Heterocyclic Linker Research Articles

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin–proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

Catalytic power of magnetic nanoparticles containing heterocyclic linker along with copper metal in increasing the efficiency of heck reaction

One of the most effective methods of performing Coupling-Heck reactions is the use of magnetic nanocatalysts. These have high catalytic power, wide functional surface and potential extraction capability. Here is one of the most unique magnetic catalysts designed, synthesized and analyzed (by SEM, TEM, IR, VSM, XRD, EDX and TGA analyzers) by silica coating, heterocyclic linker and copper metal (with ∼10% loading). The conditions for the Heck reaction are green and ethanol is used as a solvent. The resulting products have a high efficiency of 98%. Nanocatalyst has also been used repeatedly and its catalytic power was evaluated above 96%. The present project has been carried out in two stages, and the resulting products have bio-pharmaceutical applications and have been considered as new compounds in the medical industry.

Design, synthesis and biological evaluation of naphthalene-derived (arylalkyl)azoles containing heterocyclic linkers as new anticonvulsants: A comprehensive in silico, in vitro, and in vivo study

In continuation of our research to find strong and safe anticonvulsant agents, a number of (arylalkyl)azoles (AAAs) containing naphthylthiazole and naphthyloxazole scaffolds were designed and synthesized. The in vivo anticonvulsant evaluations in BALB/c mice revealed that some of them had significant anticonvulsant activity in both maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy. The best profile of activity was observed with compounds containing imidazole and triazole rings (C1, C6, G1, and G6). In particular, imidazolylmethyl-thiazole C1 with median effective dose (ED50)= 7.9 mg/kg in the MES test, ED50= 27.9 mg/kg in PTZ test, and without any sign of neurotoxicity (in the rotarod test, 100 mg/kg) was the most promising compound. The patch-clamp recording was performed to study the mechanism of action of the representative compound C1 on hippocampal dentate gyrus (DG) cells. The results did not confirm any modulatory effect of C1 on the voltage-gated ion channels (VGICs) or GABAA agonism, but suggested a significant reduction of excitatory postsynaptic currents (EPSCs) frequency on hippocampal DG neurons. Sub-acute toxicity studies revealed that administration of the most active compounds (C1, C6, G1, and G6) at 100 mg/kg bw/day for two weeks did not result in any mortality or significant toxicity as evaluated by assessment of biochemical markers such as lipid peroxidation, intracellular glutathione, total antioxidant capacity, histopathological changes, and mitochondrial functions. Other pharmacological aspects of compounds including mechanistic and ADME properties were investigated computationally and/or experimentally. Molecular docking on the NMDA and AMPA targets suggested that the introduction of the heterocyclic ring in the middle of AAAs significantly affects the affinity of the compounds. The obtained results totally demonstrated that the prototype compound C1 can be considered as a new lead for the development of anticonvulsant agents.

Structure Activity Relationships of Novel GPR52 Agonists that Suppress Psychostimulant Behavior

GPR52 is a class-A orphan G protein-coupled receptor that is selectively expressed in the striatum, and regulates various brain functions through activation of Gs/adenylyl cyclase/cAMP signaling pathways. GPR52 has been identified as a promising drug target for neurological and psychiatric disorders including schizophrenia, substance use disorders, as well as Huntington's disease. We recently synthesized and pharmacologically evaluated a series of novel GPR52 indoline-carboxamide based agonists (Wang, Felsing et al J. Med. Chem. 2020 Nov 25;63(22):13951-13972). Several potent (EC50: ~100 nM) and efficacious GPR52 agonists were identified, and in vivo proof-of-concept investigations revealed that 3 mg/kg of the lead compound PW0787 (12c) displayed antipsychotic-like activity by significantly inhibiting amphetamine-induced hyperlocomotor behavior in mice. Here, we further report our efforts to optimize our molecules for addiction-focused drug discovery in a systematic structure-activity relationship study of pharmacophore features crucial for GPR52 activation. Notably, in a HEK293 cell-based GPR52 cAMP assay, we determined the two lower aromatic moieties of the agonist lead were amenable to further medicinal chemistry with substituents shown to modulate both agonist potency and efficacy. Whereas compound modifications to the carboxamide and heterocyclic linkers were largely detrimental to agonist potency. Surprisingly, when the nitrogen containing ring of the indoline system was broken into more flexible variants, this further increased agonist potency (EC50: ~40 nM) and efficacy, while retaining target selectivity, plasma exposure and serum concentration. Collectively, our findings have resulted in several agonists with optimized potency and efficacy, with PW0787 being an orally bioavailable, brain-penetrant GPR52 agonist. This work also provides valuable pharmacological tools for investigating the physiological and therapeutic potential of GPR52 activation.

