Engineered Artesunate-Naphthalimide Hybrid Dual Drug for Synergistic Multimodal Therapy against Experimental Murine Lymphoma.

Lymphoma can effectively be treated with a chemotherapy regimen that is associated with adverse side effects due to increasing drug resistance, so there is an emergent need for alternative small-molecule inhibitors to overcome the resistance that occurs in lymphoma management and overall increase the prognosis rate. A new series of substituted naphthalimide moieties conjugated via ester and amide linkages with artesunate were designed, synthesized, and characterized. In addition to the conjugates, to further achieve a theranostic molecule, FITC was incorporated via a multistep synthesis process. DNA binding studies of these selected derivatives by ultraviolet-visible (UV-vis), fluorescence spectroscopy, intercalating dye (EtBr, acridine orange)-DNA competitive assay, and minor groove binding dye Hoechst 33342-DNA competitive assay suggested that the synthesized novel molecules intercalated between the two strands of DNA due to its naphthalimide moiety and its counterpart artesunate binds with the minor groove of DNA. Napthalimide-artesunate conjugates inhibit the growth of lymphoma and induce apoptosis, including ready incorporation and reduction in cell viability. The remodeled drug has a significant tumoricidal effect against solid DL tumors developed in BALB/c mice in a dose-dependent manner. The novel drug appears to inhibit metastasis and increase the survival of the treated animals compared with untreated littermates.

Research Progress on Structure-Activity Relationship of 1,8-Naphthalimide DNA Chimeras Against Tumor.

The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine. Naphthalimide compounds are a kind of DNA embedder, which can change the topological structure of DNA by embedding in the middle of DNA base pairs, and then affect the recognition and action of topoisomerase on DNA. Aminofide and mitonafide are the first 2 drugs to undergo clinical trials. They have good DNA insertion ability, can embed DNA double-stranded structure, and induce topoisomerase II to cut part of pBR322DNA, but not yet entered the market due to their toxicity. In this paper, the design and structure-activity relationship of mononaphthalimide and bisaphthalimide compounds were studied, and the relationship between the structure of naphthalimide and anti-tumor activity was analyzed and discussed. It was found that a variety of structural modifications were significant in improving anti-tumor activity and reducing toxicity.

Discovery and Characterization of Novel Naphthalimide Analogs as Potent Multitargeted Directed Ligands against Alzheimer's Disease.

Current therapeutic drugs for Alzheimer's disease (AD) can only offer limited symptomatic benefits and do not halt disease progression. Multitargeted directed ligands (MTDLs) have been considered to be a feasible way to treat AD due to the multiple neuropathological processes in AD. Previous studies proposed that compounds containing two aromatic groups connected by a carbon chain should act as effective amyloid ß (Aß) aggregation inhibitors although the optimal length of the carbon chain has not been explored. In the current study, a series of naphthalimide analogs were designed and synthesized based on the proposed structure and multiple bioactivities beneficial to the AD treatment were reported. In vitro studies showed that compound 8, which has two aromatic groups connected by a two-carbon chain, exhibited significant inhibition of Aß aggregation through the prevention of elongation and association of Aß fibril growth. Furthermore, this compound also displayed antioxidative activities and neuroprotection from Aß monomer induced toxicity in primary cortical neurons. The results of the present study highlight a novel naphthalimide-based compound 8 as a promising MTDL against AD. Its structural elements can be further explored for enhanced therapeutic capabilities.

Design, synthesis and anti-tumor activity of novel benzothiophenonaphthalimide derivatives targeting mitochondrial DNA (mtDNA) G-quadruplex.

