Regorafenib induces NOX5-mediated endoplasmic reticulum stress and potentiates the anti-tumor activity of cisplatin in non-small cell lung cancer cells.

Lung cancer is one of the most commonly diagnosed cancers worldwide. Although cisplatin-based chemotherapy regimens serve a pivotal role in non-small cell lung cancer (NSCLC) treatment, drug resistance and serious side effects limited its further clinical application. Regorafenib, a small-molecule multi-kinase inhibitor, was demonstrated to have promising anti-tumor activity in various solid tumors. In the present study, we found that regorafenib markedly enhanced cisplatin-induced cytotoxicity in lung cancer cells by activating reactive oxygen species (ROS)-mediated endoplasmic reticulum stress (ER Stress), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Regorafenib increased ROS generation by promoting NADPH oxidase 5 (NOX5) expression, and knocking down NOX5 attenuated ROS-mediated cytotoxicity of regorafenib in lung cancer cells. Additionally, mice xenograft model validated that synergistic anti-tumor effects of combined treatment with regorafenib and cisplatin. Our results suggested that combination therapy with regorafenib and cisplatin may serve as a potential therapeutic strategy for some NSCLC patients.

A mechanically tough and ultra-swellable microneedle for acute gout arthritis.

Acute gout arthritis (AGA) remains the fundamental research focus in the entire medical field. Hydrogel microneedles (HMNs) loaded with therapeutic molecules such as colchicine (Col) have been developed as a new tool for the management of AGA in a minimally invasive manner. However, the incompatible mechanical and swelling properties of HMNs limited the diffusion of the drug from the HMN system, which remains a challenge for practical use. Here, a mechanically tough (11.53 N per needle) and super-swelling (2708%) hydrogel microneedle (HMNs) composed of a uniform network structure was developed using a UV-responsive crosslinker through in situ photopolymerization for percutaneous delivery of Col. Such HMNs and Col loaded HMNs (Col-HMNs) present excellent biocompatibility. Moreover, Col-HMNs present considerable anti-inflammatory effects in vivo through down-regulated inflammatory responses such as related cytokines IL-1ß, IL-6, and TNF-α. These results demonstrated that the mechanically tough and super-swelling HMNs could be a promising tool for effective Col delivery to relieve AGA.

Ciprofloxacin and pegylated G-CSF combined therapy mitigates brain hemorrhage and mortality induced by ionizing irradiation.

Introduction: Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy 60Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and increasing survival from IR. Previously, we found that pegylated G-CSF therapy (PEG) (i.e., Neulasta®, an FDA-approved drug) improved survival post-IR by 20-40%. This study investigated whether Ciprofloxacin (CIP) could enhance PEG-induced survival and whether IR-induced brain hemorrhage could be mitigated by PEG alone or combined with CIP. Methods: B6D2F1 female mice were exposed to 60Co-γ-radiation. CIP was fed to mice for 21 days. PEG was injected on days 1, 8, and 15. 30-day survival and weight loss were studied in mice treated with vehicles, CIP, PEG, or PEG + CIP. For the early time point study, blood and sternums on days 2, 4, 9, and 15 and brains on day 15 post-IR were collected. Platelet numbers, brain hemorrhage, and histopathology were analyzed. The cerebellum/pons/medulla oblongata were detected with glial fibrillary acidic protein (GFAP), p53, p16, interleukin-18 (IL-18), ICAM1, Claudin 2, ZO-1, and complement protein 3 (C3). Results: CIP + PEG enhanced survival after IR by 85% vs. the 30% improvement by PEG alone. IR depleted platelets, which was mitigated by PEG or CIP + PEG. Brain hemorrhage, both surface and intracranial, was observed, whereas the sham mice displayed no hemorrhage. CIP or CIP + PEG significantly mitigated brain hemorrhage. IR reduced GFAP levels that were recovered by CIP or CIP + PEG, but not by PEG alone. IR increased IL-18 levels on day 4 only, which was inhibited by CIP alone, PEG alone, or PEG + CIP. IR increased C3 on day 4 and day 15 and that coincided with the occurrence of brain hemorrhage on day 15. IR increased phosphorylated p53 and p53 levels, which was mitigated by CIP, PEG or PEG + CIP. P16, Claudin 2, and ZO-1 were not altered; ICAM1 was increased. Discussion: CIP + PEG enhanced survival post-IR more than PEG alone. The Concurrence of brain hemorrhage, C3 increases and p53 activation post-IR suggests their involvement in the IR-induced brain impairment. CIP + PEG effectively mitigated the brain lesions, suggesting effectiveness of CIP + PEG therapy for treating the IR-induced brain hemorrhage by recovering GFAP and platelets and reducing C3 and p53.

