Synthesis and Anti-Inflammatory Activity of 1-Methylhydantoin Cinnamoyl Imides.

In this study, 1-methylhydantoin cinnamic imides were synthesized from 1-methylhydantoin and trans-cinnamic acid, and their anti-inflammatory activity was investigated. The anti-inflammatory activity in vitro was evaluated by measuring the contents of NO, TNF-α and IL-1ß in the supernatant of RAW264.7 cells stimulated by LPS. The cytotoxicity of 1-methylhydantoin cinnamoyl imides on RAW264.7 cells was detected using the CCK-8 method. The results showed that compounds 2 and 4 can significantly inhibit the release of NO and reduce the secretion of TNF-α and IL-1ß. Compound 3 inhibited the production of TNF-α. The inhibition rate of COX was evaluated in vitro. The in vivo anti-inflammatory activities of the five compounds were evaluated by establishing an animal model of xylene ear swelling. The results showed that 1-methylhydantoin cinnamic imides could alleviate xylene-induced ear edema in mice in a dose-dependent manner. Among them, the effect of compound 5 was the most significant. Under the action of high dosage, its ear swelling inhibition rate was as high as 52.08%.

Investigating the potential use of an ionic liquid (1-Butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide) as an anti-fungal treatment against the amphibian chytrid fungus, Batrachochytrium dendrobatidis.

The disease chytridiomycosis, caused by the pathogenic chytrid fungus, Batrachochytrium dendrobatidis (Bd), has contributed to global amphibian declines. Bd infects the keratinized epidermal tissue in amphibians and causes hyperkeratosis and excessive skin shedding. In individuals of susceptible species, the regulatory function of the amphibian's skin is disrupted resulting in an electrolyte depletion, osmotic imbalance, and eventually death. Safe and effective treatments for chytridiomycosis are urgently needed to control chytrid fungal infections and stabilize populations of endangered amphibian species in captivity and in the wild. Currently, the most widely used anti-Bd treatment is itraconazole. Preparations of itraconazole formulated for amphibian use has proved effective, but treatment involves short baths over seven to ten days, a process which is logistically challenging, stressful, and causes long-term health effects. Here, we explore a novel anti-fungal therapeutic using a single application of the ionic liquid, 1-Butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (BMP-NTf2), for the treatment of chytridiomycosis. BMP-NTf2 was found be effective at killing Bd in vitro at low concentrations (1:1000 dilution). We tested BMP-NTf2 in vivo on two amphibian species, one that is relatively tolerant of chytridiomycosis (Pseudacris regilla) and one that is highly susceptible (Dendrobates tinctorius). A toxicity trial revealed a surprising interaction between Bd infection status and the impact of BMP-NTf2 on D. tinctorius survival. Uninfected D. tinctorius tolerated BMP-NTf2 (mean ± SE; 96.01 ± 9.00 µl/g), such that only 1 out of 30 frogs died following treatment (at a dose of 156.95 µL/g), whereas, a lower dose (mean ± SE; 97.45 ± 3.52 µL/g) was not tolerated by Bd-infected D. tinctorius, where 15 of 23 frogs died shortly upon BMP-NTf2 application. Those that tolerated the BMP-NTf2 application did not exhibit Bd clearance. Thus, BMP-NTf2 application, under the conditions tested here, is not a suitable option for clearing Bd infection in D. tinctorius. However, different results were obtained for P. regilla. Two topical applications of BMP-NTf2 on Bd-infected P. regilla (using a lower BMP-NTf2 dose than on D. tinctorius, mean ± SE; 9.42 ± 1.43 µL/g) reduced Bd growth, although the effect was lower than that obtained by daily doses of itracanozole (50% frogs exhibited complete clearance on day 16 vs. 100% for itracanozole). Our findings suggest that BMP-NTf2 has the potential to treat Bd infection, however the effect depends on several parameters. Further optimization of dose and schedule are needed before BMP-NTf2 can be considered as a safe and effective alternative to more conventional antifungal agents, such as itraconazole.

pH-responsive perylenediimide nanoparticles for cancer trimodality imaging and photothermal therapy.