A series of new naphthalimide derivatives, benzothiophenonaphthalimides (7a-7g, 8a-8g), were designed and synthesized, of which compounds 8a-8g are hydrochloride salts of corresponding compounds 7a-7g. All compounds presented different anti-tumor activities for tumor cells tested by the CCK-8 assay. In particular, compound 7c displayed the strongest anti-tumor activity with an IC50 value of 0.59 ± 0.08 µM and the best selectivity for HepG2 cells. At the same time, it was observed that 7c could induce HepG2 cell apoptosis, hinder cancer cell migration and arrest the cell cycle at the G2/M phase. Further mechanism studies revealed that 7c selectively induced a G-rich HRCC DNA sequence in the mitochondria to form a G-quadruplex structure (G4) and stabilized it, which mediated the decrease in mitochondrial membrane potential and the production of reactive oxygen species, causing mitochondrial dysfunction. Finally, this led to proliferative inhibition and apoptosis of cancer cells and protective autophagy by promoting the expression of p-Erk1/2. The in vivo experimental results indicated that the compound 8c as a salt of 7c showed significant in vivo anti-tumor efficacy in the HepG2-xenograft mouse model with a tumor growth inhibition rate of 51.4% at a dose of 15 mg/kg. These results suggest that 7c possesses a different anti-tumor mechanism from the previous main reported mechanism of naphthalimide derivatives, which targets the nucleus. In brief, 7c has good anti-tumor activity in vitro and in vivo and may act as a leading compound in development of drugs against liver cancer.

Systemic inhibition or global deletion of CaMKK2 protects against post-traumatic osteoarthritis.

OBJECTIVE: To investigate the role of Ca2+/calmodulin-dependent protein kinase 2 (CaMKK2) in post-traumatic osteoarthritis (PTOA). METHODS: Destabilization of the medial meniscus (DMM) or sham surgeries were performed on 10-week-old male wild-type (WT) and Camkk2-/- mice. Half of the DMM-WT mice and all other cohorts (n = 6/group) received tri-weekly intraperitoneal (i.p.) injections of saline whereas the remaining DMM-WT mice (n = 6/group) received i.p. injections of the CaMKK2 inhibitor STO-609 (0.033 mg/kg body weight) thrice a week. Study was terminated at 8- or 12-weeks post-surgery, and knee joints processed for microcomputed tomography imaging followed by histology and immunohistochemistry. Primary articular chondrocytes were isolated from knee joints of 4-6-day-old WT and Camkk2-/- mice, and treated with 10 ng/ml interleukin-1ß (IL)-1ß for 24 or 48 h to investigate gene and protein expression. RESULTS: CaMKK2 levels and activity became elevated in articular chondrocytes following IL-1ß treatment or DMM surgery. Inhibition or absence of CaMKK2 protected against DMM-associated destruction of the cartilage, subchondral bone alterations and synovial inflammation. When challenged with IL-1ß, chondrocytes lacking CaMKK2 displayed attenuated inflammation, cartilage catabolism, and resistance to suppression of matrix synthesis. IL-1ß-treated CaMKK2-null chondrocytes displayed decreased IL-6 production, activation of signal transducer and activator of transcription 3 (Stat3) and matrix metalloproteinase 13 (MMP13), indicating a potential mechanism for the regulation of inflammatory responses in chondrocytes by CaMKK2. CONCLUSIONS: Our findings reveal a novel function for CaMKK2 in chondrocytes and highlight the potential for its inhibition as an innovative therapeutic strategy in the prevention of PTOA.

Identification of driver genes and key pathways of non-functional pituitary adenomas predicts the therapeutic effect of STO-609.

OBJECTIVE: Our study is to identify DEGs (Differentially Expressed Genes), comprehensively investigate hub genes, annotate enrichment functions and key pathways of Non-functional pituitary adenomas (NFPAs), and also to verify STO-609 therapeutic effect. METHODS: The gene expression level of NFPA and normal tissues were compared to identify the DEGs (Differential expressed genes) based on gene expression profiles (GSE2175, GSE26966 and GSE51618). Enrichment functions, pathways and key genes were identified by carrying out GO (Gene Ontology), KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis and PPI (Protein-Protein Interation) network analysis. Moreover, experiments in vitro were conducted to verify the anti-NFPAs effects of STO-609. RESULTS: 169 over-expression genes and 182 low expression genes were identified among 3 datasets. Dopaminergic synapse and vibrio cholerae infection pathways have distinctly changed in NFPA tissues. The Ca2+/CaM pathway played important roles in NFPA. Four hub proteins encoded by genes CALM1, PRDM10, RIPK4 and MAD2L1 were recognized as hub proteins. In vitro, assays showed that STO-609 induced apoptosis of NFPA cells to inhibit the hypophysoma cellular viability, diffusion and migration. CONCLUSION: Four hub proteins, encoded by gene CALM1, PRDM10, RIPK4 and MAD2L1, played important roles in NFPA development. The Ca2+/CaM signaling pathway had significant alternations during NFPA forming process, the STO-609, a selective CaM-KK inhibitor, inhibited NFPA cellular viability, proliferation and migration. Meanwhile, NFPA was closely related to parkinson's disease (PD) in many aspects.

