced the cellular uptake of NPs in MDA-MB-468, an EFGR-overexpressing triple negative breast cancer (TNBC) cell line. The GE11-conjugated, GFP-siRNA-complexed NPs exhibited excellent GFP gene silencing efficiency in GFP-MDA-MB-468 TNBC cells without any significant cytotoxicity. Therefore, these studies suggest that this smart unimolecular NP could be a promising nanoplatform for targeted siRNA delivery to EFGR-overexpressing cancer cells.
Project description:[reaction: see text]. Substrates having appendages that pre-encode skeletal information (sigma-elements) can be converted into products having distinct skeletons using a common set of reaction conditions. The sequential use of the Ugi 4CC-IMDA reaction, followed by allylation, hydrolysis, and acylation of a chiral amino alcohol appendage (sigma-element), leads to substrates for a ROM/RCM or RCM reaction. The stereochemistry of the sigma-element and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to the challenging problem of skeletal diversity.
Project description:A novel type of self-fluorescent unimolecular micelle nanoparticle (NP) formed by multi-arm star amphiphilic block copolymer, Boltron® H40 (H40, a 4th generation hyperbranched polymer)-biodegradable photo-luminescent polymer (BPLP)-poly(ethylene glycol) (PEG) conjugated with cRGD peptide (i.e., H40-BPLP-PEG-cRGD) was designed, synthesized, and characterized. The hydrophobic BPLP segment was self-fluorescent, thereby making the unimolecular micelle NP self-fluorescent. cRGD peptides, which can effectively target ?v?3 integrin-expressing tumor neovasculature and tumor cells, were selectively conjugated onto the surface of the micelles to offer active tumor-targeting ability. This unique self-fluorescent unimolecular micelle exhibited excellent photostability and low cytotoxicity, making it an attractive bioimaging probe for NP tracking for a variety of microscopy techniques including fluorescent microscopy, confocal laser scanning microscopy (CLSM), and two-photon microscopy. Moreover, this self-fluorescent unimolecular micelle NP also demonstrated excellent stability in aqueous solutions due to its covalent nature, high drug loading level, pH-controlled drug release, and passive and active tumor-targeting abilities, thereby making it a promising nanoplatform for targeted cancer theranostics.
Project description:BACKGROUND: In our previous papers we introduced the Modular Chemical Descriptor Language (MCDL) for providing a linear representation of chemical information. A subsequent development was the MCDL Java Chemical Structure Editor which is capable of drawing chemical structures from linear representations and generating MCDL descriptors from structures. RESULTS: In this paper we present MCDL modules and accompanying software that incorporate unique representation of molecular stereochemistry based on Cahn-Ingold-Prelog and Fischer ideas in constructing stereoisomer descriptors. The paper also contains additional discussions regarding canonical representation of stereochemical isomers, and brief algorithm descriptions of the open source LINDES, Java applet, and Open Babel MCDL processing module software packages. CONCLUSIONS: Testing of the upgraded MCDL Java Chemical Structure Editor on compounds taken from several large and diverse chemical databases demonstrated satisfactory performance for storage and processing of stereochemical information in MCDL format.
Project description:[reaction: see text] Reduction of C5-substituted 2-hydroxychromans selectively provides 2,4-cis-chromans using large silane reductants and 2,4-trans-chromans using the smaller silane PhSiH(3). The stereochemical outcome has been rationalized on the basis of a Curtin-Hammett kinetic situation arising from hydride delivery to two different conformations of an intermediate oxocarbenium ion. This method provides a powerful way to control the relative stereochemistry of these substructures which are prevalent in bioactive natural products.
Project description:Two unnatural stereoisomers of alpha,alpha-trehalose (L- and meso-trehalose) were synthesized and evaluated as cryoprotectants in order to determine the functional consequences of relative or absolute stereochemistry on their physicochemical properties. Adherent yeast cell cultures were frozen in 10% solutions of D-, L-, and meso-trehalose for periods of 7-28 days, then evaluated by a MTT viability assay. D- and L-trehalose were equally effective in maintaining high rates of cell survival, thus demonstrating the absence of chiral discrimination at the carbohydrate-lipid interface, whereas meso-trehalose was inferior in cryoprotection efficacy. Differential scanning calorimetry revealed a difference in the glass transition temperatures (Tg) of D- and meso-trehalose of nearly 75 degrees C. This can be attributed to differences in conformational behavior, as portrayed by torsional energy maps for rotation about the glycosidic bonds of D- and meso-trehalose. We conclude that the biostabilizing properties of alpha,alpha-trehalose depend on relative stereochemical factors, but are independent of absolute stereochemical configuration.
Project description:Stereochemistry is a key aspect of molecular recognition for biological systems. As such, receptors and enzymes are often highly stereospecific, only recognizing one stereoisomer of a ligand. Recently, the quorum sensing signaling molecules used by the nosocomial opportunistic pathogen, Acinetobacter baumannii, were identified, and the primary signaling molecule isolated from this species was N-(3-hydroxydodecanoyl)-L-homoserine lactone. A plethora of bacterial species have been demonstrated to utilize 3-hydroxy-acylhomoserine lactone autoinducers, and in virtually all cases, the (R)-stereoisomer was identified as the natural ligand and exhibited greater autoinducer activity than the corresponding (S)-stereoisomer. Using chemical synthesis and biochemical assays, we have uncovered a case of stereochemical insignificance in A. baumannii and provide a unique example where stereochemistry appears nonessential for acylhomoserine lactone-mediated quorum sensing signaling. Based on previously reported phylogenetic studies, we suggest that A. baumannii has evolutionarily adopted this unique, yet promiscuous quorum sensing system to ensure its survival, particularly in the presence of other proteobacteria.