Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

Predictive Validity of the Johns Hopkins Fall Risk Assessment Tool for Older Patients in Stroke Rehabilitation.

The aim of this retrospective, cross-sectional, observational study was to assess the frequency of falls and evaluate the predictive validity of the Johns Hopkins Fall Risk Assessment Tool (JHFRAT) among patients aged ≥65 years, transferred to the rehabilitation ward of a university hospital. The predictive ability was assessed using receiver operating characteristic curve analysis, and the optimal threshold was established using the Youden index. We analyzed the overall cohort (N = 175) with subacute stroke and the subgroup with a low unaffected handgrip strength (HGS; men: <28 kg, women: <18 kg). Overall, 135/175 patients (77.1%) had a low HGS. The fall rate was 6.9% overall and 5.9% for patients with a low HGS. The JHFRAT predictive value was higher for patients with a low HGS than that for the overall cohort, but acceptable in both. The optimal cutoff score for the overall cohort was 11 (sensitivity, 67%; specificity, 68%), whereas that for the subgroup was 12 (sensitivity, 75%; specificity: 72%). These results are expected to aid nurses working in rehabilitation wards in more effectively utilizing JHFRAT outcomes for post-stroke older patients with a low HGS and contribute to the development of more appropriate fall prevention strategies for high-risk patients in the future.

Belvarafenib penetrates the BBB and shows potent antitumor activity in a murine melanoma brain metastasis model.

Brain metastasis is a common complication in melanoma patients with BRAF and NRAS mutations and has a poor prognosis. Although BRAF inhibitors are clinically approved, their poor brain penetration limits their efficacy in brain metastasis. Thus, melanoma brain metastasis still requires better treatment. Belvarafenib, a pan-RAF inhibitor, has reported antitumor activity in melanoma with RAF and RAS mutations in animal models and patients. However, brain permeability and antitumor efficacy on brain metastasis have not been determined. This study confirmed the brain penetration of belvarafenib, the antitumor activity on BRAF and NRAS mutant melanoma, and the efficacy on melanoma within the brain. Belvarafenib strongly suppressed melanoma in BRAF V600E mutant A375SM tumor-bearing mice. It also significantly inhibited tumor growth in NRAS mutant SK-MEL-30 and K1735 tumor-bearing mice and synergized to enhance the antitumor activity combined with cobimetinib or atezolizumab. Belvarafenib was penetrated at considerable levels into the brains of mice and rats following oral administration. The exposure of belvarafenib in the brain was similar to or higher than that in plasma, and this high brain penetration differed significantly from that of other BRAF inhibitors with low brain penetration. Most importantly, belvarafenib strongly reduced tumor burden and markedly improved survival benefits in mice intracranially implanted with A375SM melanoma. These results demonstrated that belvarafenib, which has favorable BBB permeability, and potent antitumor activity on the tumors with BRAF/NRAS mutations, may be a promising therapeutic option for patients with BRAF/NRAS mutant melanoma brain metastasis.

Design, synthesis and biological evaluation of new bivalent quinazoline analogues as IAP antagonists.

We recently reported the biological evaluations of monovalent IAP antagonist 7 with good potency (MDA-MB-231, IC50 = 19 nM). In an effort to increase cellular activity and improve favorable drug-like properties, we newly designed and synthesized bivalent analogues based on quinazoline structure of 7. Optimization of cellular potency and CYP inhibition led to the identification of 27, which showed dramatic increase of over 100-fold (IC50 = 0.14 nM) and caused substantial tumor regressions in MDA-MB-231 xenograft model. These results strongly support 27 as a promising bivalent antagonist for the development of an effective anti-tumor approaches.

Delayed Establishment of Gut Microbiota in Infants Delivered by Cesarean Section.

The maternal vaginal microbiome is an important source for infant gut microbiome development. However, infants delivered by Cesarean section (CS) do not contact the maternal vaginal microbiome and this delivery method may perturb the early establishment and development of the gut microbiome. The aim of this study was to investigate the early gut microbiota of Korean newborns receiving the same postpartum care services for two weeks after birth by delivery mode using fecal samples collected at days 3, 7, and 14. Early gut microbiota development patterns were examined using 16S rRNA gene-based sequencing from 132 infants either born vaginally (VD, n = 64) or via Cesarean section (CS, n = 68). VD-born neonates showed increased alpha diversity in infant fecal samples collated at days 7 and 14 compared to those from day 3, while those of CS infants did not differ (p < 0.015). Bacterial structures of infants from both groups separated at day 7 (p < 0.001) and day 14 (p < 0.01). The bacterial structure of VD infants gradually changed over time (day 3 vs. day 7, p < 0.012; day 3 vs. day 14, p < 0.001). Day 14 samples of CS infants differed from day 3 and 7 samples (day 3 vs. day 14, p < 0.001). VD infant relative abundance of Bifidobacterium (days 7, 14), Bacteroides (days 7, 14), and Lachnospiraceae (day 7) significantly increased compared to CS infants, with a lower abundance of Enterobacteriaceae (found in all periods of the CS group) (LDA > 3.0). Relative abundances of Bifidobacterium, Lactobacillus, and Staphylococcus were significantly increased in both VD and CS groups at day 14 (LDA > 3.0). Predicted functional analysis showed that VD infants had overrepresented starch/sucrose, amino acid and nucleotide metabolism in gut microbiota with depleted lipopolysaccharide biosynthesis until day 14 compared to CS infants. This study confirmed that delivery mode is the major determinant of neonatal intestinal microbiome establishment and provides a profile of microbiota perturbations in CS infants. Our findings provide preliminary insight for establishing recovery methods to supply the specific microbes missing in CS infants.