Rubia cordifolia L. ameliorates DSS-induced ulcerative colitis in mice through dual inhibition of NLRP3 inflammasome and IL-6/JAK2/STAT3 pathways.

The aerial part of â€‹Rubia cordifolia â€‹L. has been used as an herbal medicine for a long time with various pharmacological activities, including anti-inflammatory, anticancer, and antibacterial activities. The most notable usage of these was that this herbal medicine had good therapeutic effects on diarrhea caused by various factors. However, the mechanism for the ethanolic extract of â€‹R. cordifolia â€‹L. (RCEE) to treat Ulcerative colitis (UC) effectively is still unclear. In this study, DSS successfully induced UC mice and then intervene using different polar parts of RCEE. The results indicated that RCEE-treatment inhibited colonic combination NLRP3 inflammasome formation and IL-6/JAK2/STAT3 activation in vivo, significantly ameliorating the clinical symptoms, including alleviating colonic mucosal damage and infiltration of macrophages, suppressing the release of inflammatory cytokines, and reducing mortality. Taken together, this study suggests that dual inhibition of NLRP3 inflammasome and IL-6/JAK2/STAT3 pathways activation using RCEE may be a promising therapeutic strategy for preventing the progression of UC.

Dihydroartemisinin enhances the anti-tumor activity of oxaliplatin in colorectal cancer cells by altering PRDX2-reactive oxygen species-mediated multiple signaling pathways.

BACKGROUND: Globally, colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Oxaliplatin based treatments are frequently used as chemotherapeutic methods for CRC, however, associated side effects and drug resistance often limit their clinical application. Dihydroartemisinin (DHA) induces apoptosis in various cancer cells by increasing reactive oxygen species (ROS) production. However, the direct target of DHA and underlying molecular mechanisms in oxaliplatin-mediated anti-tumor activities against CRC are unclear. METHODS: We used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), flow cytometry, and colony formation assays to investigate cell phenotype alterations and ROS generation. We also used quantitative Real-Time PCR (qRT-PCR) and western blotting to measure relative gene and protein expression. Finally, an in vivo mouse xenograft model was used to assess the anti-tumor activity of oxaliplatin and DHA alone, and combinations. RESULTS: DHA synergistically enhanced the anti-tumor activity of oxaliplatin in colon cancer cells by regulating ROS-mediated ER stress, signal transducer and activator of transcription 3 (STAT3), C-Jun-amino-terminal kinase (JNK), and p38 signaling pathways. Mechanistically, DHA increased ROS levels by inhibiting peroxiredoxin 2 (PRDX2) expression, and PRDX2 knockdown sensitized DHA-mediated cell growth inhibition and ROS production in CRC cells. A mouse xenograft model showed strong anti-tumor effects from combination treatments when compared with single agents. CONCLUSIONS: We demonstrated an improved therapeutic strategy for CRC patients by combining DHA and oxaliplatin treatments.

PEG-G-CSF and L-Citrulline Combination Therapy for Mitigating Skin Wound Combined Radiation Injury in a Mouse Model.

