Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Benzothiazoles are a class of heterocycles with multiple applications as anticancer, antibiotic, antiviral, and anti-inflammatory agents. Benzothiazole is a privileged scaffold in drug discovery programs for modulating a variety of biological functions. This review focuses on the design and synthesis of new benzothiazole derivatives targeting hypoxic tumors. Cancer is a major health problem, being among the leading causes of death. Tumor-hypoxic areas promote proliferation, malignancy, and resistance to drug treatment, leading to the dysregulation of key signaling pathways that involve drug targets such as vascular endothelial growth factor, epidermal growth factor receptor, hepatocyte growth factor receptor, dual-specificity protein kinase, cyclin-dependent protein kinases, casein kinase 2, Rho-related coil formation protein kinase, tunica interna endothelial cell kinase, cyclooxygenase-2, adenosine kinase, lysophosphatidic acid acyltransferases, stearoyl-CoA desaturase, peroxisome proliferator-activated receptors, thioredoxin, heat shock proteins, and carbonic anhydrase IX/XII. In turn, they regulate angiogenesis, proliferation, differentiation, and cell survival, controlling the cell cycle, inflammation, the immune system, and metabolic alterations. A wide diversity of benzothiazoles were reported over the last years to interfere with various proteins involved in tumorigenesis and, more specifically, in hypoxic tumors. Many hypoxic targets are overexpressed as a result of the hypoxia-inducible factor activation cascade and may not be present in normal tissues, providing a potential strategy for selectively targeting hypoxic cancers.

BACKGROUND: Ectopic calcification is inappropriate biomineralization of soft tissues occurring due to genetic or acquired causes of hyperphosphataemia and rarely in normophosphataemic individuals. Tumoral Calcinosis (TC) is a rare metabolic bone disorder commonly presenting in childhood and adolescence with periarticular extra-capsular calcinosis. Three subtypes of TC have been recognised: primary hyperphosphataemic familial TC (HFTC), primary normophosphataemic familial TC and secondary TC most commonly seen in chronic renal failure. In the absence of established treatment, management is challenging due to variable success rates with medical therapies and recurrence following surgery.
OBJECTIVE: We outline the successful treatment approaches in four children with TC (2 normophosphatemic TC, 2 HFTC) aged 2.5-10 years at initial presentation.
METHODS: Patient 1 (P1) presented at 10 years with a painless lump behind the right knee, P2 with swelling of the right knee anteriorly at 9 years, P3 and P4 with pain and swelling over the right elbow at 5 and 2.5 years respectively. All patients were of Black African-Caribbean origin and were previously reported to be fit and well with no family history of TC.
RESULTS: P1, P2 had normophosphataemic TC and P3, P4 had HFTC with genetically confirmed GALNT3 mutation. All four patients had initial surgical resection with TC confirmed on histology. P1 had complete surgical resection with no recurrence at 27 months post-operatively. P2 had significant overgrowth of the tumour following surgery and was subsequently successfully managed with 25 % topical sodium metabisulphite (total duration of 8 months with a 4 month gap during which there was recurrence). P3 had post-surgical recurrence of TC on the right elbow and a new lesion on left elbow which resolved with oral acetazolamide monotherapy (15-20 mg/kg/day). P4 had recurrence of right elbow lesion following surgery and developed an extensive new hip lesion on sevelamer therapy which resolved completely with additional acetazolamide therapy (18-33 mg/kg/day). Acetazolamide was well tolerated with normal growth for 5 years in P3 and 6.5 years in P4 and no recurrence of lesions.
CONCLUSIONS: The frequent post-surgical recurrence in TC and successful medical therapy on the other hand indicates that medical management as first line therapy should be adopted. Monotherapies with topical 25 % sodium metabisulphite in normophosphataemic and oral acetazolamide in HFTC are effective treatment strategies which are well tolerated.

