RESUMEN
Sensitivity is an important parameter for a molecular probe. Hill-type pH probes exhibit improved detection sensitivity compared to the traditional pH probes following the Henderson-Hasselbalch equation. Exploiting positive cooperativity, we recently devised a novel molecular scaffold (PHX) to offer such an unconventional Hill-type pH titration profile. We previously confirmed that PHX is not a pure Hill-type probe yet. Only 64% of its absorbance/fluorescence turn-on is the result of a Hill-type pathway. The remaining 36% is from an undesired Henderson-Hasselbalch-type pathway (HH pathway). In this work, the Thorpe-Ingold dialkylation was harnessed to further suppress the percent contribution of the HH pathway down to 16%. We also propose that PHX is a viable molecular model for assessing the efficacy of the steric compressing effect induced by different Thorpe-Ingold dialkylations.
Asunto(s)
Sondas Moleculares , Concentración de Iones de Hidrógeno , Modelos MolecularesRESUMEN
By combining a Hill-type pH probe and a pH-insensitive naphthalimide fluorophore, we synthesized a FRET-based ratiometric pH probe (PHHF), exhibiting a reduced pH transition width, representing a unique approach for development of sensitive probes for detection of biorelevant pH changes.
Asunto(s)
Colorantes Fluorescentes , Naftalimidas , Células HeLa , Humanos , Concentración de Iones de HidrógenoRESUMEN
The pH-responsive profile of the traditional pH probes (the HH-type pH probes) is governed by the Henderson-Hasselbalch equation. Despite their widespread use, pH probes with further enhanced pH sensitivity, i.e., Hill-type pH probes, are sought after. As a result of positive cooperativity toward protonation, they exhibit a smaller acid-base transition width than that of a HH-type pH probe, which is 2 pH unit. As a result, the Hill-type pH probes have an improved capability to differentiate minor biorelevant pH changes. We previously devised a class of small-molecule Hill-type pH probes (PHX) with pKa in the range of 6.2-6.8. Subcellular organelles with a physiological pH lower than 6.2 are abundant and consequently Hill-type probes for use in these organelles are expected to exhibit a pKa lower than 6.2 as well. Through a rational and systematic structure-property relationship study, we showcased that the pKa values of the PHN type probes could be lowered by increasing the steric bulkiness or the electron-withdrawing capability of the dialkylamino groups on the bottom phenol moiety. The pKa values of the PHN-type probes now cover the wide biorelevant acidic range from 3.5 to 6.8. The potentials of these probes for biological imaging are exemplified and they are expected to be adopted in biological studies and medical diagnosis.
Asunto(s)
Materiales Biocompatibles/química , Sondas Moleculares/química , Concentración de Iones de Hidrógeno , Ensayo de Materiales , Estructura Molecular , Tamaño de la PartículaRESUMEN
Antimicrobial resistance is a public health emergency and warrants coordinated global efforts. Challenge is that no alternative molecular platform has been identified for discovery of abundant antimicrobial hit compounds. Xanthene libraries have been screened for bioactive compounds. However, the potentially accessible chemistry space of xanthene dyes is limited by the existing xanthene synthesis. Herein we report a mild one-step synthesis, which permits late-stage introduction of a xanthene moiety onto i.e. natural products, pharmaceuticals, and bioactive compounds and construction of a focused library of rhodamine dyes exhibiting facile functional, topographical and stereochemical diversity. In vitro screening yields 37 analogs with mid-to-high bactericidal activity against WHO priority drug-resistant pathogens. These findings suggest that synthetic dye libraries exhibiting high structural diversity is a feasible chemical space combating antibacterial resistance, to complement the natural sources.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Rodaminas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antibacterianos/síntesis química , Bacterias/genética , Bacterias/ultraestructura , Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Técnicas Químicas Combinatorias , Desarrollo de Medicamentos/métodos , Farmacorresistencia Bacteriana/genética , Eritrocitos , Estudios de Factibilidad , Genoma Bacteriano/efectos de los fármacos , Genoma Bacteriano/genética , Células HeLa , Hemólisis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Estructura Molecular , Rodaminas/síntesis química , Ovinos , Bibliotecas de Moléculas Pequeñas/síntesis química , Secuenciación Completa del GenomaRESUMEN
By structure transformation of benzo[k,l]thioxanthene-naphthalimide derivatives (ND-S), a novel series of nonplanar thio-heterocyclic bisnaphthalimide derivatives are designed and synthesized. They display high molar absorptivity and large Stokes shifts. They are also heavy-atom-free photosensitizers with high singlet oxygen quantum yields of 0.75 and 0.82. Thus, these new structures based on the naphthalimide skeleton have great potential for singlet oxygen applications.