Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) mimetic that induces the same “closed” conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.
INTRODUCTION The boronic acid is a functional group of enormous utility in materials science, chemosensor development, and drug discovery. In medicinal chemistry, boronic acids have been harnessed as a replacement for various structural motifs (a bioisostere) to improve the potency or pharmacokinetic profiles of lead compounds. However, the widespread incorporation of alkyl boronic acids has been largely hampered by the challenges associated with their preparation. Consequently, only two alkyl boronic acids are currently in clinical use, namely Velcade and Ninlaro. Few methods are capable of delivering alkyl boronates from readily available starting materials; most exhibit modest functional group compatibility. Indeed, boronate motifs are often installed at the early stage of a synthesis and thus consume disproportionate effort from the standpoint of planning and manipulation in multistep processes. RATIONALE Alkyl carboxylic acids, as the most variegated chemical building blocks on Earth, are present in a myriad of natural products and medicines. They represent an ideal precursor to boronic acids. Previous efforts from our laboratory revealed that, through the intermediacy of simple redox-active esters (RAEs, e.g., N-hydroxyphthalimide esters), alkyl carboxylic acids could be harnessed as convenient alkyl halide surrogates in metal-catalyzed decarboxylative cross-coupling reactions with carbon nucleophiles, using the same activating principles as amide bond formation. It was therefore surmised that such reactivity could be exploited in a decarboxylative borylation process wherein structurally diverse and ever-present carboxylic acids could be converted directly into high-value boronic acids. RESULTS Through the exclusive use of N-hydroxyphthalimide RAEs, a simple means to convert carboxylic acids into boronate esters was enabled with an inexpensive nickel catalyst. This reaction was broad in scope (>40 examples) and demonstrated excellent functional group compatibility (tolerating alkyl/aryl halides, amides/carbamates, alcohols, ketones, and olefins), and high levels of diastereoselectivity, allowing transformations of densely functionalized drug molecules (e.g., vancomycin and Lipitor) and natural products (e.g., enoxolone) into the analogous boronic acids. This method’s unique capacity to access α-amino boronic acids from native peptides not only allowed the concise syntheses of both Velcade and Ninlaro, it also enabled the expedient discovery of three highly potent human neutrophil elastase (HNE) inhibitors, the most potent of which has shown improved in vitro inhibitory activities (IC50 = 15 pM, Ki = 3.7 pM) relative to leading candidates previously tested in clinical trials. Enzymatic and pharmacokinetic studies indicated high functional stability in physiologically relevant media. CONCLUSION The nickel-catalyzed decarboxylative cross-coupling of RAEs enables substitution of ubiquitous alkyl carboxylic acids with boronate esters using an inexpensive boron source: B2pin2 (Bpin = pinacol boronate). Th...
5-Fluorouracil is used in the treatment of colorectal cancer along with oxaliplatin as first line treatment, but it is having lack of site specificity and poor therapeutic effect. Also toxic effects to healthy cells and unavailability of major proportion of drug at the colon region remain as limitations. Toxic effects prevention and drug localization at colon area was achieved by preparing enteric-coated chitosan polymeric nanoparticles as it can be delivered directly to large bowel. Enteric coating helps in preventing the drug degradation at gastric pH. So the main objective was to prepare chitosan polymeric nanoparticles by solvent evaporation emulsification method by using different ratios of polymer (1:1, 1:2, 1:3, 1:4). Optimized polymer ratio was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), entrapment efficiency and particle size and further subjected to enteric coating. In vitro drug release studies were done using dialysis bag technique using simulated fluids at various pH (1.2, 4.5, 7.5, 7.0) to mimic the GIT tract. 5-FU nanoparticles with drug: polymer ratio of 1:2 and 1:3 has shown better particle size (149 ± 1.28 nm and 138 ± 1.01 nm respectively), entrapment efficiency (48.12 ± 0.08% and 69.18 ± 1.89 respectively). 5-FU E1 has shown better drug release after 4 h and has shown 82% drug release till 24 h in a sustained manner comparable to the non-enteric coated tablets, which released more than 50% of the drug before entering the colon region. So we can conclude that nanoparticles prepared by this method using the same polymer with the optimized ratio can represent as potential drug delivery approach for effective delivery of the active pharmaceutical ingredient to the colorectal tumors.
Objective:The present study investigates the neuroprotective activity of ethanol extract of Tinospora cordifolia aerial parts against 6-hydroxy dopamine (6-OHDA) lesion rat model of Parkinson's disease (PD).Materials and Methods:T. cordifolia ethanol extract (TCEE) was standardized with high performance thin layer chromatography using berberine. Experimental PD was induced by intracerebral injection of 6-OHDA (8 μg). Animals were divided into five groups: sham operated, negative control, positive control (levodopa 6 mg/kg) and two experimental groups (n = 6/group). Experimental groups received 200 and 400 mg/kg of TCEE once daily for 30 days by oral gavage. Biochemical parameters including dopamine level, oxidative stress, complex I activity and brain iron asymmetry ratio and locomotor activity including skeletal muscle co-ordination and degree of catatonia were assessed.Results:TCEE exhibited significant neuroprotection by increasing the dopamine levels (1.96 ± 0.20 and 2.45 ± 0.40 ng/mg of protein) and complex I activity (77.14 ± 0.89 and 78.50 ± 0.96 nmol/min/mg of protein) at 200 and 400 mg/kg respectively when compared with negative control group. Iron asymmetry ratio was also significantly attenuated by TCEE at 200 (1.57 ± 0.18) and 400 mg/kg (1.11 ± 0.15) when compared with negative control group. Neuroprotection by TCEE was further supported by reduced oxidative stress and restored locomotor activity in treatment groups.Conclusion:Results show that TCEE possess significant neuroprotection in 6-OHDA induced PD by protecting dopaminergic neurons and reducing the iron accumulation.