Being aware of the need to develop more efficient therapies against cancer, herein we disclose an innovative approach for the design of selective antiproliferative agents. We have accomplished the conjugation of a coumarin fragment with lipophilic cations (triphenylphosphonium salts, guanidinium) for providing mitochondriotropic agents that simultaneously target also carbonic anhydrases IX and XII, involved in the development and progression of cancer. The new compounds prepared herein turned out to be strong inhibitors of carbonic anhydrases IX and XII of human origin (low-to-mid nM range), also endowed with high selectivity, exhibiting negligible activity towards cytosolic CA isoforms. Key interactions with the enzyme were analysed using docking and molecular dynamics simulations. Regarding their in vitro antiproliferative activities, an increase of the tether length connecting both pharmacophores led to a clear improvement in potency, reaching the submicromolar range for the lead compounds, and an outstanding selectivity towards tumour cell lines (S.I. up to >357). Cytotoxic effects were also analysed on MDR cell lines under hypoxic and normoxic conditions. Chemoresistance exhibited by phosphonium salts, and not by guanidines, against MDR cells was based on the fact that the former were found to be substrates of P-glycoprotein (P-gp), the pump responsible for extruding foreign chemicals; this situation was reversed by administrating tariquidar, a third generation P-gp inhibitor. Moreover, phosphonium salts provoked a profound depolarization of mitochondria membranes from tumour cells, thus probably compromising their oxidative metabolism. To gain insight into the mode of action of title compounds, continuous live cell microscopy was employed; interestingly, this technique revealed two different antiproliferative mechanisms for both families of mitocans. Whereas phosphonium salts had a cytostatic effect, blocking cell division, guanidines led to cell death via apoptosis.

The three-components one-pot Kabachnik-Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide-phosphonates (3a-3p) in good to excellent yields (78%-91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X-ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide-phosphonates were evaluated for their inhibitory properties against four isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform.

Carbonic anhydrases (CAs) from the pathogenic bacteria Nesseria gonorrhoeae and vancomycin-resistant enterococci (VRE) have recently been validated as antibacterial drug targets. Here we explored the inhibition of the α-CA from N. gonorrhoeae (α-NgCA), of α- and γ-class enzymes from Enterococcus faecium (α-EfCA and γ-EfCA) with a panel of aliphatic, heterocyclic and aryl-alkyl primary/secondary monothiocarbamates (MTCs). α-NgCA was inhibited in vitro with KIs ranging from 0.367 to 0.919 µM. The compounds inhibited the α-EfCA and γ-EfCA with KI ranges of 0.195-0.959 µM and of 0.149-1.90 µM, respectively. Some MTCs were also investigated for their inhibitory effects on the growth of clinically-relevant N. gonorrhoeae and VRE strains. No inhibitory effects on the growth of VRE were noted for all MTCs, whereas one compound (13) inhibited the growth N. gonorrhoeae strains at concentrations ranging from 16 to 64 µg/mL. This suggests that compound 13 may be a potential antibacterial agent against N. gonorrhoeae.

Background: Inhibition of human carbonic anhydrase (hCA) isoforms IX and XII with concurrent inhibition of cathepsin B is a promising approach for targeting cancers. Methods/results: 28 keto-bridged dual triazole-containing benzenesulfonamides were synthesized and tested, following the multitarget approach, for their efficacy as inhibitors of cathepsin B and hCA isoforms (I, II, IX, XII). The synthesized compounds showed excellent inhibition of CA isoforms (IX and XII) and cathepsin B. Compound 8i exhibited better and more selective inhibition of the cancer-associated isoform hCA IX as compared with acetazolamide (reference drug) and SLC-0111 (potent lead as carbonic anhydrase inhibitor). Molecular docking studies were also carried out. Conclusion: The present work gives important generalizations for the development of isoform-selective hCA inhibitors endowed with anti-cathepsin properties.

