Design, synthesis, and biological evaluation of HDAC6 inhibitors targeting L1 loop and serine 531 residue.

Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones, leading to the silencing of genes. Targeting specific isoforms of HDACs has emerged as a promising approach for cancer therapy, as it can overcome drawbacks associated with pan-HDAC inhibitors. HDAC6 is a unique HDAC isoform that deacetylates non-histone proteins and is primarily located in the cytoplasm. It also has two catalytic domains and a zinc-finger ubiquitin binding domain (Zf-UBD) unlike other HDACs. HDAC6 plays a critical role in various cellular processes, including cell motility, protein degradation, cell proliferation, and transcription. Hence, the deregulation of HDAC6 is associated with various malignancies. In this study, we report the design and synthesis of a series of HDAC6 inhibitors. We evaluated the synthesized compounds by HDAC enzyme assay and identified that compound 8g exhibited an IC50 value of 21 nM and 40-fold selective activity towards HDAC6. We also assessed the effect of compound 8g on various cell lines and determined its ability to increase protein acetylation levels by Western blotting. Furthermore, the increased acetylation of α-tubulin resulted in microtubule polymerization and changes in cell morphology. Our molecular docking study supported these findings by demonstrating that compound 8g binds well to the catalytic pocket via L1 loop of HDAC6 enzyme. Altogether, compound 8g represents a preferential HDAC6 inhibitor that could serve as a lead for the development of more potent and specific inhibitors.

Exploring new histone deacetylase 6 inhibitors and their effects on reversing the α-tubulin deacetylation and cell morphology changes caused by methamphetamine.

Indazole-based HDAC6 inhibitors with novel zinc-binding modifications were synthesized and evaluated to determine their potential to inhibit HDAC6. The analogs were subjected to a histone deacetylase (HDAC) enzyme assay, which led to identification of compounds 3a and 3b. Both compounds demonstrated higher potency and selectivity as HDAC6 inhibitors with IC50 values of 9.1 nM and 9.0 nM, respectively, and highlighted the importance of the hydroxamic acid moiety for binding to Zn2+ inside the catalytic pocket of HDAC enzymes. In the neuroblastoma SH-SY5Y cell line, both compounds efficiently acetylated α-tubulin but not histone H3 at a low concentration of 0.5 µM. Moreover, compounds 3a and 3b effectively reversed the deacetylation of α-tubulin caused by methamphetamine in the SH-SY5Y cell line, suggesting the potential usefulness of HDAC6 selective inhibition in restoring blood brain barrier integrity by reversing methamphetamine-induced deacetylation.

SPC-180002, a SIRT1/3 dual inhibitor, impairs mitochondrial function and redox homeostasis and represents an antitumor activity.

Since sirtuins (SIRTs) are closely associated with reactive oxygen species (ROS) and antioxidant system, the development of their selective inhibitors is drawing attention for understanding of cellular redox homeostasis. Here, we describe the pharmacological properties of SPC-180002, which incorporates a methyl methacrylate group as a key pharmacophore, along with its comprehensive molecular mechanism as a novel dual inhibitor of SIRT1/3. The dual inhibition of SIRT1/3 by SPC-180002 disturbs redox homeostasis via ROS generation, which leads to an increase in both p21 protein stability and mitochondrial dysfunction. Increased p21 interacts with and inhibits CDK, thereby interfering with cell cycle progression. SPC-180002 leads to mitochondrial dysfunction by inhibiting mitophagy, which is accompanied by a reduction in oxygen consumption rate. Consequently, SPC-180002 strongly suppresses the proliferation of cancer cells and exerts anticancer effect in vivo. Taken together, the novel SIRT1/3 dual inhibitor, SPC-180002, impairs mitochondrial function and redox homeostasis, thereby strongly inhibiting cell cycle progression and cancer cell growth.

Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group.

