Squaramide Formation for DNA-Encoded Library Synthesis.

DNA-encoded libraries (DELs) can be considered as one of the most powerful tools for the discovery of small molecules of biological interest. However, the ability to access large DELs is contingent upon having chemical transformations that work in aqueous phase and generate minimal DNA alterations and the availability of building blocks compatible with on-DNA chemistry. In addition, accessing scaffolds of interest to medicinal chemists can be challenging in a DEL setting because of inherent limitations of DNA-supported chemistry. In this context, a squaramide formation reaction was developed by using a two-step process. The mild and high-yielding reaction tolerates a wide array of functional groups and was shown to be safe for DNA, thereby making this methodology ideal for DELs.

Anticancer efficacy triggered by synergistically modulating the homeostasis of anions and iron: Design, synthesis and biological evaluation of dual-functional squaramide-hydroxamic acid conjugates.

Targeting the homeostasis of anions and iron has emerged as a promising therapeutic approach for the treatment of cancers. However, single-targeted agents often fall short of achieving optimal treatment efficacy. Herein we designed and synthesized a series of novel dual-functional squaramide-hydroxamic acid conjugates that are capable of synergistically modulating the homeostasis of anions and iron. Among them, compound 16 exhibited the most potent antiproliferative activity against a panel of selected cancer cell lines, and strong in vivo anti-tumor efficacy. This compound effectively elevated lysosomal pH through anion transport, and reduced the levels of intracellular iron. Compound 16 could disturb autophagy in A549 cells and trigger robust apoptosis. This compound caused cell cycle arrest at the G1/S phase, altered the mitochondrial function and elevated ROS levels. The present findings clearly demonstrated that synergistic modulation of anion and iron homeostasis has high potentials in the development of promising chemotherapeutic agents with dual action against cancers.

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside.

Molecular imaging with antibodies radiolabeled with positron-emitting radionuclides combines the affinity and selectivity of antibodies with the sensitivity of Positron Emission Tomography (PET). PET imaging allows the visualization and quantification of the biodistribution of the injected radiolabeled antibody, which can be used to characterize specific biological interactions in individual patients. This characterization can provide information about the engagement of the antibody with a molecular target such as receptors present in elevated levels in tumors as well as providing insight into the distribution and clearance of the antibody. Potential applications of clinical PET with radiolabeled antibodies include identifying patients for targeted therapies, characterization of heterogeneous disease, and monitoring treatment response.Antibodies often take several days to clear from the blood pool and localize in tumors, so PET imaging with radiolabeled antibodies requires the use of a radionuclide with a similar radioactive half-life. Zirconium-89 is a positron-emitting radionuclide that has a radioactive half-life of 78 h and relatively low positron emission energy that is well suited to radiolabeling antibodies. It is essential that the zirconium-89 radionuclide be attached to the antibody through chemistry that provides an agent that is stable in vivo with respect to the dissociation of the radionuclide without compromising the biological activity of the antibody.This Account focuses on our research using a simple derivative of the bacterial siderophore desferrioxamine (DFO) with a squaramide ester functional group, DFO-squaramide (DFOSq), to link the chelator to antibodies. In our work, we produce conjugates with an average ∼4 chelators per antibody, and this does not compromise the binding of the antibody to the target. The resulting antibody conjugates of DFOSq are stable and can be easily radiolabeled with zirconium-89 in high radiochemical yields and purity. Automated methods for the radiolabeling of DFOSq-antibody conjugates have been developed to support multicenter clinical trials. Evaluation of several DFOSq conjugates with antibodies and low molecular weight targeting agents in tumor mouse models gave PET images with high tumor uptake and low background. The promising preclinical results supported the translation of this chemistry to human clinical trials using two different radiolabeled antibodies. The potential clinical impact of these ongoing clinical trials is discussed.The use of DFOSq to radiolabel relatively low molecular weight targeting molecules, peptides, and peptide mimetics is also presented. Low molecular weight molecules typically clear the blood pool and accumulate in target tissue more rapidly than antibodies, so they are usually radiolabeled with positron-emitting radionuclides with shorter radioactive half-lives such as fluorine-18 (t1/2 ∼ 110 min) or gallium-68 (t1/2 ∼ 68 min). Radiolabeling peptides and peptide mimetics with zirconium-89, with its longer radioactive half-life (t1/2 = 78 h), could facilitate the centralized manufacture and distribution of radiolabeled tracers. In addition, the ability to image patients at later time points with zirconium-89 based agents (e.g. 4-24 h after injection) may also allow the delineation of small or low-uptake disease sites as the delayed imaging results in increased clearance of the tracer from nontarget tissue and lower background signal.

Dosis letales del sulfato de quinina y de quinidina en el ratón: influencia del sexo / Lethal doses of quinine sulfate and quinidine in mice: sex influence

La influencia del sexo sobre la letalidad del sulfato de quinina y de quinidina en el ratón se estudió mediante 2 series experimentales; cálculo de las dosis letales según el método de Litchfield y Wilcoxon y observación de la mortalidad producida por la administración de una dosis única prefijada de cada droga. Los resultados de la primera serie se procesaron tal como describe el método referido (límites, linealidad, paralelismo, potencia relativa), en tanto que en la segunda serie se utilizó la prueba de probabilidad exacta de Fisher. Con ambas drogas se obtuvieron valores de dosis letales semejantes entre sí según el sexo, pero se observó una diferencia significativa entre hembras y machos. Se concluyó que el ratón hembra fue mucho más sensible al efecto letal de las drogas estudiadas. Se analizan algunos factores que pudieron influir sobre los valores de dosis efectivas de estas drogas

Dosis letales del sulfato de quinina y de quinidina en el ratón: influencia del sexo / Lethal doses of quinine sulfate and quinidine in mice: sex influence

La influencia del sexo sobre la letalidad del sulfato de quinina y de quinidina en el ratón se estudió mediante 2 series experimentales; cálculo de las dosis letales según el método de Litchfield y Wilcoxon y observación de la mortalidad producida por la administración de una dosis única prefijada de cada droga. Los resultados de la primera serie se procesaron tal como describe el método referido (límites, linealidad, paralelismo, potencia relativa), en tanto que en la segunda serie se utilizó la prueba de probabilidad exacta de Fisher. Con ambas drogas se obtuvieron valores de dosis letales semejantes entre sí según el sexo, pero se observó una diferencia significativa entre hembras y machos. Se concluyó que el ratón hembra fue mucho más sensible al efecto letal de las drogas estudiadas. Se analizan algunos factores que pudieron influir sobre los valores de dosis efectivas de estas drogas(AU)