Tumor vasculature-targeting PEGylated peptide-drug conjugate prodrug nanoparticles improve chemotherapy and prevent tumor metastasis.

Metastasis is the main cause of death in cancer patients; therefore, new strategies or technologies that can inhibit the growth of primary tumors and their metastatic spread are extremely valuable. In this study, we selected an E-selectin-binding peptide as a targeting ligand and an inhibitor of metastasis, and conjugated this peptide with SN38 and PEG to produce an amphiphilic PEGylated peptide-drug conjugate (PDC). Novel self-assembled nanoparticles were then formed by the amphiphilic conjugate. The particles were actively targeted to the tumor vasculature by the peptide and passively to the tumor site by the enhanced permeability and retention (EPR) effect. As a nano-prodrug, this multifunctional conjugate (PEG-Pep-SN38) could reduce tumor growth, with an effect similar to that of irinotecan. Moreover, it could prolong the survival of mice bearing primary HCT116 tumors, which was not observed for its parent drug, SN38, nor the clinical prodrug of SN38 (irinotecan). Furthermore, this PDC prodrug prevented B16-F10 colonization in the lungs of mice. This study describes a new tumor vasculature-targeting PDC nano-prodrug with convenient preparation and high potential for cancer therapy, with the potential to be applied to other chemotherapeutic drugs.

Cooperative Stapling of Native Peptides at Lysine and Tyrosine or Arginine with Formaldehyde.

Stapling of peptides by intramolecular crosslinking of two neighboring amino acid side chains offers an important tool to modulate the structure and properties of peptides. In comparison to the stapling of artificially engineered peptide substrates, methods for stapling native peptides are more desirable for easier accessibility and genetic encodability. However, the existing strategy for selectivity control in the stapling of native peptides is relatively limited: the site of anchoring is often dominated by Cys, and the means for achieving the position selectivity among the same type of residues at different locations is lacking. We have developed a simple and powerful strategy for stapling native peptides at lysine residues with formaldehyde by the cooperation of nearby tyrosine or arginine residues. The stapling reactions can proceed with high efficiency and residue selectivity under mild conditions, and generate linchpins with distinct physiochemical properties. The new method for peptide stapling enables unique control of position-selectivity for substrates bearing multiple reaction sites by reactivity that can be readily built in the peptide sequence.

Magnetic nanoparticle supported polyoxometalates (POMs) via non-covalent interaction: reusable acid catalysts and catalyst supports for chiral amines.

Magnetic polyoxometalates (POMs) are obtained by a simple sonication between functionalized magnetic nanoparticles and polyoxometalates. This material can be used not only as a highly active acid catalyst, but also as a catalyst support for chiral amines.

Chiral primary-tertiary diamine-Brønsted acid salt catalyzed syn-selective cross-aldol reaction of aldehydes.

Highly syn-selective cross-aldol reaction of aldehydes has remained a challenging subject in the field of aminocatalysis. To achieve this end, chiral primary amines have been explored and the primary-tertiary diamine-Brønsted acid salts are found to promote the cross-aldol reactions of aldehydes with high activity and syn selectivity. Among various vicinal diamines screened, l-phenylalanine derived 2a/TfOH conjugate is identified as the optimal catalyst, showing good catalytic activity (up to 97% yield) and high syn selectivities (syn/anti up to 24:1, 87% ee). The current catalysis works selectively with small aliphatic aldehydes donors such as propionaldehyde and isobutyraldehyde, but not with aliphatic aldehydes bearing larger beta-substitute (>Me). In addition, the use of 2a/TfOH conjugate has also enabled the first syn-selective cross-aldol reactions of glycoaldehyde donors.

Asymmetric supramolecular primary amine catalysis in aqueous buffer: connections of selective recognition and asymmetric catalysis.

A new approach of asymmetric supramolecular catalysis has been developed by combining the supramolecular recognition of beta-cyclodextrin (beta-CD) and the superior property of a chiral primary amine catalyst. The resulted beta-CD enamine catalysts could effectively promote asymmetric direct aldol reactions with excellent enantioselectivity in an aqueous buffer solution (pH = 4.80). The identified optimal catalyst CD-1 shows interesting characteristics of supramolecular catalysis with selective recognition of aldol acceptors and donors. A detailed mechanistic investigation on such supramolecular catalysis was conducted with the aid of NMR, fluorescence, circular dichroism, and ESI-MS analysis. It is revealed that the reaction is initialized first by binding substrates into the cyclodextrin cavity via a synergistic action of hydrophobic interaction and noncovalent interaction with the CD-1 side chain. A rate-limiting enamine forming step is then involved which is followed by the product-generating C-C bond formation. A subsequent product release from the cavity completes the catalytic cycle. The possible connections between molecular recognition and asymmetric catalysis as well as their relevance to enamine catalysis in both natural enzymes and organocatalysts are discussed based on rational analysis.

