The design of stimuli-responsive nanocarriers has raised much attention to achieve higher local concentration of therapeutics and mitigate the appearance of drug resistance. The combination of imaging properties and controlled photorelease of active molecules within the same nanoconjugate has a great potential for theranostic applications. In this study, a system for NIR light-triggered release of molecular cargos induced by the second harmonic emission from bismuth ferrite harmonic nanoparticles (BFO HNPs) is presented. Silica-coated BFO HNPs were covalently conjugated to a photocaging tether based on coumarin (CM) and l-tryptophan (Trp) as a model molecular cargo. Upon femtosecond pulsed irradiation at 790 nm, Trp was efficiently released from the NP surface in response to the harmonic emission of the nanomaterial at 395 nm. The emitted signal induced the photocleavage of the CM-Trp carbamate linkage resulting in the release of Trp, which was monitored and quantified by ultrahigh performance liquid chromatography–mass spectrometry (UHPLC–MS). While a small fraction of the uncaging process could be attributed to the nonlinear absorption of CM derivatives, the main trigger responsible for Trp release was established as the second harmonic signal from BFO HNPs. This strategy may provide a new way for the application of functionalized HNPs in dual imaging delivery theranostic protocols.

Dedicated to Philippe Renaud on the occasion of his 60th birthdayWhile chemotherapy is one of the most used treatments in oncology, the systemic administration of chemotherapeutics generally results in undesired damages to healthy tissues and cells, side effects such as severe nausea and leukopenia, and reduced efficacy due to multidrug resistance and poor target accessibility. The limitations of conventional chemotherapy formulation have prompted the development of alternative nanomaterials-based strategies to achieve targeted and stimuli sensitive payload delivery to reach optimal local drug concentration at tumor sites. In this study, the anticancer drug chlorambucil (Clb) was conjugated to the surface of silica coated lithium niobate (LNO) harmonic nanoparticles (HNPs) using a photocaging tether based on coumarin-4-yl methyl derivative. Upon laser pulsed femtosecond irradiation at 790 nm, the second harmonic emission from the metal oxide core induced the efficient release of Clb, with concomitant contribution from the nonlinear absorption of the coumarin (CM)-based moiety.

Harmonic nanoparticles, functionalized with a selective inhibitor of FAP, provide imaging probes targeting the fibroblastic element of the tumor stroma.

ABSTRACT:The first [4+2]-annulation between aminocyclobutanes and aldehydes to access tetrahydropyranyl amines is reported. With phthalimido cyclobutane dicarboxylates and aromatic aldehydes, tetrahydropyrans were obtained in 53-92% yield and 3:1-17:1 dr using scandium triflate or iron trichloride as catalyst. The use of thymine-or fluorouracil-substituted cyclobutanes gave direct access to six-membered ring nucleoside analogues. Finally, the [4+2]-annulation between aminocyclobutanes and enol ethers led to the corresponding cyclohexylamines.Six-membered nitrogen-substituted carbo-and heterocycles are among the most frequently encountered scaffolds in natural and synthetic bioactive compounds (Figure 1). A cyclohexylamine or a tetrahydropyranylamine ring for example can be found in the core of the natural alkaloids strychnine (1) and staurosporine (2) respectively. The synthetic antiviral drug Tamiflu (3) is constituted by a cyclohexenyldiamine core. Synthetic methods giving access to these important scaffolds with high efficiency and broad scope are desirable to accelerate the discovery of new bioactive compounds. Whereas the Diels-Alder reaction has emerged as a powerful method to synthesize cyclohexenylamines and dihydropyranylamines, 1 there is currently a lack of transformations giving straightforward access to saturated ring systems with high convergence. The use of annulation reactions of donor-acceptor substituted strained rings constitutes a valuable alternative for the synthesis of saturated carbo-or heterocycles. In the case of sixmembered rings, the [4+2]-annulation between donor-acceptor cyclobutanes and olefins or carbonyl compounds appears particularly attractive (Scheme 1, A). Nevertheless, the chemistry of donor-acceptor cyclobutanes has been much less developed than for the corresponding cyclopropanes. 2 It is only very recently that more general catalytic methods have been developed in the groups of Johnson, Christie and Pritchard, and Pagenkopf in particular (Scheme 1, B). 3 However, these works focused on the use of oxygen and carbon as electron-donating groups, and the scope of substituents on the cyclobutanes was often limited. In the case of nitrogen as donor, an important pioneering result has been reported by Saigo and co-workers in 1991. 4 Unfortunately, the precious nitrogen functionality could not be conserved in the final product, as hydrolysis occurred upon work-up. Scheme 1.[4+2]-Annulations for the Synthesis of SixMembered Rings.Recognizing the underexploited potential of nitrogensubstituted strained rings for the synthesis of bioactive compounds, 5 our group has initially focused on the discovery of new types of donor-acceptor systems which could be broadly applied in annulation reactions. In particular, we reported that imido-substituted cyclopropane dicarboxylates can be used in [3+2]-annulations with both enol ethers and carbonyl compounds under mild catalytic conditions. 6 In 2013, we reported a new method to access the corresponding imido substituted cyclobutane dicarbo...