AMPK Alters Detrusor Contractility During Emptying in Normal Bladder and Hypertrophied Bladder with Partial Bladder Outlet Obstruction via CaMKKß.

AMP-activated protein kinase (AMPK) has been implicated in contractility changes in bladders with partial bladder outlet obstruction (PBOO), but the role of AMPK in the contractile response of normal bladder remains unclear. We investigated the phosphorylation of AMPKα and expression of the involved upstream AMPK kinases (AMPKKs) in a model of bladders with PBOO and sought to determine whether the pharmacological inhibition of these two factors affected detrusor contractility in normal bladders, using female Sprague-Dawley rats. Cystometry and Western blot analysis were performed in rats that were subjected to PBOO induction or a sham operation. Cystometry was performed in normal rats that received selective inhibitors of AMPKα and Ca2+/calmodulin-dependent protein kinase kinase (CaMKKß) (compound C and STO-609, respectively) at doses determined in the experiments. In the PBOO bladders, bladder weight and micturition pressure (MP) were higher and AMPKα phosphorylation (T172) and CaMKKß expression was significantly reduced. Compound C and STO-609 increased MP. The increased contractile response in bladders with PBOO-induced hypertrophy was related to decreased CaMKKß/AMPK signaling activity, and the pharmacological inhibition of this pathway in normal bladders increased detrusor contractility, implying a role of CaMKKß/AMPK signaling in the bladder in the regulation of detrusor contractility.

6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.

Hepatocellular carcinoma (HCC) is the third leading form of cancer worldwide, and its incidence is increasing rapidly in the United States, tripling over the past 3 decades. The current chemotherapeutic strategies against localized and metastatic HCC are ineffective. Here we report that 6-methoxyethylamino-numonafide (MEAN) is a potent growth inhibitor of murine xenografts of 2 human HCC cell lines. At the same dose and with the same treatment strategies, MEAN was more efficacious in inhibiting tumor growth in mice than sorafenib, the only approved drug for HCC. Treatment by MEAN at an effective dose for 6 wk was well tolerated by animals. Combined therapy using both sorafenib and MEAN enhanced tumor growth inhibition over monotherapy with either agent. Additional experiments revealed that MEAN inhibited tumor growth through mechanisms distinct from those of either its parent compound, amonafide, or sorafenib. MEAN suppressed C-MYC expression and increased expression of several tumor suppressor genes, including Src homology region 2 domain-containing phosphatase-1 (SHP-1) and TXNIP (thioredoxin-interacting protein). As an encouraging feature for envisioned clinical application, the IC50 of MEAN was not significantly changed in several drug-resistant cell lines with activated P-glycoprotein drug efflux pumps compared to drug-sensitive parent cells, demonstrating the ability of MEAN to be effective in cells resistant to existing chemotherapy regimens. MEAN is a promising candidate for clinical development as a single-agent therapy or in combination with sorafenib for the management of HCC.-Liu, Y., Lou, G., Norton, J. T., Wang, C., Kandela, I., Tang, S., Shank, N. I., Gupta, P., Huang, M., Avram, M. J., Green, R., Mazar, A., Appella, D., Chen, Z., Huang, S. 6-Methoxyethylamino-numonafide inhibits hepatocellular carcinoma xenograft growth as a single agent and in combination with sorafenib.