UNASSIGNED: Macular edema (ME) is a vision-threatening condition that commonly develops as a consequence of ocular diseases, including age-related macular degeneration, retinal vaso-occlusion of the central retinal vein and its branches, diabetic retinopathy, central serous chorioretinopathy, uveitis, retinitis pigmentosa, pseudophakia, ocular trauma, and drug toxicity. The treatment of ME remains challenging, although steroids and vascular endothelial growth factor inhibitors are available. Cost-effective therapy using a noninvasive administration route is required. This study aimed at reviewing the role of carbonic anhydrase inhibitors (CAIs) in the management of ME.
UNASSIGNED: A literature search was conducted using PubMed/MEDLINE and Google Scholar for studies from January 2000 to March 2022. The following keywords were used in various combinations: \"macular edema\", \"carbonic anhydrase\", \"carbonic anhydrase inhibitors\", \"acetazolamide\", \"dorzolamide\", and \"brinzolamide\".
UNASSIGNED: Articles with high or medium clinical relevance were selected for this review. We found that multiple studies have demonstrated the relevance and efficacy rates of CAIs in the management of ME. Most published studies focused on acetazolamide and dorzolamide, with nearly all studies reporting therapeutic responses.
UNASSIGNED: ME is the leading cause of vision loss and requires noninvasive and cost-effective pharmacotherapy. With progress in the understanding of ME, particularly the role of carbonic anhydrase as a key driver, CAIs are the focus of research. Further optimization of the choice of CAIs and retinal bioavailability, potentially with nanoparticle formulations, is required to enable the effective management of ME. Further research is warranted to address the therapeutic effects of CAIs in different formulations.

Second near-infrared window (NIR-II) fluorescence imaging has shown great potential in the field of bioimaging. To achieve a better imaging effect, variety of NIR-II fluorescence probes have been designed and developed. Among them, semiconducting oligomers (SOs) have shown unique advantages including high photostability and quantum yield, making them promise in NIR-II fluorescence imaging. Herein, we design a SO nanoparticle (ASONi) for NIR-II fluorescence imaging of tumor. ASONi is composed of an azido-functionalized semiconducting oligomer as the NIR-II fluorescence emitter, and a benzene sulfonamide-ended DSPE-PEG (DSPE-PEG-CAi) as the stabilizer. Owing to the benzene sulfonamide groups on the surface, ASONi has the capability of targeting the carbonic anhydrase IX (CA IX) of MDA-MB-231 breast cancer cell. Compared with ASON without benzene sulfonamide groups on the surface, ASONi has a 1.4-fold higher uptake for MDA-MB-231 cells and 1.5-fold higher breast tumor accumulation after i.v. injection. The NIR-II fluorescence signal of ASONi can light the tumor up within 4 h, demonstrating its capability of active tumor targeting and NIR-II fluorescence imaging.

Brinzolamide is an effective carbonic anhydrase inhibitor widely used in glaucoma therapy but limits its application due to inadequate aqueous solubility and permeability. The aim of the present research work is the development and characterization of brinzolamide-loaded ultradeformable bilosomes to enhance the corneal permeation of the drug. These ultradeformable bilosomes were prepared by ethanol injection method and evaluated for physicochemical properties, particle size, morphology, drug release, ultra-deformability, corneal permeation, and irritation potential. The optimized formulation exhibited an average particle size of 205.4 ± 2.04 nm with mono-dispersity (0.109 ± 0.002) and showed entrapment efficiency of 75.02 ± 0.017%, deformability index of 3.91, and release the drug in a sustained manner. The brinzolamide-loaded ultradeformable bilosomes released 76.29 ± 3.77% of the drug in 10 h that is 2.25 times higher than the free drug solution. The bilosomes were found non-irritant to eyes with a potential irritancy score of 0 in Hen\'s egg-chorioallantoic membrane assay. Brinzolamide-loaded ultradeformable bilosomes showed 83.09 ± 5.1% of permeation in 6 h and trans-corneal permeability of 8.78 ± 0.14 cm/h during the ex vivo permeation study. The acquired findings clearly revealed that the brinzolamide-loaded ultradeformable bilosomes show promising output and are useful in glaucoma therapy.