The optimal management approach to advanced or metastatic renal cell cancer of the clear cell type continues to rapidly evolve. Risk stratification of patients into favorable-, intermediate-, and poor-risk categories is now routinely performed. In selected individuals with low-volume indolent disease, active surveillance may be an appropriate option. Cytoreductive nephrectomy and/or surgical metastasectomy may be also be considered for selected patients after evaluation by a multidisciplinary tumor board. Systemic frontline therapy options now include immune checkpoint inhibitor–based combination (IBC) therapies such as pembrolizumab/axitinib, nivolumab/ipilimumab, and avelumab/axitinib. With unusual exceptions, monotherapy with vascular growth factor receptor tyrosine kinase inhibitors or mTOR inhibitors are no longer appropriate options in the frontline setting. Despite the established efficacy of frontline IBC, most patients will ultimately require additional lines of therapy, and oncologists must think carefully when switching to another therapy, particularly in situations of drug intolerance or apparent disease progression. Systemic therapy options after IBC are generally tyrosine kinase inhibitor–based, and ongoing clinical trials will help optimize the treatment algorithm further. Despite many recent drug approvals for renal cell cancer (RCC), there remains a pressing need to identify new therapeutic targets. Finally, other systemic therapy or supportive care approaches must be considered for special patient populations such as those with poor performance status, end-organ dysfunction, brain metastases, or who have undergone metastasectomy.
Oxaliplatin is one of the chemotherapeutic agents in the first line therapy for treatment of colorectal cancer. But, limitations of chemotherapy affects the clinical applicability of oxaliplatin depriving its activity at targeted site attributed to the lack of site specificity. This limitation paves the way for undesirable toxic effects to healthy cells resulting in sub-standard drug amount at the tumors obliging for increased dose. The present study emphasizes on formulating gold nanoparticles encapsulating oxaliplatin and later conjugating with anti-DR5 antibody for improved anti-cancer activity in a synergistic and site-specific manner. Oxaliplatin immuno-nanoparticles (Co-Ox-AuNPs) had shown sustained release and confirmed by fluorescence and flow cytometry studies. MTT assay exhibited 3-fold decrease in cell viability of nanoparticles comparable to oxaliplatin. Triple fluorescence method employed in HCT 116 and MCF-7 cells justified its site specificity. Annexin-propidium iodide (PI) and Acridine orangeethidium bromide assays further supported the apoptotic activity. Moreover, caspasedependent molecular mechanism behind oxaliplatin induced anti-cancer activity was explored by western blot analysis. Reduction in tumor size and volume in xenograft tumor models justified its in vitro activity. Oxaliplatin side effects were analyzed in mice and were confirmed for their clinical efficacy highlighting our formulation as an alternative to chemotherapy.
Tumor necrosis factor related apoptosis inducing ligand (TRAIL) proved to be a promising new target for colorectal cancer treatment. Elevated expression of TRAIL protein in tumor cells distinguishes it from healthy cells, thereby delivering the drug at the specific site. Here, we formulated oxaliplatin immunohybrid nanoparticles (OIHNPs) to deliver oxaliplatin and anti-TRAIL for colorectal cancer treatment in xenograft tumor models. The polymeric chitosan layer binds to the lipid film with the mixture of phospholipids by an ultra sound method followed by conjugating with thiolated antibody using DSPE-PEG-mal3400, resulting in the formation of OIHNPs. The polymer layer helps in more encapsulation of the drug (71 ± 0.09%) with appreciable particle size (95 ± 0.01 nm), and lipid layer prevents degradation of the drug in serum by preventing nanoparticle aggregation. OIHNPs have shown a 4-fold decrease in the IC50 value compared to oxaliplatin in HT-29 cells by the MTT assay. These immunonanoparticles represent the successful uptake and internalization of oxaliplatin in HT-29 cells rather than in MCF-7 cells determined by triple fluorescence method. Apoptotic activity in vitro of OIHNPs was determined by the change in the mitochondria membrane potential that further elevates its anti-tumor property. Furthermore, the conjugated nanoparticles can effectively deliver the drug to the tumor sites, which can be attributed to its ability in reducing tumor mass and tumor volume in xenograft tumor models in vivo along with sustaining its release in vitro. These findings indicated that the oxaliplatin immuno-hybrid nanoparticles would be a promising nano-sized active targeted formulation for colorectal-tumor targeted therapy.
Melanoma is the most aggressive type of skin cancer and resistance to the conventional chemotherapy is the major cause for its poor prognosis. Metabolic perturbations leading to increased production of reactive oxygen species activate NRF2-dependent anti-oxidative responses to survive oxidative stress. This protective function of NRF2 is the primary cause for therapy resistance in cancer as anti-cancer agents such as BRAF inhibitors also induce NRF2-dependent antioxidative response. We had reported that type I interferons produced upon activation of STING, abrogates NRF2 function. Therefore, we investigated if STING agonists such as the newly developed dimeric aminobenzimidazole (diABZI) could sensitize melanoma cells to the clinically used BRAF inhibitors. Our results reveal that pharmacological activation of STING by diABZI, down regulates NRF2-dependent anti-oxidative responses and potentiates cell-death in melanoma cells when used in combination with BRAF inhibitors.
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