Nucleoside analogues are widely employed as bioactive compounds against cancer and viral infections. Consequently, it is important to develop efficient synthetic methods to access them with high efficiency and structural diversity. Herein, we present a full account of our work on the synthesis of nucleoside analogues via annulations of donor acceptor aminocyclopropanes and aminocyclobutanes. Thymine-and uracil-derived diester cyclopropanes were accessed from the corresponding nucleobases via vinylation and rhodium-catalyzed cyclopropanation, and were then used in (3+2) annulations with aldehydes, ketones and enol ethers.The obtained analogues could be transformed into important hydroxymethyl derivatives. Thymine and fluoro-uracil derived diester cyclobutanes obtained from the nucleobases via vinylation and (2+2) cycloaddition could also be used in a (4+2) annulation with aldehydes. Finally, purine-derived diester cyclopropanes could be accessed using the condensation of nucleobases with chloromethyl ethylidene malonates, but annulation reactions with this class of substrates was not successful.

Harmonic nanoparticles (HNPs) emerged as appealing exogenous probes for optical bio-imaging due to their distinctive features such as long-term photostability and spectral flexibility, allowing multiphoton excitation in the classical (NIR-I) and extended near infrared spectral windows (NIR-II and III). However, like all other optical labels, HNPs are not suitable for whole body imaging applications. In this work, we developed a bimodal nonlinear optical/magnetic resonance imaging (MRI) contrast agent through the covalent conjugation of Gd(III) chelates to coated lithium niobate (LNO) HNPs. We show that the resulting nanoconjugates exert strong contrast both in T1 weighted MRI of agarose gel-based phantoms and in cancer cells by second harmonic generation upon excitation in the NIR region. Their capabilities for dual T1/T2 MRI was also emphasized by quantitative mapping of the phantom in both modes. The functionalization protocol ensured high stability of the Gd-functionalized HNPs in physiological environment and provided high r1 3 relaxivity value per NP (5.20x10 5 mM -1 s -1 ) while preserving their efficient nonlinear optical response.

Nanoparticle-based drug delivery systems have the potential for increasing the efficiency of chemotherapeutics by enhancing the drug accumulation at specific target sites, thereby reducing adverse side effects and mitigating patient acquired resistance. In particular, photo-responsive nanomaterials have attracted much interest due to their ability to release molecular cargos on demand upon light irradiation. In some settings, they can also provide complementary information by optical imaging on the (sub)cellular scale. We herein present a system based on lithium niobate harmonic nanoparticles (LNO HNPs) for the decoupled multi-harmonic cell imaging and near-infrared light-triggered delivery of an erlotinib derivative (ELA) for the treatment of epidermal growth factor receptor (EGFR)-overexpressing carcinomas. The ELA cargo was covalently conjugated to the surface of silica-coated LNO HNPs through a coumarinyl photo-cleavable linker, achieving a surface loading of the active molecule of 27 nmol/mg NPs. The resulting nanoconjugates (LNO-CM-ELA NPs) were successfully imaged upon pulsed laser excitation at 1250 nm in EGFR-overexpressing human prostate cancer cells DU145 by detecting the second harmonic emission at 625 nm, in the tissue transparency window. Tuning the laser at 790 nm resulted in the uncaging of the ELA cargo as a result of the second harmonic emission of the inorganic HNP core at 395 nm. This protocol induced a significant growth inhibition in DU145 cells, which was only observed upon specific irradiation at 790 nm, highlighting the promising capabilities of LNO-CM-ELA NPs for theranostic applications.

4 + 2]-Annulations of Aminocyclobutanes. -The first [4 + 2]-annulation between aminocyclobutanes and aldehydes to access tetrahydropyranyl amines is reported. Various tetrahydropyrans are obtained in high yields and diastereoselectivities by reaction of cyclobutane dicarboxylates and aromatic aldehydes using scandium triflate or iron trichloride as catalyst. Annulation between aminocyclobutanes and enol ethers (IV) leads to the corresponding cyclohexylamines (V). The use of thymine-or fluorouracil-substituted cyclobutanes (VI) gives direct access to six-membered ring nucleoside analogues (VII). -(PERROTTA, D.; RACINE, S.; VUILLEUMIER, J.; DE NANTEUIL, F.; WASER*, J.; Org. Lett. 17 (2015) 4, 1030-1033, http://dx.doi.org/10.1021/acs.orglett.5b00149 ; Lab. Catal. Org. Synth., Ec. Polytech. Fed. Lausanne, CH-1015 Lausanne, Switz.; Eng.) -S. Adam