A novel triazolonaphthalimide induces apoptosis and inhibits tumor growth by targeting DNA and DNA-associated processes.

DNA and DNA-associated processes have been classes of the most important targets of chemotherapeutic drugs. As classic DNA intercalators and topoisomerase inhibitors, naphthalimides have been extensively investigated as potential anti-cancer drugs. We recently synthesized a novel series of triazolonaphthalimides with excellent anti-cancer activities. In the present study, one of the most potent triazolonaphthalimides, LSS-11, was investigated. LSS-11 bound to DNA in vitro and in cell mainly by minor groove binding and significantly increased the stability of DNA, which could be fundamental for the biological activities of LSS-11. In addition to inhibiting DNA topoisomerase II-catalyzed decatenation of knotted circulated DNA, LSS-11 dramatically inhibited DNA replication mediated by polymerase chain reaction and isothermal helicase-dependent amplification, as well as the expression of luciferase driven by a minimal TA promoter in cell. Furthermore, LSS-11 exhibited strong cytotoxicity in selected human colon cancer cell lines by inducing cell cycle arrest and apoptosis, which was accompanied by DNA damage response. Finally, LSS-11 potently inhibited the growth of S180 murine sarcoma and SW480 human colorectal cancer xenografts in vivo without significant major toxicities. These results suggest that LSS-11 deserves further research and development as a novel anti-cancer agent, and provided new understandings of mechanisms by which LSS-11 inhibited multiple DNA-associated processes and tumor growth.

Combination strategy of PARP inhibitor with antioxidant prevent bioenergetic deficits and inflammatory changes in CCI-induced neuropathy.

Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats. Quercetin (25 mg/kg, p.o.) and 4-ANI (3 mg/kg, p.o.) were administered either alone or in combination for 14 days to examine sciatic functional index, allodynia and hyperalgesia using walking track analysis, Von Frey, acetone spray and hot plate tests respectively. Malondialdehyde, nitrite and glutathione levels were estimated to detect oxidative/nitrosative stress; mitochondrial membrane potential and cytochrome c oxidase activity to assess mitochondrial function; NAD & ATP levels to examine the bioenergetic status and levels of inflammatory markers were evaluated in ipsilateral sciatic nerve. Quercetin and 4-ANI alone improved the pain behaviour and biochemical alterations but the combination therapy demonstrated an appreciable reversal of CCI-induced changes. Nitrotyrosine and Poly ADP-Ribose (PAR) immunopositivity was decreased and nuclear factor erythroid 2-related factor (Nrf-2) levels were increased significantly in micro-sections of the sciatic nerve and dorsal root ganglion (DRG) of treatment group. These results suggest that simultaneous inhibition of oxidative stress-PARP activation cascade may potentially be useful strategies for management of trauma induced neuropathic pain.

Novel bisnaphthalimidopropyl (BNIPs) derivatives as anticancer compounds targeting DNA in human breast cancer cells.