INTRODUCTION: Histone deacetylases (HDACs) have emerged as important therapeutic targets for various diseases, such as cancer and neurological disorders. Although a majority of HDAC inhibitors use hydroxamic acids as zinc binding groups, hydroxamic acid zinc-binding groups suffer from poor bioavailability and nonspecific metal-binding properties, necessitating a new zinc-binding group. Salicylic acid and its derivatives, well-known for their therapeutic value, have also been reported to chelate zinc ions in a bidentate fashion. This drew our attention towards replacing hydroxamic acid with salicylamide as a zinc-binding group. METHODS: In this study, for the first time, compound 5 possessing a novel salicylamide zinc-binding group was synthesized and evaluated biologically for its ability to inhibit various HDAC isoforms and induce acetylation upon α-tubulin and histone H3 among MDA-MB-231 cells. RESULTS: Compound 5 exhibits selective inhibition against class I HDAC isoforms (HDAC1, 2, and 3) over class II and IV HDAC isoforms (HDAC4, 6, and 11). The exposure of MDA-MB-231 cells to compound 5 efficiently induced the acetylation of more histone H3 than α-tubulin, suggesting that compound 5 is a class I selective HDAC inhibitor. Moreover, the molecular docking study indicated that the salicylamide zinc-binding group of compound 5 coordinates the active zinc ion of class I HDAC2 in a bidentate fashion. CONCLUSION: Overall, salicylamide represents a novel zinc-binding group for the development of class I selective HDAC inhibitors. GRAPHICAL ABSTRACT: (http://links.lww.com/MD/G668).

Comprehensive overview of IRVAN syndrome: a structured review of Case Reports and Case Series.

Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome is a rare spectrum of retinal vasculitis, aneurysms, and neuroretinitis affecting young individuals in their third decade. Most of our current knowledge is based on case reports, case series, and a handful of collaborative studies. There is much diversity in treatment approaches and outcomes in the reported literature. We have aggregated published case reports and case series into quantitative and narrative synthesis to draw evidence-based conclusions toward clinical features, atypical and rare findings, systemic associations, disease course, and treatment outcomes. The analysis suggested the disease mostly affects young individuals with a female predilection. Anterior chamber and vitreous inflammation are common than previously believed. The most prevalent pattern of retinal vasculitis in IRVAN eyes is mixed vasculitis, followed by arteritis and phlebitis. Most eyes at the time of presentation have capillary nonperfusion and require treatment. Most eyes retain good visual acuity; however, treatment is required to maintain visual function. Intravitreal antivascular endothelial growth factors administered as an adjunct to retinal laser photocoagulation are more likely to improve visual outcomes. Besides, we have discussed the different hypotheses on the etiopathogenesis of the disease and stronger evidence suggests an inflammatory origin of the disease.

Simvastatin-loaded solid lipid nanoparticles for enhanced anti-hyperlipidemic activity in hyperlipidemia animal model.

The objective of current study was to develop solid lipid nanoparticles-loaded with simvastatin (SIM-SLNs) and investigate their in vivo anti-hyperlipidemic activity in poloxamer-induced hyperlipidemia model. Nano-template engineering technique was used to prepare SIM-SLNs with palmityl alcohol as lipid core and a mixture of Tween 40/Span 40/Myrj 52 to stabilize the core. The prepared SIM-SLNs were evaluated for physicochemical parameters including particle diameter, surface charge, morphology, incorporation efficiency, thermal behaviour and crystallinity. In vitro release profile of SIM-SLNs in simulated gastric and intestinal fluids was evaluated by using dialysis bag technique and anti-hyperlipidemic activity was assessed in hyperlipidemia rat model. SIM-SLNs revealed uniform particle size with spherical morphology, zeta potential of -24.9 mV and high incorporation efficiency (∼85%). Thermal behaviour and crystallinity studies demonstrated successful incorporation of SIM in the lipid core and its conversion to amorphous form. SIM-SLNs demonstrated a sustained SIM release from the lipid core of nanoparticles. SIM-SLNs significantly reduced the elevated serum lipids as indicated by ∼3.9 and ∼1.5-times decreased total cholesterol compared to those of untreated control and SIM dispersion treated hyperlipidemic rats. In conclusion, SIM-SLNs showed a great promise for improving the therapeutic outcomes of SIM via its effective oral delivery.