Divergent Synthesis of Porous Tetraphenylmethane Dendrimers.

Tetraphenylmethane-ethynylene-based shape-persistent dendrimers are a new class of nanoobjects with an intriguing 3D architecture. We report an efficient divergent strategy for their synthesis based on the Sonogashira Pd-catalyzed coupling of terminal alkynes with aryl iodides. As repeat unit, we prepared a tetraphenylmethane derivative bearing a terminal alkyne and three triazene moieties. Coupling of this building block to tetrakis(p-iodophenyl)methane afforded, after triazene activation, a dodecaiodo-terminated first generation dendrimer, which was transformed by another Sonogashira coupling into a methoxy-terminated second generation dendrimer with persistent globular shape and well-defined cavities. This work also unveils new aspects of triazene chemistry, i.e., the unprecedented efficient generation of an azo compound by mixing of a triazene with phenol.

A Global View on Block Copolymers.

In this systematic review, a total of 45,143 publications on block copolymers, issued between 1952 and 2019, are analyzed in terms of number, source, language, institution, country, keywords, and block copolymer type, to find out their evolution and predict research trends. The number of publications devoted to block copolymers has been growing for over six decades, maintaining a consistent level throughout the last few years. In their majority, documents came out of the United States, although more recently, Chinese institutions are those displaying the largest production. Keywords analysis indicated that one-third of the publications concerned synthesis, around 20% explored self-assembly and morphological aspects, and another 20% referred to block copolymer applications in solution. In particular, 2019 confirmed the expansion of studies related to drug delivery, and in minor extent, to a deeper view of self-assembling. Styrene-butadiene-styrene block copolymer was the most popular in studies covering both basic and industrially oriented aspects. Other highly investigated copolymers are PEO-b-PPO-b-PEO (Pluronic©) and amphiphilic block copolymers based on polycaprolactone or poly(lactic acid), which owed their success to their potential as delivery vehicles. Future trending topics will concern nanomedicine challenges and technology-related applications, with a special attention toward the orientation and ordering of mesophase-separated morphologies.

Dissolution of amorphous nifedipine from micelle-forming carboxymethylcellulose derivatives.

We show that a novel amphiphilic graft copolymer combining the biodegradability and biocompatibility of oxidized carboxymethylcellulose (CMC) with that of hydrophilic poly(ethylene glycol) (PEG), and hydrophobic dodecylamine (DDA), improves the solubility and dissolution performance of nifedipine (NIF), considered as a model hydrophobic drug. The hydrophobic components of the graft copolymer have the multiple effect of favouring micelle formation and loading. At the same time, the interaction between the hydrophobic core and NIF has the secondary effect to suppress drug crystallization, favouring its dissolution, and to increase photostability. Oxidized CMC-g-PEG-DDA micelles reached values of drug concentration, loading capacity and encapsulation efficiency as high as 340 µg mL-1, 6.4 % and 34.1 %, respectively. Loaded micelles showed a good stability with a limited release profile at pH 1.2, whereas at pH 7.4 the swollen cores enable much higher and progressive release, that reaches 3.4 and 6.6 % after 3 and 5 h, respectively, corresponding to very competitive concentration of 34 and 66 µg mL-1.

Some Guidelines for the Synthesis and Melting Characterization of Azide Poly(ethylene glycol) Derivatives.

We provide fundamental guidelines in the form of a tutorial to be taken into account for the preparation and characterization of a specific class of poly(ethylene glycol) (PEG) derivatives, namely azide-terminated PEGs. Special attention is given to the effect of these chain end groups and their precursors on properties affecting the PEGylation of proteins, nanoparticles and nanostructured surfaces. Notwithstanding the presence of 13C satellite peaks, we show that 1H NMR enables not only the routine quantitative determination of chain-end substitution, but is also a unique method to calculate the absolute number average molecular weight of PEG derivatives. In the use of size exclusion chromatography to get molecular weight distributions, we highlight the importance of distinguishing between eventual secondary reactions involving molecular weight changes and the formation of PEG complexes due to residual amounts of metal cations from reactants. Finally, we show that azide end groups affect PEG melting behavior. In contrast to oxygen-containing end groups, azides do not interact with PEG segments, thus inducing defect formation in the crystal lattice and the reduction of crystal sizes. Melting temperature and degree of crystallinity decrease become especially relevant for PEGs with very low molecular weight, and its comprehension is particularly important for solid-state applications.