Organic chromophores have been well developed for multimodality imaging-guided photothermal therapy (PTT) due to their outstanding optical properties and excellent designability. However, the theranostic efficiencies of most currently available organic chromophores are restricted intrinsically, owing to their poor photostability or complex synthesis procedures. These drawbacks not only increase their cost of synthesis, but also cause side effects in PTT. Method: We presented a facile strategy for constructing a near-infrared (NIR)-absorbing perylenediimide structured with pH-responsive piperazine ring at the bay region. The chromophore was conjugated with carboxyl-end-capped PEG as side chains that can self-assemble into nanoparticles (NPs) in aqueous solution. The NIR optical properties and photothermal conversation ability of PPDI-NPs were investigated. We then studied the imaging-guided PTT of PPDI-NPs under NIR light illumination in 4T1 cells and mice respectively. Results: The excellent photostable PPDI-NPs had near-infrared fluorescence (NIRF) emission and high photothermal conversion efficiency in acidic microenvironment. Importantly, PPDI-NPs can be utilized for the precise detection of tumors by NIRF/photoacoustic/thermal trimodality imaging. Efficient PTT of PPDI-NPs was applied in vitro and in vivo with high biosafety. Conclusion: In summary, we developed pH-responsive perylenediimide nanoparticles as multifunctional phototheranostic agent with high stability and simple synthesis procedures. This study offers a promising organic chromophore for developing phototheranostics in cancer therapy.

A Water-Soluble, NIR-Absorbing Quaterrylenediimide Chromophore for Photoacoustic Imaging and Efficient Photothermal Cancer Therapy.

Precision phototheranostics, including photoacoustic imaging and photothermal therapy, requires stable photothermal agents. Developing such agents with high stability and high photothermal conversion efficiency (PTCE) remains a considerable challenge. Herein, we introduce a new photothermal agent based on water-soluble quaterrylenediimide (QDI) that can self-assemble into nanoparticles (QDI-NPs) in aqueous solution. Incorporating polyethylene glycol (PEG) into the QDI core significantly enhances both physiological stability and biocompatibility of QDI-NPs. The highly photostable QDI-NPs offer advantages including intense absorption in the near-infrared (NIR) and high PTCE of up to 64.7±4 %. This is higher than that of commercial indocyanine green (ICG). Their small size (ca. 10 nm) enables sustained retention in deep tumor sites and also proper clearance from the body. QDI-NPs allow high-resolution photoacoustic imaging and efficient 808 nm laser-triggered photothermal therapy of cancer in vivo.

Terrylenediimide-Based Intrinsic Theranostic Nanomedicines with High Photothermal Conversion Efficiency for Photoacoustic Imaging-Guided Cancer Therapy.

Activatable theranostic nanomedicines involved in photothermal therapy (PTT) have received constant attention as promising alternatives to traditional therapies in clinic. However, the theranostic nanomedicines widely suffer from instability and complicated nanostructures, which hamper potential clinical applications. Herein, we demonstrated a terrylenediimide (TDI)-poly(acrylic acid) (TPA)-based nanomedicine (TNM) platform used as an intrinsic theranostic agent. As an exploratory paradigm in seeking biomedical applications, TDI was modified with poly(acrylic acid)s (PAAs), resulting in eight-armed, star-like TPAs composed of an outside hydrophilic PAA corona and an inner hydrophobic TDI core. TNMs were readily fabricated via spontaneous self-assembly. Without additional vehicle and cargo, the as-prepared TNMs possessed a robust nanostructure and high photothermal conversion efficiency up to approximately 41%. The intrinsic theranostic properties of TNMs for use in photoacoustic (PA) imaging by a multispectral optoacoustic tomography system and in mediating photoinduced tumor ablation were intensely explored. Our results suggested that the TNMs could be successfully exploited as intrinsic theranostic agents for PA imaging-guided efficient tumor PTT. Thus, these TNMs hold great potential for (pre)clinical translational development.

Structure-based design and evaluation of naphthalene diimide G-quadruplex ligands as telomere targeting agents in pancreatic cancer cells.