Bisnaphthalimidopropyl (BNIP) derivatives are a family of compounds that exert anti-cancer activities in vitro and, according to previous studies, variations in the linker sequence have increased their DNA binding and cytotoxic activities. By modifying the linker sequence of bisnaphthalimidopropyl diaminodicyclohexylmethane (BNIPDaCHM), a previously synthesised BNIP derivative with anti-cancer properties, three novel BNIP derivatives were designed. Bisnaphthalimidopropyl-piperidylpropane (BNIPPiProp), a structural isomer of BNIPDaCHM, bisnaphthalimidopropyl ethylenedipiperidine dihydrobromide (BNIPPiEth), an isoform of BNIPDaCHM with a shorter linker chain, and (trans(trans))-bisnaphthalimidopropyl diaminodicyclohexylmethane (trans,trans-BNIPDaCHM), a stereoisomer of BNIPDaCHM, were successfully synthesised (72.3-29.5% yield) and characterised by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS). Competitive displacement of ethidium bromide (EtBr) and UV binding studies were used to study the interactions of BNIP derivatives with Calf Thymus DNA. The cytotoxicity of these derivatives was assessed against human breast cancer MDA-MB-231 and SKBR-3 cells by MTT assay. Propidium iodide (PI) flow cytometry was conducted in order to evaluate the cellular DNA content in both breast cancer cell lines before and after treatment with BNIPs. The results showed that all novel BNIPs exhibit strong DNA binding properties in vitro, and strong cytotoxicity, with IC50 values in the range of 0.2-3.3 µM after 24 hours drug treatment. Two of the novel BNIP derivatives, BNIPPiEth and trans,trans-BNIPDaCHM, exhibited greater cytotoxicity against the two breast cancer cell lines studied, compared to BNIPDaCHM. By synthesising enantiopures and reducing the length of the linker sequence, the cytotoxicity of the BNIP derivatives was significantly improved compared to BNIPDaCHM, while maintaining DNA binding and bis-intercalating properties. In addition, cell cycle studies indicated that trans,trans-BNIPDaCHM, the most cytotoxic BNIP derivative, induced sub-G1 cell cycle arrest, indicative of apoptotic cell death. Based on these findings, further investigation is under way to assess the potential efficacy of trans,trans-BNIPDaCHM and BNIPPiEth in treating human breast cancer.

Heterocyclic Naphthalimides as New Skeleton Structure of Compounds with Increasingly Expanding Relational Medicinal Applications.

Naphthalimide compounds are an important type of nitrogen-containing aromatic heterocycles with cyclic double imides and the naphthalene framework. This π-deficient large conjugated planar structure enables naphthalimide derivatives to readily interact with various biological cations, anions, small molecules and macromolecules such as DNAs, enzymes and recetors in living organism via noncovalent bonds, therefore exhibiting extensive potentiality in relatively medicinal applications. Currently, some naphthalimides as anticancer agents have entered into clinical trials and other naphthalimide-based medicinal developments as potential drugs for treatment of various diseases are actively and unprecedentedly expanding. Naphthalimide-derived artificial ion receptors, fluorescent probes and cell imaging agents are being overwhelmingly investigated and have a diversity of potential applications in real-time detecting ions and biomolecules, understanding biological processes and determining pharmacological and pharmacokinetic properties. All the above mentions have strongly implied that naphthalimide-based derivatives as new skeleton structure of compounds possess increasingly expanding relational medicinal applications, and the related research is becoming a quite attractive active topic and newly rising highlight. Combining with our research and referring other works from literature, this work systematically reviews the current research and development of heterocyclic naphthalimides as anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antidepressant agents as well as artificial cation and anion receptors, diagnostic agents and pathologic probes, and cell imaging agents for biologically important species. Some rational design strategies, structure-activity relationships and action mechanisms are discussed. The perspectives of the future development of naphthalimide-based medicinal chemistry are also presented.

MEAN inhibits hepatitis C virus replication by interfering with a polypyrimidine tract-binding protein.

MEAN (6-methoxyethylamino-numonafide) is a small molecule compound, and here, we report that it effectively inhibits hepatitis C virus (HCV) infection in an HCV cell culture system using a JC1-Luc chimeric virus, with a 50% effective concentration (EC50) of 2.36 ± 0.29 µM. Drug combination usage analyses demonstrated that MEAN was synergistic with interferon α, ITX5061 and ribavirin. In addition, MEAN effectively inhibits N415D mutant virus and G451R mutant viral infections. Mechanistic studies show that the treatment of HCV-infected hepatocytes with MEAN inhibits HCV replication but not translation. Furthermore, treatment with MEAN significantly reduces polypyrimidine tract-binding protein (PTB) levels and blocks the cytoplasmic redistribution of PTB upon infection. In the host cytoplasm, PTB is directly associated with HCV replication, and the inhibition of HCV replication by MEAN can result in the sequestration of PTB in treated nuclei. Taken together, these results indicate that MEAN is a potential therapeutic candidate for HCV infection, and the targeting of the nucleo-cytoplasmic translocation of the host PTB protein could be a novel strategy to interrupt HCV replication.

Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione.

Familial amyloid polyneuropathy (FAP) is a genetic, adult-onset, neurodegenerative disorder caused by amyloid formation of transthyretin (TTR), a thyroxine-binding protein. Mutation in TTR causes a propensity of TTR tetramer to dissociate to monomer, which is the first step to amyloidosis. Thus, a drug that can stabilize the tetramer structure will have therapeutic benefit. Here, by virtual screening and biochemical assays, we identified small molecule 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione (L6) that can prevent the dissociation of TTR to monomer. X-ray crystallography reveals that L6 binds to the T4 binding pocket of TTR. These findings show that L6 is a candidate TTR stabilizer.

Sensitization of cisplatin therapy by a naphthalimide based organoselenium compound through modulation of antioxidant enzymes and p53 mediated apoptosis.

The widely used anti-cancer drug cisplatin imparts various toxic manifestations in the host, with nephrotoxicity being the most severe one. The trace element selenium shows antioxidant activity in both human and animals. The present study was designed to assess the chemoprotecting and chemoenhancing efficacy of a naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione during cisplatin chemotherapy in mice bearing Ehrlich ascites carcinoma cells. Cisplatin (5 mg/kg b.w.) was administered intraperitoneally and the organoselenium compound (3 mg/kg b.w.) was given by oral gavage in concomitant and pretreatment schedule. The effects of the test compound was evaluated by assaying biochemical, hematological, histological, genotoxicity parameters and by investigating induction of apoptosis in tumor cells, and calculating tumor growth response in the host. The organoselenium compound significantly prevented cisplatin induced generation of reactive oxygen species (ROS), reactive nitrogen species, and onset of lipid peroxidation in the kidney tissue of the experimental mice. In addition, the test compound was also substantially restored cisplatin induced depleted activities of the renal antioxidant enzymes and reduced glutathione level; prevented the serum blood urea nitrogen level, creatinine level, chromosomal aberration, DNA damage, histological alterations of kidney, and normalized the hematological profile of the tumor bearing mice. Furthermore, the organoselenium compound alone or during combination therapy induced apoptosis in tumor cells through mitochondria mediated and DNA damage mediated pathway and ultimately increased the life span of the tumor bearing host. Hence, the results showed that the test compound not only reduced the toxicity of cisplatin but also enhanced its anti-tumor efficacy.

In vitro and in vivo evaluation of 2-chloroethylnitrosourea derivatives as antitumor agents.

AIM: To evaluate potential of Naphthal-NU, Napro-NU and 5-Nitro-naphthal-NU, 2-chloroethylnitrosourea compounds with substituted naphthalimide in the pre-clinical studies. MATERIALS AND METHODS: In vitro cytotoxicity of three nitrosoureas was determined in human and mouse tumor cell lines by MTT assays. In vivo anti-tumor potential was evaluated in Sarcoma-180 (S-180) and Ehrlich's carcinoma (EC) solid tumors. Apoptosis in S-180 cells was analyzed by using Annexin V-Propidium Iodide (PI). Histological analysis of liver and kidney was performed at optimum dose (50 mg/kg). Expression status of CD4(+), CD8(+) and CD25(+) cells in treated mouse were also examined. RESULTS: Significant tumor growth retardation by the compounds was noted in early and advanced disease groups, as the life span of drug treated mice increased considerably. Drug induced killing was observed by induction of apoptosis. Naphthal-NU and 5-Nitro-naphthal-NU were effective to normalize the tumor induced structural abnormalities of liver and kidney. The compounds have no immunotoxic effect on CD4(+) and CD8(+) T cells and down regulate CD4(+)CD25(+) regulatory T cells. CONCLUSION: Overall data holds promise for the antitumor activity with lower toxicity of the compounds that can be utilized for the treatment of human malignant tumors.

Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.

Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system.

Attenuation of cyclophosphamide-induced pulmonary toxicity in Swiss albino mice by naphthalimide-based organoselenium compound 2-(5-selenocyanatopentyl)-benzo[de]isoquinoline 1,3-dione.