Organocatalytic kinetic resolution via intramolecular aldol reactions: enantioselective synthesis of both enantiomers of chiral cyclohexenones.

Kinetic resolution of 6-aryl-2,6-hexanediones was achieved with chiral secondary amine catalyzed intramolecular aldolization. The current kinetic resolution protocol enables the synthesis of both enantiomers of cyclohexenones with moderate to good enantioselectivity.

Asymmetric retro- and transfer-aldol reactions catalyzed by a simple chiral primary amine.

One stone four birds: A single chiral primary amine was found to catalyze unprecedented asymmetric retro-aldol and transfer-aldol reactions, leading to four different chiral aldol adducts from one common chiral source with up to 99:1 d.r. and 99 % ee (see scheme).

Asymmetric direct aldol reactions of acetoacetals catalyzed by a simple chiral primary amine.

An asymmetric direct aldol reaction of acetoacetals is described. Under the catalysis of a simple chiral primary amine, the direct aldol reactions of acetoacetals occur exclusively on the gamma-position to give vinylogous-type aldol products with high diastereo- and enantioselectivity.

Chiral primary-tertiary diamine catalysts derived from natural amino acids for syn-aldol reactions of hydroxy ketones.

A series of primary-tertiary diamine catalysts were designed and synthesized from primary natural amino acids. Application of these new chiral catalysts in direct aldol reactions of alpha-hydroxyketones showed very good catalytic activity (up to 97% yield) and high syn selectivity (up to syn/ anti = 30:1, 99% ee).

Highly enantioselective direct syn- and anti-aldol reactions of dihydroxyacetones catalyzed by chiral primary amine catalysts.

We present herein simple primary-tertiary diamine-Brønsted acid conjugates that catalyze both syn- and anti-aldol reactions of dihydroxyacetones (DHAs) with high diastereoselectivities and enantioselectivities. This type of organocatalysts functionally mimics all four DHA aldolases, namely L-fuculose-1-phosphate aldolase, D-tagatose-1,6-diphosphate aldolase, D-fructose-1,6-diphosphate aldolase, and L-rhamnulose-1-phosphate aldolase.

Noncovalently supported heterogeneous chiral amine catalysts for asymmetric direct aldol and Michael addition reactions.

A new strategy for the immobilization of asymmetric organocatalysts by combining polystyrene (PS)/sulfonic acids and chiral amines in situ through acid-base interactions is presented. The PS/sulfonic acids play a dual role as catalyst anchors and modulators for activity and stereoselectivity. Different types of polymeric sulfonic acids were examined and 1% divinylbenzene (DVB) cross-linked PS/sulfonic acid 1 e with a medium loading of sulfonic acid moieties was found to be the optimal support. Furthermore, the noncovalency of this system allows combinatorial screening of optimal catalysts for the targeted reactions. In this regard, highly efficient and enantioselective heterogeneous catalysts were identified for the asymmetric direct aldol and Michael addition reactions. The catalysts could be easily recovered by filtration and reused for six cycles with similar stereoselectivity but slightly decreased activity. Significantly, the deactivated catalysts could be regenerated following an acidic washing/amine recharging procedure.

Chiral amine-polyoxometalate hybrids as highly efficient and recoverable asymmetric enamine catalysts.

Chiral amine and polyoxometalate (POM) acids were combined to give highly efficient, stereoselective, and recoverable enamine-based catalysts. Less than 1 mol % of chiral amine loading was sufficient for good catalytic activity, and the catalyst could be recovered and reused 6 times with unchanged enantioselectivity and slightly decreased activity.

Evolution of pyrrolidine-type asymmetric organocatalysts by "click" chemistry.

Click chemistry has been employed to construct a library of the pyrrolidine-type asymmetric organocatalysts. The clicked organocatalysts were evaluated in asymmetric Michael addition of ketones to nitroolefins, showing good catalytic activity and stereoselectivity (up to 100% yield, syn:anti = 99:1, 96% ee).