Radiation combined injury (RCI, radiation exposure coupled with other forms of injury, such as burn, wound, hemorrhage, blast, trauma and/or sepsis) comprises approximately 65% of injuries from a nuclear explosion, and greatly increases the risk of morbidity and mortality when compared to that of radiation injury alone. To date, no U.S. Food and Drug Administration (FDA)-approved countermeasures are available for RCI. Currently, three leukocyte growth factors (Neupogen®, Neulasta® and Leukine®) have been approved by the FDA for mitigating the hematopoietic acute radiation syndrome. However these granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) products have failed to increase 30-day survival of mice after RCI, suggesting a more complicated biological mechanism is in play for RCI than for radiation injury. In the current study, the mitigative efficacy of combination therapy using pegylated (PEG)-G-CSF (Neulasta) and -citrulline was evaluated in an RCI mouse model. L-citrulline is a neutral alpha-amino acid shown to improve vascular endothelial function in cardiovascular diseases. Three doses of PEG-G-CSF at 1 mg/kg, subcutaneously administered on days 1, 8 and 15 postirradiation, were supplemented with oral -citrulline (1 g/kg), once daily from day 1 to day 21 postirradiation. The combination treatment significantly improved the 30-day survival of mice after RCI from 15% (vehicle-treated) to 42%, and extended the median survival time by 4 days, as compared to vehicle controls. In addition, the combination therapy significantly increased body weight and bone marrow stem and progenitor cell clonogenicity in RCI mice, and accelerated recovery from RCI-induced intestinal injury, compared to animals treated with vehicle. Treatment with -citrulline alone also accelerated skin wound healing after RCI. In conclusion, these data indicate that the PEG-G-CSF and -citrulline combination therapy is a potentially effective countermeasure for mitigating RCI, likely by enhancing survival of the hematopoietic stem/progenitor cells and accelerating recovery from the RCI-induced intestinal injury and skin wounds.

Co-Therapy of Pegylated G-CSF and Ghrelin for Enhancing Survival After Exposure to Lethal Radiation.

Exposure to ionizing radiation (radiation injury, RI) in nuclear-related episode is evident to be life-threatening. RI occurs at levels of organs, tissues, cytosols, or nucleus. Their mechanisms are still not fully understood. FDA approves pegylated granulocyte colony-stimulating factor (Neulasta™, Peg-G-CSF) for acute hematopoietic syndrome and has been shown to save lives after lethal RI. We aimed to test whether Ghrelin enhanced Peg-G-CSF's efficacy to save more lives after lethal RI. B6D2F1/J female mice were used for the study. They received 9.5 Gy (LD50/30 at 0.4 Gy/min) emitted from the 60Co-γ-photon radiation facility. Peg-G-CSF was injected subcutaneously at 1 mg/kg once on days 1, 8, and 15 after irradiation. Ghrelin contains 28 amino acid and is a hunger peptide that has been shown to stimulate food intake, promote intestinal epithelial cell proliferation, elevates immunity, inhibits brain hemorrhage, and increases stress-coping. Ghrelin was injected subcutaneously at 113 µg/kg once on days 1, 2, and 3 after irradiation. Survival, body weight, water consumption, hematology, spleen weight, splenocytes, bone marrow cells, and histology of bone marrow and ileum were performed. We observed that radiation resulted in 30-days survival by 30%. RI decreased their body weights and water consumption volumes. On the 30th day post-RI, platelets and WBCs such as basophils, eosinophils, monocytes, lymphocytes, neutrophils and leukocytes were still significantly decreased in surviving mice. Likewise, their RBC, hemoglobin, hematocrit, and splenocytes remained low; splenomegaly was found in these mice. Bone marrow in surviving RI animals maintained low cellularity with high counts of fat cells and low counts of megakaryocytes. Meanwhile, ileum histology displayed injury. However, mice co-treated with both drugs 24 h after RI resulted in 30-days survival by 45% above the vehicle group. Additionally, the body-weight loss was mitigated, the acute radiation syndrome was reduced. This co-therapy significantly increased neutrophils, eosinophils, leukocytes, and platelets in circulation, inhibited splenomegaly, and increased bone marrow cells. Histopathological analysis showed significant improvement on bone marrow cellularity and ileum morphology. In conclusion, the results provide a proof of concept and suggest that the co-therapy of Peg-G-CSF and Ghrelin is efficacious to ameliorate RI.

CRISPR-Cas adaptive immune systems in Sulfolobales: genetic studies and molecular mechanisms.

