Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.

The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. High-content screening of this library for antimitotic activity followed by chemical modification identified 'Dosabulin', which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect vinblastine binding to tubulin; however, experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.This is the author's accepted manuscript. The final version was published in Nature Communications here: http://www.nature.com/ncomms/2014/140117/ncomms4155/full/ncomms4155.html#affil-auth

Approaches to asymmetric catalysis with polymer-supported pyrrolidines

El presente proyecto de investigación se centra en la inmovilización de sistemas catalíticos derivados de pirrolidinas sobre polímeros entrecruzados de PS que permiten realizar enantioselectivamente la formación de enlaces carbono-carbono y carbono-heteroátomo a través de procedimientos con las características de mejora de la sostenibilidad en procesos organocatalíticos altamente eficientes vía mecanismos tipo enamina e ión iminio así como reacciones en cascada así como su aplicación en condiciones de flujo continuo. También se describen ligandos quirales para la reducción asimétrica de cetonas mediante complejos de rutenio en medio orgánico y acuoso y de boro, donde la enantioselectividad depende de cómo se haya anclado la unidad catalítica sobre el polímero.The present research project developed is focused in the immobilization of catalytic systems allowing the formation of carbon-carbon and carbonheteroatom bonds through enantioselective procedures with improved sustainability characteristics (suppression of catalyst separation steps, preferential use of water as a solvent under aerobic conditions, avoidance of protecting groups and, hence, of protection and deprotection steps). In particular, the study is directed towards the organocatalysis field, although also asymmetric catalytic processes mediated by metal complexes have been developed. The approach introduced by our group combines the optimization of the catalytic properties of the ligands, which is greatly facilitated by their modular nature, with a design principle consisting in performing the anchoring to the polymer through auxiliary functional groups, positioned on the ligand molecule for minimal perturbation of the catalytic site. In this manner, we have been able to develop polymersupported ligands that do not show any decrease in catalytic activity or in enantioselectivity with respect to their homogeneous counterparts. The usual anchoring strategy used is the Cu-catalyzed azide/alkyne 1,3 dipolar cycloaddition. In this manner, in this work proline and pyrrolidine derivatives have been synthesized to catalyze organic transformations via enamine and iminium ion mechanisms as Mannich or Michael reactions. Organocatalytic cascade process has also been reported as useful method for the preparation of highly functionalized cyclohexane derivatives in a straightforward and efficient manner and the use of supported organocatalysts has allowed us to implement this reactions not only in batch processes but also in continuous flow conditions obtaining large amount of desired product with high enantiopurity. As have been mentioned, asymmetric catalysis mediated by metal complexes has been investigated. One project collect the study of the asymmetric reduction of ketones with borane and oxazaborolidine type catalysts as aminoalcohols in homogeneous phase and the application of diphenylprolinol derivatives supported on polymers by click-chemistry or by direct nucleophilic substitution to the Merrifield resin. It is verified experimentally that the triazole ring formed by anchoring the monomer to the polymer matrix by click reaction has an important role in the selectivity of the catalyst because leads to a not enantioselective path due to the boron coordination to the triazole. When triazole ring is not present, aromatic ketones are reduced with high enantioselectivities (90-99%) and complete conversion after 30 minutes of reaction with qualitative yield because the easy removing of the catalyst from the product by filtration. Also a series of new modular Ru/aminoalcohol systems has been developed and used as enantioselective catalysts in the asymmetric transfer hydrogenation reaction of ketones in both water and 2-propanol. The catalytic behaviour exhibited in these two media follows different tendencies regarding the tuneable ligand structure. While the bulkiness of the R1 group has a positive effect on the activity for reactions in 2-propanol, ligands with bulky R1 groups are generally less active in water. Additionally, cationic, anionic, and neutral surfactants do not improve the catalytic behaviour in water

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of β-aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min

Synthesis of a novel polycyclic ring scaffold with antimitotic properties via a selective domino Heck-Suzuki reaction.

The synthesis of a previously undescribed sp3-rich 6-5-5-6 tetracyclic ring scaffold using a palladium catalysed domino Heck-Suzuki reaction is reported. This reaction is high-yielding, selective for the domino process over the direct Suzuki reaction and tolerant towards a variety of boronic acids. The novel scaffold can also be accessed via domino Heck-Stille and radical cyclisations. Compounds based around this scaffold were found to be effective antimitotic agents in a human cancer cell line. Detailed phenotypic profiling showed that the compounds affected the congression of chromosomes to give mitotic arrest and apoptotic cell death. Thus, a novel structural class of antimitotic agents that does not disrupt the tubulin network has been identified

Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.

Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action

Selective Aurora A‑TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents

Publication status: PublishedAurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein–protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action