RESUMEN

The pursuit of small molecule inhibitors targeting hexokinase 2 (HK2) has significantly captivated the field of cancer drug discovery. Nevertheless, the creation of selective inhibitors aimed at specific isoforms of hexokinase (HK) remains a formidable challenge. Here, we present a multiple-pharmacophore modeling approach for designing ligands against HK2 with a marked anti-proliferative effect on FaDu and Cal27 oral cancer cell lines. Molecular dynamics (MD) simulations showed that the prototype ligand exhibited a higher affinity towards HK2. Complementing this, we put forth a sustainable synthetic pathway: an environmentally conscious, single-step process facilitated through a direct amidation of the ester with an amine under transition-metal-free conditions with an excellent yield in ambient temperature, followed by a column chromatography avoided separation technique of the identified lead bioactive compound (H2) that exhibited cell cycle arrest and apoptosis. We observed that the inhibition of HK2 led to the loss of mitochondrial membrane potential and increased mitophagy as a potential mechanism of anticancer action. The lead H2 also reduced the growth of spheroids. Collectively, these results indicated the proof-of-concept for the prototypical lead towards HK2 inhibition with anti-cancer potential.

RESUMEN

The generation of solid-state emitters is a challenge due to the intrinsic aggregation-caused quenching feature of the fluorophores. A conformationally twisted pyridyl π-conjugate as a solid-state emitter is appended with well-known and inexpensive poly(methylmethacrylate) [PMMA] to afford a handy, portable, and reusable solid-state emitting polymer matrix. Entrapment of the probe is noticed through non-covalent interactions, resulting in a green-emitting platform. It quickly accepts a proton upon acid vapor exposure and switches emission from green to red with a significant 107 nm redshift. This shift is reversible with red to green emissions while exposed to base vapor. Thus, polymer-blended, homogeneous red-emitting pyridyl salt is employed as potential material to detect various basic vapors optically. Among different bases, naked-eye detection of essential analytes such as ammonia vapor and melamine shows potential demands. Hence, we have established an easy detection of ammonia vapor and aqueous melamine as low as 2.5 and 0.126 ppm, respectively, using this solid-state emitter that displays an emission color change with an enhancement of emission intensity even in an aqueous solution.

RESUMEN

Dual-state emissive fluorogens (DSE-gens) are currently defining their importance as a transpiring tool in biological and biomedical applications. This work focuses on designing and synthesizing indole-anthracene-based solid-state emitting twisted π-conjugates using a metal-free protocol to achieve AIE-active DSE-gens, expanding their scope in biological applications. Special effort has been made to introduce proficient and photo/thermostable DSE-gens that inhibit cancer but not normal cells. Here, the lead DSE-gen initially detects cancer and normal cells by bioimaging; however, it could also confirm and distinguish cancer cells from normal cells by its abated fluorescence signal after killing cancer cells. In contrast, the fluorescence signals for a normal cell remain unscathed. Surprisingly, these molecules displayed decent anticancer properties against FaDu and 4T1 but not MCF-7 cell lines. From a series of newly designed indole-based molecules, we report one single 2,3,4-trimethoxybenzene-linked DSE-gen (the lead), exhibiting high ROS generation, less haemolysis, and less cytotoxicity than doxorubicin (DOX) for normal cells, crucial parameters for a biocompatible in vitro anticancer probe. Thus, we present a potentially applicable anticancer drug, offering a bioactive material with bioimaging efficacy and a way to detect dead cancer cells selectively. The primary mechanism behind the identified outcomes is deciphered with the support of experimental (steady-state and time-resolved fluorescence, biological assays, cellular uptake) and molecular docking studies.

Asunto(s)

Antineoplásicos , Neoplasias , Humanos , Simulación del Acoplamiento Molecular , Antineoplásicos/farmacología , Doxorrubicina/farmacología

RESUMEN

The present study demonstrates binding interactions and Förster resonance energy transfer (FRET) between bovine serum albumin (BSA) and a series of structurally and electronically diverse phenothiazine (PTZ) and anthracene (ANT) dyes. Upon selective excitation of tryptophan (Trp) residues of BSA, radiationless energy transfer to a dye takes place, resulting in fluorescence quenching of the former. Fluorescence quenching mechanisms, FRET parameters, possible locations, and binding constants of dyes with the BSA have been examined to deduce a structure-property relationship. The mechanism of quenching is apparently static in nature. PTZ dyes with heteroatoms and a pentyl tail (C5-PTZ) attached to them were found to have a stronger binding affinity with BSA as compared to ANT dyes. Stronger binding affinities of C5-PTZ dyes with BSA result in greater energy transfer efficiencies (E T). A dye with a strong electron-withdrawing group present in it has shown better energy accepting capability. A FRET study with dicyanoaniline (DCA) analogs of PTZ and ANT dyes (C5-PTZDCA and ANTDCA, respectively) revealed that E T depends on electronic and structural factors of molecules. An almost orthogonal geometry between ANT and DCA moieties (∼79°) in ANTDCA induces the greater extent of electron transfer from ANT to DCA, showing a higher E T for this dye as compared to C5-PTZDCA in which the torsion angle is only ∼38°. Further, the observed facts have been validated by experimentally determined bandgaps (using cyclic voltammetry experiments) for all the dyes. Thus, the hydrophobic character and the presence of interactive substituents along with the electron-accepting abilities majorly control the FRET for such dyes with BSA.