CRISPR-Cas systems provide the small RNA-based adaptive immunity to defend against invasive genetic elements in archaea and bacteria. Organisms of Sulfolobales, an order of thermophilic acidophiles belonging to the Crenarchaeotal Phylum, usually contain both type I and type III CRISPR-Cas systems. Two species, Saccharolobus solfataricus and Sulfolobus islandicus, have been important models for CRISPR study in archaea, and knowledge obtained from these studies has greatly expanded our understanding of molecular mechanisms of antiviral defense in all three steps: adaptation, expression and crRNA processing, and interference. Four subtypes of CRISPR-Cas systems are common in these organisms, including I-A, I-D, III-B, and III-D. These cas genes form functional modules, e.g., all genes required for adaptation and for interference in the I-A immune system are clustered together to form aCas and iCas modules. Genetic assays have been developed to study mechanisms of adaptation and interference by different CRISPR-Cas systems in these model archaea, and these methodologies are useful in demonstration of the protospacer-adjacent motif (PAM)-dependent DNA interference by I-A interference modules and multiple interference activities by III-B Cmr systems. Ribonucleoprotein effector complexes have been isolated for Sulfolobales III-B and III-D systems, and their biochemical characterization has greatly enriched the knowledge of molecular mechanisms of these novel antiviral immune responses.

A seed motif for target RNA capture enables efficient immune defence by a type III-B CRISPR-Cas system.

CRISPR-Cas systems provide an adaptive defence against foreign nucleic acids guided by small RNAs (crRNAs) in archaea and bacteria. The Type III CRISPR systems are reported to carry RNase, RNA-activated DNase and cyclic oligoadenylate (cOA) synthetase activity, and are significantly different from other CRISPR systems. However, detailed features of target recognition, which are essential for enhancing target specificity remain unknown in Type III CRISPR systems. Here, we show that the Type III-B Cmr-α system in S. islandicus generates two constant lengths of crRNA independent of the length of the spacer. Either mutation at the 3'-end of crRNA or target truncation greatly influences the target capture and cleavage by the Cmr-α effector complex. Furthermore, we found that cleavage at the tag-proximal site on the target RNA by the Cmr-α RNP complex is delayed relative to the other sites, which probably provides Cas10 more time to function as a guard against invaders. Using a mutagenesis assay in vivo, we discovered that a seed motif located at the tag-distal region of the crRNA is required by Cmr1α for target RNA capture by the Cmr-α system thereby enhancing target specificity and efficiency. These findings further refine the model for immune defence of Type III-B CRISPR-Cas system, commencing on capture, cleavage and regulation.

Bright near-infrared fluorescence bio-labeling with a biliprotein triad.

Biliproteins have extended the spectral range of fluorescent proteins into the near-infrared region (NIR, 700-770 nm) of maximal transmission of most tissues and are also favorable for multiplex labeling. Their application, however, presents considerable challenges to increase their stability under physiological conditions and, in particular, to increase their brightness while maintaining the emission in near-infrared regions: their fluorescence yield generally decreases with increasing wavelengths, and their effective brightness depends strongly on the environmental conditions. We report a fluorescent biliprotein triad, termed BDFP1.1:3.1:1.1, that combines a large red-shift (722 nm) with high brightness in mammalian cells and high stability under changing environmental conditions. It is fused from derivatives of the phycobilisome core subunits, ApcE2 and ApcF2. These two subunits are induced by far-red light (FR, 650-700 nm) in FR acclimated cyanobacteria. Two BDFP1.1 domains engineered from ApcF2 covalently bind biliverdin that is accessible in most cells. The soluble BDFP3 domain, engineered from ApcE2, binds phytochromobilin non-covalently, generating BDFP3.1. This phytochromobilin chromophore was added externally; it is readily generated by an improved synthesis in E. coli and subsequent extraction. Excitation energy absorbed in the FR by covalently bound biliverdins in the two BDFP1.1 domains is transferred via fluorescence resonance energy transfer to the non-covalently bound phytochromobilin in the BDFP3.1 domain fluorescing in the NIR around 720 nm. Labeling of a variety of proteins by fusion to the biliprotein triad is demonstrated in prokaryotic and mammalian cells, including human cell lines.

Far-red acclimating cyanobacterium as versatile source for bright fluorescent biomarkers.

