RESUMEN

A new immobilization strategy using compartmentalized nanoreactors is herein reported for two biocatalytic processes: (1) N-acetylneuraminate lyase (NAL) is internalized in NAL-c-CLEnAs and used in a continuous flow aldol condensation of N-acetyl-d-mannosamine with sodium pyruvate to N-acetylneuraminic acid; (2) two hydroxysteroid dehydrogenases (HSDH) 7α- and 7ß-HSDH are incorporated in c-CLEnAs and used in a two-step cascade batch synthesis of ursodeoxycholic acid (UDCA). The versatile use of c-CLEnA demonstrates that this immobilization methodology is a valuable addition to the toolbox of synthetic chemists.

RESUMEN

The therapeutic effects of molecules produced by the plant species Cannabis sativa have since their discovery captured the interest of scientists and society, and have spurred the development of a multidisciplinary scientific field with contributions from biologists, medical specialists and chemists. Decades after the first isolation of some of the most bioactive tetrahydrocannabinols, current research is mostly dedicated to exploiting the chemical versatility of this relevant compound class with regard to its therapeutic potential. This review will primarily focus on synthetic pathways utilised for the synthesis of tetrahydrocannabinols and derivatives thereof, including chiral pool-based and asymmetric chemo- and biocatalytic approaches.

RESUMEN

The synthesis of N-acetylneuraminic acid (Neu5Ac) derivatives is drawing more and more attention in glycobiology research because of the important role of sialic acids in e. g. cancer, bacterial, and healthy cells. Chemical preparation of these carbohydrates typically relies on multistep synthetic procedures leading to low overall yields. Herein we report a continuous flow process involving N-acetylneuraminate lyase (NAL) immobilized on Immobead 150P (Immobead-NAL) to prepare Neu5Ac derivatives. Batch experiments with Immobead-NAL showed equal activity as the native enzyme. Moreover, by using a fivefold excess of either N-acetyl-D-mannosamine (ManNAc) or pyruvate the conversion and isolated yield of Neu5Ac were significantly improved. To further increase the efficiency of the process, a flow setup was designed providing a chemoenzymatic entry into a series of N-functionalized Neu5Ac derivatives in conversions of 48-82%, and showing excellent stability over 1 week of continuous use.

RESUMEN

A revised modular approach to various synthetic (-)-trans-Δ8-THC derivatives through late-stage Suzuki-Miyaura cross-coupling reactions is disclosed. Ten derivatives were synthesized allowing both sp2- and sp3-hybridized cross-coupling partners with minimal ß-hydride elimination. Importantly, we demonstrate that a para-bromo-substituted THC scaffold for Suzuki-Miyaura cross-coupling reactions has been initially reported incorrectly in recent literature.

RESUMEN

Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to the immunosuppressive microenvironment and tumor immune evasion. However, the mechanisms by which these sugars modulate antitumor immunity as well as therapeutic strategies directed against them are limited. Here we report that intratumoral injections with a sialic acid mimetic Ac53FaxNeu5Ac block tumor sialic acid expression in vivo and suppress tumor growth in multiple tumor models. Sialic acid blockade had a major impact on the immune cell composition of the tumor, enhancing tumor-infiltrating natural killer cell and CD8+ T-cell numbers while reducing regulatory T-cell and myeloid regulatory cell numbers. Sialic acid blockade enhanced cytotoxic CD8+ T-cell-mediated killing of tumor cells in part by facilitating antigen-specific T-cell-tumor cell clustering. Sialic acid blockade also synergized with adoptive transfer of tumor-specific CD8+ T cells in vivo and enhanced CpG immune adjuvant therapy by increasing dendritic cell activation and subsequent CD8+ T-cell responses. Collectively, these data emphasize the crucial role of sialic acids in tumor immune evasion and provide proof of concept that sialic acid blockade creates an immune-permissive tumor microenvironment for CD8+ T-cell-mediated tumor immunity, either as single treatment or in combination with other immune-based intervention strategies.Significance: Sialic acid sugars function as important modulators of the immunosuppressive tumor microenvironment that limit potent antitumor immunity.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3574/F1.large.jpg Cancer Res; 78(13); 3574-88. ©2018 AACR.

Asunto(s)

Antineoplásicos/farmacología , Linfocitos T CD8-positivos/inmunología , Melanoma Experimental/terapia , Ácido N-Acetilneuramínico/antagonistas & inhibidores , Escape del Tumor/efectos de los fármacos , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Linfocitos T CD8-positivos/trasplante , Línea Celular Tumoral/trasplante , Femenino , Glicosilación/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Inmunoterapia Adoptiva/métodos , Inyecciones Intralesiones , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Ácido N-Acetilneuramínico/análisis , Ácido N-Acetilneuramínico/inmunología , Ácido N-Acetilneuramínico/metabolismo , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/uso terapéutico , Escape del Tumor/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología

RESUMEN

Sialic acid sugars that terminate cell-surface glycans form the ligands for the sialic acid binding immunoglobulin-like lectin (Siglec) family, which are immunomodulatory receptors expressed by immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. Here, we report a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs. Using bioorthogonal chemistry, a library of cells with more than sixty different sialic acid modifications was generated that showed dramatically increased binding toward the different Siglec family members. Rational design reduced cross-reactivity and led to the discovery of three selective Siglec-5/14 ligands. Furthermore, glycoengineered cells carrying sialic acid ligands for Siglec-3 dampened the activation of Siglec-3+ monocytic cells through the NF-κB and IRF pathways.