Tetra-substituted naphthalene diimide (ND) derivatives with positively charged termini are potent stabilizers of human telomeric and gene promoter DNA quadruplexes and inhibit the growth of human cancer cells in vitro and in vivo. The present study reports the enhancement of the pharmacological properties of earlier ND compounds using structure-based design. Crystal structures of three complexes with human telomeric intramolecular quadruplexes demonstrate that two of the four strongly basic N-methyl-piperazine groups can be replaced by less basic morpholine groups with no loss of intermolecular interactions in the grooves of the quadruplex. The new compounds retain high affinity to human telomeric quadruplex DNA but are 10-fold more potent against the MIA PaCa-2 pancreatic cancer cell line, with IC50 values of ~10 nM. The lead compound induces cellular senescence but does not inhibit telomerase activity at the nanomolar dosage levels required for inhibition of cellular proliferation. Gene array qPCR analysis of MIA PaCa-2 cells treated with the lead compound revealed significant dose-dependent modulation of a distinct subset of genes, including strong induction of DNA damage responsive genes CDKN1A, DDIT3, GADD45A/G, and PPM1D, and repression of genes involved in telomere maintenance, including hPOT1 and PARP1.

Microwave-assisted synthesis of N-substituted cyclic imides and their evaluation for anticancer and anti-inflammatory activities.

A number of N-substituted cyclic imides 3a-e, 5a-e, 7a-d, and 9a-e have been synthesized in very high yields, by condensation of various diacids 2, 4, 6, and 8 with different amines under microwave irradiation. These compounds were screened for anticancer and anti-inflammatory activities, and compounds 3c, 3e, 5c, 9c, and 9d exhibited anticancer activity against colon (COLO 205) cancer better than 5-fluorouracil and mitomycin-C, and compound 9b exhibited anti-inflammatory activity better than standard drug phenyl butazone.

Metastatic breast cancer.

The management of metastatic breast cancer continues to provide enormous challenges. The taxanes have significant activity in patients with resistant disease, and combination regimens are being evaluated as first-line therapy. The combination of paclitaxel and doxorubicin appears to have substantial activity, but troublesome cardiac toxicity has been noted in a recently reported study. Docetaxel has been shown to be very active in initial phase II evaluation, notably in women with anthracycline-resistant disease. The controversy over high-dose therapy continues, and its role in the management of metastatic breast cancer outside the confines of clinical trials remains unclear. The HER-2 protein appears to be a predictive factor for patients with metastatic disease. Antibody therapy directed at this target can produce responses in a proportion of patients. Bisphosphonates appear to be beneficial to patients with lytic bony metastases when administered in conjunction with cytotoxic or hormonal therapy.

Amonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642).

Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.

Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck. An Illinois Cancer Center study.

Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0-2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m2 for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3-4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.

A Gynecologic Oncology Group phase II study of amonafide (NSC #308847) in squamous cell carcinoma of the cervix.

Twenty evaluable patients with squamous cell carcinoma of the cervix, who had previously received a cisplatin-containing regimen, were treated with amonafide 300 mg/m2 over 1 hour for 5 consecutive days every 3 weeks. One partial response (5%) was seen. Hematologic toxicity was substantial with severe or life-threatening events occurring as follows: leukopenia, 5 patients (25%); thrombocytopenia, 4 patients (20%); granulocytopenia, 2 patients (10%). One patient experienced acute bilateral open-angle glaucoma immediately after treatment, and another developed gastric ulceration with life-threatening gastrointestinal bleeding. In view of the low response rate and high toxicity, amonafide does not warrant further investigation as second-line chemotherapy in squamous cell carcinoma of the cervix.

[Paramagnetic diethyleneimides of urethane phosphoric acids as antitumor agents]. / Paramagnitnye diétilenimidy uretanfosfornykh kislot kak protivoopukholevye agenty.

Under study were paramagnetic diethylene imides of urethan phosphoric acids containing three type groups showing carcinostatic activity. There was found small toxicity and a wide spectrum of the antitumor effect of the compounds, also the correlation between the chemical structure and carcinostatic effect was investigated. The nitroxyl radical was shown to participate in the antitumor effect manifestation.

A preliminary report on the antiarrhythmic action of some newly synthesized glutarimide compounds.

The effects of a new series of glutarimide compounds have been studied in acetylcholine induced auricular fibrillation in anaesthetized cats and epinephrine induced ventricular arrhythmmias in conscious pigeons. Some of the compounds showed varying degree of protective action against experimental arrhythmias. However these compounds were found to be less potent than quinidine. The mechanism of antiarrhythmic action has been discussed.