Far-red and near-infrared emitting chromophores extend applications of fluorescent proteins to regions of maximal transmission of most tissues, but present considerable engineering challenges. Far-red adapting cyanobacteria generate a novel set of biliproteins. One of them, ApcF2, from a thermophilic cyanobacterium was subjected to structure-guided, site-directed random and specific mutagenesis, and was screened for bright far-red emission. We report the generation of chromoproteins, termed BDFPs, that are small, bind auto-catalytically the ubiquitous biliverdin as chromophore, express well, and retain their fluorescence in mammalian cells and in the nematode, C. elegans. They are, moreover, photostable and tolerate high temperature, low pH and chemical denaturation. Homo-bichromophoric tandems of these proteins improve labeling, while hetero-bichromophoric systems with large Stokes shifts are suitable for applications like FRET, multi-channel or super-resolution microscopy. The BDFPs compare favorably to other biliproteins and provide a novel, extremely versatile labeling tool-box.

Small monomeric and highly stable near-infrared fluorescent markers derived from the thermophilic phycobiliprotein, ApcF2.

Biliproteins have extended the spectral range of fluorescent proteins into the region of maximal transmission of most tissues and are favorable for multiplexing, but their application presents considerable challenges. Their fluorescence derives from open-chain tetrapyrrole chromophores which often require the introduction of dedicated reductases and lyases. In addition, their fluorescence yield generally decreases with increasing wavelengths and depends strongly on the state of the binding protein. We report fluorescent biliproteins, termed BDFPs, that are derived from the phycobilisome core subunit, ApcF2: this subunit is induced in the thermophilic cyanobacterium, Chroococcidiopsis thermalis, by far-red light and binds phycocyanobilin non-covalently. The BDFPs obtained by molecular evolution of ApcF2 bind the more readily accessible biliverdin covalently while retaining the red-shifted fluorescence in the near-infrared spectral region (~710nm). They are small monomers (~15kDa) and not only show excellent photostability, but are also thermostable up to 80°C, tolerate acid down to pH2 and high concentrations of denaturants. The result indicates far-red adapting cyanobacteria as a useful source for designing extremely red-shifted fluorescent markers. In vivo performance of BDFPs as biomarkers in conventional and super-resolution microscopy, alone or fused to target proteins, is exemplified in several mammalian cells, including, human cell lines, in the nematode, Caenorhabditis elegans and, at low pH, in Lactobacillus lactis.

Combined Therapy of Pegylated G-CSF and Alxn4100TPO Improves Survival and Mitigates Acute Radiation Syndrome after Whole-Body Ionizing Irradiation Alone and Followed by Wound Trauma.

Exposure to ionizing radiation alone or combined with traumatic tissue injury is a crucial life-threatening factor in nuclear and radiological incidents. Radiation injuries occur at the molecular, cellular, tissue and systemic levels; their mechanisms, however, remain largely unclear. Exposure to radiation combined with skin wounding, bacterial infection or burns results in greater mortality than radiation exposure alone in dogs, pigs, rats, guinea pigs and mice. In the current study we observed that B6D2F1/J female mice exposed to 60Co gamma-photon radiation followed by 15% total-body-surface-area skin wounds experienced an increment of 25% higher mortality over a 30-day observation period compared to those subjected to radiation alone. Radiation exposure delayed wound healing by approximately 14 days. On day 30 post-injury, bone marrow and ileum in animals from both groups (radiation alone or combined injury) still displayed low cellularity and structural damage. White blood cell counts, e.g., neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets, still remained very low in surviving irradiated alone animals, whereas only the lymphocyte count was low in surviving combined injury animals. Likewise, in surviving animals from radiation alone and combined injury groups, the RBCs, hemoglobin, hematocrit and platelets remained low. We observed, that animals treated with both pegylated G-CSF (a cytokine for neutrophil maturation and mobilization) and Alxn4100TPO (a thrombopoietin receptor agonist) at 4 h postirradiation, a 95% survival (vehicle: 60%) over the 30-day period, along with mitigated body-weight loss and significantly reduced acute radiation syndrome. In animals that received combined treatment of radiation and injury that received pegylated G-CSF and Alxn4100TPO, survival was increased from 35% to 55%, but did not accelerate wound healing. Hematopoiesis and ileum showed significant improvement in animals from both groups (irradiation alone and combined injury) when treated with pegylated G-CSF and Alxn4100TPO. Treatment with pegylated G-CSF alone increased survival after irradiation alone and combined injury by 33% and 15%, respectively, and further delayed wound healing, but increased WBC, RBC and platelet counts after irradiation alone, and only RBCs and platelets after combined injury. Treatment with Alxn4100TPO alone increased survival after both irradiation alone and combined injury by 4 and 23%, respectively, and delayed wound healing after combined injury, but increased RBCs, hemoglobin concentrations, hematocrit values and platelets after irradiation alone and only platelets after combined injury. Taken together, the results suggest that combined treatment with pegylated G-CSF and Alxn4100TPO is effective for mitigating effects of both radiation alone and in combination with injury.