Metal–Organic Frameworks in Italy: From synthesis and advanced characterization to theoretical modeling and applications

• This review summarizes the work of the Italian groups working in the field of MOFs • The document is a celebration of ICCC 2022 that will take place in Italy (Rimini) • This review will strengthen the scientific relationship among these Italian groups. As a celebration of the 44th International Conference on Coordination Chemistry (ICCC2022) that will take place in Italy, the Italian groups working in the research field of Metal–Organic Frameworks (MOFs) have decided to gather together and collect the results they have obtained in this area over the past 15 years. A survey that starts from the synthesis of novel heterocyclic linkers and the related MOFs and moves through advanced characterization techniques, theoretical investigations and assorted applications in the fields of gas storage and separation, heterogeneous catalysis, magnetism and sensing.

New and Enzymatic Targeted Magnetic Macromolecular Nanodrug System Which Delivers Methadone and Rifampin Simultaneously.

An indicator for cytochrome P450 (CYP-450) enzymes includes CYP-450 which has the most fundamental role in methadone metabolism in the liver. The aim of this study is to design and interface a macromolecular nanodrug system to deliver rifampin (RIF) and methadone (MTD) simultaneously to the liver based on magnetic nanoparticles (MNPs). RIF increases the metabolism of MTD in the liver. In this study, MTD was linked to a magnetic nanocapsule including RIF by a heterocyclic linker. This heterocyclic linker was prepared in five steps. Fourier transform infrared spectroscopy and NMR indicated the synthesis of the heterocyclic linker, scanning electron microscopy and confocal fluorescence microscopy exhibited the morphology of NPs and loading MTD. Atomic force microscopy was applied to indicate the three-dimensional topology of NPs and the conglomeration on them. Magnetization properties of loaded and unloaded NPs were characterized by vibrating-sample magnetometer. These patterns indicated superparamagnetic properties of MNPs therefore these NPs do not retain any magnetism after removal of a magnetic field. In vitro release studies of RIF and MTD by UV-vis measurements in several buffer solutions demonstrated that behavior of drug release is related to pH. The histopathology study was performed on the liver of rats injected with MTD, morphine (MOR), and the prepared drug. Cytotoxicity of the prepared sample on MCF-7 cell line assay was assessed via 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide solution. The histopathology study indicated that the cotreatment of the synthesized drug attenuated hepatic lesions. Delivery of RIF and MTD simultaneously to the liver by MNPs (1) increases MTD metabolism because of increasing CYP-450 enzymes induced by RIF and (2) decreases hepatic lesions via injection of the synthesized drug with cotreatment by MOR.

Design of Porous Metal-Organic Frameworks for Adsorption Driven Thermal Batteries

ABSTRACTThermal batteries based on a reversible adsorption/desorption of a working fluid (water, methanol, ammonia) rather than the conventional vapor compression is a promising alternative to exploit waste thermal energy for heat reallocation. In this context, there is an increasing interest to find novel porous solids able to adsorb a high energy density of working fluid under low relative vapor pressure condition combined with an easy ability of regeneration (desorption) at low temperature, which are the major requirements for adsorption driven heat pumps and chillers. The porous crystalline hybrid materials named Metal–Organic Frameworks (MOF) represent a great source of inspiration for sorption based-applications owing to their tunable chemical and topological features associated with a large variability of pore sizes. Recently, we have designed a new MOF named MIL-160 (MIL stands for Materials of Institut Lavoisier), isostructural to CAU-10, built from the assembly of corner sharing aluminum chains octahedra AlO4(OH)2 with the 2,5-furandicarboxylic linker substituting the pristine organic linker, 1,4-benzenedicarboxylate. This ligand replacement strategy proved to enhance both the hydrophilicity of the MOF and its amount of water adsorbed at low p/p0. This designed solid was synthesized and its chemical stability/adsorption performances verified. Here, we have extended this study by incorporating other polar heterocyclic linkers and a comparative computational study of the water adsorption performances of these novel structures has been performed. To that purpose, the cell and geometry optimizations of all hypothetical frameworks were first performed at the density functional theory level and their water adsorption isotherms were further predicted by using force-field based Grand-Canonical Monte Carlo simulations. This study reveals the ease tunable water affinity of MOF for the desired application.