CONTEXT: The widely used antineoplastic drug cyclophosphamide causes pulmonary toxicity by inducing oxidative stress. Selenium, a dietary micronutrient, has been found to protect various organs from oxidative injuries. OBJECTIVE: This study was designed to investigate the protective efficacy of an organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione against cyclophosphamide-induced pulmonary toxicity in Swiss albino mice. MATERIALS AND METHODS: Cyclophosphamide (25 mg/kg b.w.) was administered intraperitoneally for 10 d and the organoselenium compound (3 mg/kg b.w.) was given by oral gavage in concomitant and pretreatment schedules. Various biochemical parameters related to oxidative stress and antioxidant enzymes along with histology of lungs were evaluated to assess the effect of the test compound. RESULTS: The oral LD50 of the test compound was more than 1000 mg/kg b.w. in Swiss albino mice. The test compound substantially ameliorated cyclophosphamide-induced pulmonary injury by reducing the levels of reactive oxygen species, reactive nitrogen species, and lipid peroxidation, respectively, by 14.88, 18.54, and 21.10% in concomitant treatment schedule and by 23.89, 35.73, and 30.76% in the pretreatment schedule as well as by restoring the level of reduced glutathione and activities of glutathione-S-transferase, superoxide dismutase, catalase, and glutathione peroxidase, respectively, by 36.88, 42.43, 38.0, 35.0, and 34.06% in the concomitant treatment schedule and by 66.02, 59.29, 57.23, 71.59, and 57.22% in the pretreatment schedule. The test compound also attenuated cyclophosphamide-induced histological alterations of lung tissue. DISCUSSION AND CONCLUSION: The test compound emerged as an efficient antioxidant protecting lungs tissue from cyclophosphamide-induced injury.

Spectroscopical study of bacteriopurpurinimide-naphthalimide conjugates for fluorescent diagnostics and photodynamic therapy.

Two novel bis(chromophoric) dyads ABPI-NI1 and ABPI-NI2 containing 1,8-naphthalimide and bacteriopurpurinimide units linked by p-phenylene-methylene (ABPI-NI1) and pentamethylene (ABPI-NI2) spacers were prepared to test their ability to be used in the design of effective agents for both photodynamic therapy (PDT) and fluorescent tumor imaging. Photophysical studies revealed that the emission from the naphthalimide chromophore in both conjugates was partially quenched due to resonance energy transfer between the photoactive components. Compound ABPI-NI2 with more sterically flexible oligomethylene group demonstrated higher fluorescence intensity as compared with that for ABPI-NI1.

Naphthalimide derivatives with therapeutic characteristics: a patent review.

INTRODUCTION: Naphthalimides are important aromatic heterocycles with immense pharmacological significance as they serve as core scaffold for many antitumor, anti-inflammatory, antidepressant, antiprotozoal and antiviral agents, etc. The tricyclic planar ring system of naphthalimide is primarily responsible for its intercalation with DNA to perturb the cellular events and the substitution pattern of the molecule leads to several other applications. The promising pharmacological activity profile and ease of synthesis have been attractive in design and development of new class of naphthalimides and their conjugates as various potential therapeutic agents. Few of such molecules are currently under preclinical and clinical evaluations. AREAS COVERED: Important patents focusing on naphthalimides as potential class of therapeutics, published between the period of 2006 - 2011 have been covered. The reports are presented together with a review of the related structural chemical space. This review mainly focuses on the therapeutic applications, structural modifications of naphthalimide scaffold, their conjugates and heterocyclics bearing naphthalimide moiety. EXPERT OPINION: The tricyclic planar ring system of naphthalimide restrains important pharmaceutical properties along with excellent fluorescent after proper substitution pattern. Linking these active naphthalimide derivatives with other active pharmacophore has become an interesting area of research. The utility of naphthalimide derivatives as novel pharmaceutical and photochemical agents can be further enhanced by introducing polar side chains and fusing functionalized heterocyclic rings with naphthalimide cores.