Adamantoid Scaffolds for Multiple Cargo Loading and Cellular Delivery as ß-Cyclodextrin Inclusion Complexes.

There is huge demand for developing guests that bind ß-CD and can conjugate multiple cargos for cellular delivery. We synthesized trioxaadamantane derivatives, which can conjugate up to three cargos per guest. 1 H NMR titration and isothermal titration calorimetry revealed these guests form 1 : 1 inclusion complexes with ß-CD with association constants in the order of 103  M-1 . Co-crystallization of ß-CD with guests yielded crystals of their 1 : 1 inclusion complexes as determined by single-crystal X-ray diffraction. In all cases, trioxaadamantane core is buried within the hydrophobic cavity of ß-CD and three hydroxyl groups are exposed outside. We established biocompatibility using representative candidate G4 and its inclusion complex with ß-CD (ß-CD⊂G4), by MTT assay using HeLa cells. We incubated HeLa cells with rhodamine-conjugated G4 and established cellular cargo delivery using confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) analysis. For functional assay, we incubated HeLa cells with ß-CD-inclusion complexes of G4-derived prodrugs G6 and G7, containing one and three units of the antitumor drug (S)-(+)-camptothecin, respectively. Cells incubated with ß-CD⊂G7 displayed the highest internalization and uniform distribution of camptothecin. ß-CD⊂G7 showed higher cytotoxicity than G7, camptothecin, G6 and ß-CD⊂G6, affirming the efficiency of adamantoid derivatives in high-density loading and cargo delivery.

Azide-Alkyne Interactions: A Crucial Attractive Force for Their Preorganization for Topochemical Cycloaddition Reaction.

A new class of attractive intermolecular interaction between azide and ethynyl structural entities in a wide range of molecular crystals is reported. This interaction was systematically evaluated by using 11 geometrically different structural motifs that are preorganized to direct a solid-state topochemical azide-alkyne cycloaddition (TAAC) reaction. The supramolecular features of the azide-alkyne interaction were mapped by various crystallographic and quantum chemical approaches. Topological analysis shows the noticeable participation of electron density in the azide⋅⋅⋅alkyne interactions. Interestingly, reorientation of the atomic polarizabilities in vicinal azide and alkyne groups upon interaction in crystals favors soft orbital-guided TAAC reactions. Moreover, various solid-state and gas-phase energy decomposition methods of individual azide⋅⋅⋅alkyne interactions summarize that the strength (varies from -5.7 to -30.1 kJ mol-1 ) is primarily guided by the dispersion forces with a influencing contribution from the electrostatics.

Sulfonylative and Azidosulfonylative Cyclizations by Visible-Light-Photosensitization of Sulfonyl Azides in THF.

The generation of sulfonyl radicals from sulfonyl azides using visible light and a photoactive iridium complex in THF is described. This process was used to promote sulfonylative and azidosulfonylative cyclizations of enynes to give several classes of highly functionalized heterocycles. The use of THF as the solvent is critical for successful reactions. The proposed mechanism of radical initiation involves the photosensitized formation of a triplet sulfonyl nitrene, which abstracts a hydrogen atom from THF to give a tetrahydrofuran-2-yl radical, which then reacts with the sulfonyl azide to generate the sulfonyl radical.

The topochemical synthesis of triazole-linked homobasic DNA.

Triazolyl-DNA ((TL)DNA), a DNA-analog wherein phosphodiester units are replaced by triazole motifs, is of great interest. We have synthesized (TL)DNA oligomers by adopting the Topochemical Azide-Alkyne Cycloaddition (TAAC) reaction. A nucleoside decorated with the azide and alkyne units crystallized with the proximal placement of the azide and alkyne units of the adjacent molecules and underwent the TAAC reaction to form (TL)DNA oligomers.

Synthesis of triazole-linked homonucleoside polymers through topochemical azide-alkyne cycloaddition.

There is a great deal of interest in developing stable modified nucleic acids for application in diverse fields. Phosphate-modified DNA analogues, in which the phosphodiester group is replaced with a surrogate group, are attractive because of their high stability and resistance to nucleases. However, the scope of conventional solution or solid-phase DNA synthesis is limited for making DNA analogues with unnatural linkages. Other limitations associated with conventional synthesis include difficulty in making larger polymers, poor yield, incomplete reaction, and difficult purification. To circumvent these problems, a single-crystal-to-single-crystal (SCSC) synthesis of a 1,5-triazole-linked polymeric ssDNA analogue from a modified nucleoside through topochemical azide-alkyne cycloaddition (TAAC) is reported. This is the first solvent-free, catalyst-free synthesis of a DNA analogue that proceeds in quantitative yield and does not require any purification.

Reverse-CD mimics with flexible linkages offer adaptable cavity sizes for guest encapsulation.

Reverse-CD mimics with adaptable cavity sizes have been synthesized. The adaptability has been demonstrated through single crystal structure determination and guest binding studies.

Chemoselective alcoholysis/acetolysis of trans-ketals over cis-ketals and its application in the total synthesis of the cellular second messenger, D-myo-inositol-1,4,5-trisphosphate.

The involvement of natural phosphoinositols in various cellular signalling processes and the use of synthetic inositol derivatives in catalysis, supramolecular chemistry, natural product synthesis etc. gave momentum to myo-inositol chemistry. The presence of six secondary hydroxyl groups necessitates efficient protection-deprotection strategies for the synthesis of inositol derivatives. An important strategy for the initial protection of myo-inositol is the di-ketalization, which gives a mixture of three diketals, each having both cis-fused and trans-fused ketals. It is important to have methodologies either to selectively hydrolyze one of the two ketals or to convert one of the two acid labile ketals to an orthogonal base labile protecting group. By exploiting the difference in strain between trans-ketals and cis-ketals, we developed two operationally simple, high yielding methodologies for the chemoselective hydrolysis/acetolysis of trans-ketals (both isopropylidene and cyclohexylidene) of inositols, leaving the cis-ketal undisturbed, using cheap and easily preparable H2SO4-silica as the catalyst. Also, terminal ketal moieties of carbohydrates and acyclic polyols could be selectively hydrolyzed/acetolyzed leaving the internal ketals intact. The use of methanol as the solvent leads to chemoselective alcoholysis but the use of DCM and acetic anhydride leads to chemoselective acetolysis. Applying this methodology, a short synthesis of D-myo-inositol-1,4,5-trisphosphate has been achieved.