Redox-State Dependent Spectroscopic Properties of Porous Organic Polymers Containing Furan, Thiophene, and Selenophene

A series of electroactive triarylamine porous organic polymers (POPs) with furan, thiophene, and selenophene (POP-O, POP-S, and POP-Se) linkers have been synthesised and their electronic and spectroscopic properties investigated as a function of redox state. Solid state NMR provided insight into the structural features of the POPs, while in situ solid state Vis-NIR and electron paramagnetic resonance spectroelectrochemistry showed that the distinct redox states in POP-S could be reversibly accessed. The development of redox-active porous organic polymers with heterocyclic linkers affords their potential application as stimuli responsive materials in gas storage, catalysis, and as electrochromic materials.

Synthetic and Medicinal Prospective of Structurally Modified Curcumins

Curcumin, a natural yellow phenolic compound, is present in various types of herbs, particularly in Turmeric, Curcuma longa Linn. (Zingiberaceae family) rhizomes. Curcumin is a polyphenolic natural compound with diverse and attractive biological activities. In the last decade curcumine and its various synthetic analogues have been prepared and evaluated for various pharmacological activities that prove it as a lead molecule against several biological targets. It is a natural antioxidant and exhibited many pharmacological activities such as anti-inflammatory, anti-microbial, anticancer, anti-Alzheimer in both preclinical and clinical studies. Moreover, Curcumin and its analogues have anti-tubercular, cardioprotective, anti-diabetic, hepatoprotective, neuroprotective, nephroprotective, antirheumatic and anti-viral activities. The substitutions of 1,6-heptadiene linkage moiety via carbonyl group sustituion and addition of heterocyclic linker; isoxazole, 1H-pyrazole, cyclopentanone, piperidin-4-one, N-methylpiperidin-4-one enhance biological activities. The structure activity relationship of various curcumin analogues is studied for medicinal purposes and it reveals that monocarbonyl linkage analogues have anticancer properties. The current review gives an insight of the history, chemistry, analogues and most interesting in vitro and in vivo studies on the biological effects of Curcumin and its analogues.

Resveratrol analogs: promising chemopreventive agents

Although resveratrol can modulate multiple stages of carcinogenesis, by most common standards it is not a good drug candidate. Resveratrol lacks potency, high efficacy, and target specificity; it is rapidly metabolized and serum concentrations are low. Using resveratrol as a scaffold, we produced over 100 derivatives, some of which have target specificity in the nanomolar range. Aromatase inhibition was enhanced over 6000-fold by using 1,3-thiazole as the central ring of resveratrol. Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to selective QR1 induction with a CD value of 87 nM. Several derivatives have been selected for evaluation of synergistic effects. Preliminary results with pairs of compounds are promising and further experiments, in a constant multidrug manner, will allow us to create polygonograms for larger combinations of derivatives. The objective is to develop a highly efficacious cocktail of derivatives based on the structure of resveratrol.

Optimization of thiazole analogues of resveratrol for induction of NAD(P)H:quinone reductase 1 (QR1)

NAD(P)H:quinone reductase 1 (QR1) belongs to a class of enzymes called cytoprotective enzymes. It exhibits its cancer protective activity mainly by inhibiting the formation of intracellular semiquinone radicals, and by generating α-tocopherolhydroquinone, which acts as a free radical scavenger. It is therefore believed that QR1 inducers can act as cancer chemopreventive agents. Resveratrol (1) is a naturally occurring stilbene derivative that requires a concentration of 21μM to double QR1 activity (CD=21μM). The stilbene double bond of resveratrol was replaced with a thiadiazole ring and the phenols were eliminated to provide a more potent and selective derivative 2 (CD=2.1μM). Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to a highly potent and selective QR1 inducer 9o with a CD value of 0.087μM.

Finasteride, a Selective 5-Alpha-Reductase Inhibitor, in the Prevention and Treatment of Human Prostate Cancer

NAD(P)H:quinone reductase 1 (QR1) belongs to a class of enzymes called cytoprotective enzymes. It exhibits its cancer protective activity mainly by inhibiting the formation of intracellular semiquinone radicals, and by generating α-tocopherolhydroquinone, which acts as a free radical scavenger. It is therefore believed that QR1 inducers can act as cancer chemopreventive agents. Resveratrol (1) is a naturally occurring stilbene derivative that requires a concentration of 21 μM to double QR1 activity (CD = 21 μM). The stilbene double bond of resveratrol was replaced with a thiadiazole ring and the phenols were eliminated to provide a more potent and selective derivative 2 (CD = 2.1 μM). Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to a highly potent and selective QR1 inducer 9o with a CD value of 0.087 μM.