Antimalarial activities and therapeutic properties of febrifugine analogs.

Febrifugine is the active principal isolated 50 years ago from the Chinese herb chang shan (Dichroa febrifuga Lour), which has been used as an antimalarial in Chinese traditional medicine for more than 2,000 years. However, intensive study of the properties of febrifugine has been hindered for decades due to its side effects. We report new findings on the effects of febrifugine analogs compared with those of febrifugine extracted from the dry roots of D. febrifuga. The properties of the extracted febrifugine were comparable to those obtained from the standard febrifugine provided by our collaborators. A febrifugine structure-based computer search of the Walter Reed Chemical Information System identified 10 analogs that inhibited parasite growth in vitro, with 50% inhibitory concentrations ranging from 0.141 to 290 ng/ml. The host macrophages (J744 cells) were 50 to 100 times less sensitive to the febrifugine analogs than the parasites. Neuronal (NG108) cells were even more insensitive to these drugs (selectivity indices, >1,000), indicating that a feasible therapeutic index for humans could be established. The analogs, particularly halofuginone, notably reduced parasitemias to undetectable levels and displayed curative effects in Plasmodium berghei-infected mice. Recrudescence of the parasites after treatment with the febrifugine analogs was the key factor that caused the death of most of the mice in groups receiving an effective dose. Subcutaneous treatments with the analogs did not cause irritation of the gastrointestinal tract when the animals were treated with doses within the antimalarial dose range. In summary, these analogs appear to be promising lead antimalarial compounds that require intensive study for optimization for further down-selection and development.

Antileishmanial activity of the antiulcer agent omeprazole.

The benzimidazole compound omeprazole, used widely for the treatment of peptic ulcer disease, inhibits the growth of Leishmania donovani, the causative agent of visceral leishmaniasis. Promastigotes cultured at acidic pH and amastigotes within infected macrophages are reduced 90% or more with 150 microM omeprazole. Antiparasitic action of the drug is due to its inhibition of the P-type K(+),H(+)-ATPase on the surface membrane. This enzyme is important for pH homeostasis and the maintenance of proton motive force across the membrane in Leishmania. The drug is effective only at acidic pH, a condition that mimics the in vivo environment within the phagolysosomal vesicles where the amastigote form of the parasite resides. Omeprazole deserves consideration as an alternative to currently available chemotherapeutics, which have severe toxic side effects.

Syntheses and bioactivities of substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrones. Unusual reactivities with amines.

A number of substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrones have been synthesized and their anticancer and antimalarial activities evaluated. A one-pot synthesis of 2,5,8-trimethoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4-dione (4) was achieved by heating a mixture of 1,4-dimethoxyanthracene, methoxyhydroquinone, silver oxide, and zinc iodide in toluene. Regioselective bromination of 4 and 2-methoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone (7) with N-bromosuccinimide provided 2-bromo-3,5,8-trimethoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4-dione and 2-bromo-3-methoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone (1), respectively. The reactions of 1 with aliphatic primary amines and secondary amines, respectively, produced different products, a result most likely attributed to the different basicities (or nucleophilicities) and steric effects of the two kinds of amines. The structure of the displacement product, 2-bromo-3-[2-(tert-butoxycarbonyl)ethylamino]-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone, from the reaction of 1 with tert-butyl 3-aminopropanoate was unequivocally determined by a single-crystal X-ray analysis. IC(50) values of triptycene bisquinones for the inhibition of L1210 leukemia cell viability are in the 0.11-0.27 microM range and for the inhibition of Plasmodium falciparum 3D7 are in the 4.7-8.0 microM range.