Synthesis of 25-hydroxyvitamin D(3) and 26,26,26,27,27,27-hexadeutero-25-hydroxyvitamin D(3) on solid support.

A convenient five-step route to 25-hydroxylated vitamin D(3) compounds on (hydroxymethyl)polystyrene support is reported. A CD-side chain fragment was anchored to the solid phase through an ester group at C25 and coupled to an A ring building block to assemble the vitamin D triene system by the Wittig-Horner approach. Deprotection of the hydroxy group was carried out on the support, prior to functionalization at C25. The title compounds were released from the resin in excellent global yield by nucleophilic attack on the ester carbonyl group using commercially available organometallic reagents. This key last step offers an opportunity for the efficient generation of 26,27-labeled compounds and also for diversification at the side chain without need for a pool of side chain fragments.

Novel synthetic approach to 1alpha,25-dihydroxyvitamin D3 and analogues.

A mild and stereoconvergent synthesis of 1alpha,25-dihydroxyvitamin D(3) (calcitriol, 1a) is described. The key step is a cascade process consisting of two consecutive transformations: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflate 4 followed by a Negishi cross-coupling reaction with alkenyl zinc 3. This approach is of interest for the rapid synthesis of a variety of new vitamin D(3) analogues of therapeutic potential, especially those modified at the triene and ring-A. The mildness of the method also allows the preparation of thermal sensitive vitamin D(3) analogues.

Synthesis of 1α,25-dihydroxyvitamin D3 analogues with α-hydroxyalkyl substituents at C12.

Convergent syntheses of three new analogues of 1α,25-dihydroxyvitamin D3 with α-hydroxyalkyl substituents at C12 (4a-c) are described. The A-ring and triene system of each analogue were assembled by a tandem Pd-catalysed intramolecular cyclization and Suzuki-Miyaura coupling process. The stereoselective introduction of substituents at C12 was achieved by Johnson-Claisen rearrangement on allylic alcohol 15 as the key step. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D3 analogues with a long side chain at C12 and short C17 side chains.

Structure-guided optimization was used to design new analogues of 1α,25-dihydroxyvitamin D3 bearing the main side chain at C12 and a shorter second hydroxylated chain at C17. The new compounds 5a-c were efficiently synthesized from ketone 9 (which is readily accessible from the Inhoffen-Lythgoe diol) with overall yields of 15%, 6%, and 3% for 5a, 5b, and 5c, respectively. The triene system was introduced by the Pd-catalyzed tandem cyclization-Suzuki coupling method. The new analogues were assayed against human colon and breast cancer cell lines and in mice. All new vitamin D3 analogues bound less strongly to the VDR than 1α,25-dihydroxyvitamin D3 but had similar antiproliferative, pro-differentiating, and transcriptional activity as the native hormone. In vivo, the three analogues had markedly low calcemic effects.

Synthesis and biological evaluation of 1α,25-dihydroxyvitamin D(3) analogues hydroxymethylated at C-26.

We designed by docking and synthesized two novel analogues of 1α,25-dihydroxyvitamin D(3) hydroxymethylated at C-26 (2 and 3). The syntheses were carried out by the convergent Wittig-Horner approach via epoxide 12a as a common key intermediate. The antiproliferative and transactivation potency of the compounds was evaluated in colon and breast cancer cell lines. The analogues showed a similar but reduced activity compared to 1,25(OH)(2)D(3). Analogue 3 was more potent than analogue 2, and in some assays it exhibited potency similar to that of the natural ligand.