Synthesis and biological evaluation of novel thienopyrimidine derivatives as diacylglycerol acyltransferase 1 (DGAT-1) inhibitors.

A novel series of thieno[3,2-d]pyrimidine derivatives were synthesised and their inhibitory effects against diacylglycerol acyltransferase 1 (DGAT-1) were assessed. cis-Isomer 17a showed potent and selective inhibitory activity against DGAT-1 in SF9 cells. In addition, 17a had an acceptable pharmacokinetic profile and accumulated mainly in the small intestine and liver. Oral administration of 17a led to a significant reduction in plasma triacylglycerol level during an oral lipid tolerance test (OLTT) in murine and canine models. Taken together, 17a is a high-quality candidate that deserves further investigation.

Increased risk of refeeding syndrome-like hypophosphatemia with high initial amino acid intake in small-for-gestational-age, extremely-low-birthweight infants.

BACKGROUND: Recent nutrition guidelines for extremely-low-birth-weight infants (ELBWIs) recommend implementation of high initial amino acid (AA) supplementation in parenteral nutrition. OBJECTIVE: We sought to evaluate the influence of AA intake on refeeding syndrome-like electrolyte disturbances including hypophosphatemia in ELBWIs. STUDY DESIGN: Medical records of 142 ELBWIs were reviewed. Demographic, nutritional, outcome, and electrolyte data were compared between ELBWIs with initial low (1.5 g/kg/day) and high (3 g/kg/day) AA intake. Multivariate analysis was conducted to determine the odds ratio of hypophosphatemia with high AA intake and small-for-gestational-age (SGA) ELBWIs. RESULTS: The incidence of hypophosphatemia and severe hypophosphatemia increased from 51% and 8% in period I to 59% and 20% in period II, respectively (p = 0.36 and < 0.01). Specifically, SGA ELBWIs showed higher incidence of hypophosphatemia than appropriate-for-gestational age (AGA) ELBWIs in period II, whereas there was no difference in period I. For severe hypophosphatemia, SGA ELBWIs presented a 27% incidence versus a 2% incidence in AGA ELBWIs, even with low initial AA intake. Despite no difference in phosphate intake between infants with and without hypophosphatemia, serum phosphate level reached a nadir at the sixth postnatal day and gradually recovered over the second week in infants with hypophosphatemia. In multivariate analyses, the odds ratios for severe hypophosphatemia were 3.6 and 6.6 with high AA intake and SGA status, respectively, with the highest being 18.0 with combined high AA intake and SGA status. CONCLUSIONS: In summary, high initial AA intake significantly increased the risk of refeeding syndrome-like electrolyte dysregulations including severe hypophosphatemia in ELBWIs. In SGA ELBWIs, the risk of electrolyte disturbance was significantly higher, even with low initial AA intake. Therefore, new tailored parenteral nutrition protocols starting with lower energy intake and a gradual increase over the first week may be warranted for application in high-risk SGA ELBWIs.

Natural evolution of ductus arteriosus with noninterventional conservative management in extremely preterm infants born at 23-28 weeks of gestation.

This study aimed to determine the natural course of patent ductus arteriosus (PDA) with noninterventional conservative management and whether the presence and/or prolonged duration of hemodynamically significant (HS) PDA increased the risk of mortality and morbidities in extremely preterm (EPT) infants. We retrospectively reviewed the medical records of EPT infants born at 23-28 weeks of gestation (n = 195) from January 2011 to June 2014, when PDA was managed with noninterventional conservative treatment. We stratified infants into three subgroups of 23-24, 25-26, and 27-28 weeks and analyzed the prevalence and natural evolution of HS PDA, defined as ventilator dependency and PDA size ≥2 mm. Multivariate regression analyses determined if the presence and/or prolonged duration of HS PDA increased the risk for mortality and/or morbidities. The overall incidence of HS PDA was 57% (111/195) at the end of the first postnatal week. In subgroup analyses, infants with 23-24 weeks of gestation had the highest incidence (93%, 50/54), with 64% (47/74) for 25-26 weeks and 21% (14/67) for 27-28 weeks. Six (5%) of 111 infants with HS PDA were discharged without ductus closure, 4 had spontaneous PDA closure on follow up, and device closure was performed for 2 infants. In the multivariate analyses, the presence or prolonged duration (per week) of HS PDA was not associated with the risk of mortality and/or morbidities. Spontaneous closure of HS PDA was mostly achieved, even in EPT infants, with a noninterventional conservative approach. In conclusion, our data showed the incidence and natural course of HS PDA in EPT infants and suggested that the presence or prolonged duration of HS PDA might not increase the rate of mortality or morbidities.

Studies on lysozyme modifications induced by substituted p-benzoquinones.

Protein misfolding can facilitate a protein damaging process and makes it susceptible to a series of events such as unfolding, adduct formation, oligomerization, or aggregation. Loss of a protein's native structure may result in its biological malfunction and/or cellular toxicity that could cause associated diseases. Several factors were identified for causing structural changes of a protein, however quinone-induced protein modifications received very little attention whether for amyloidal or non-amyloidal proteins. In this paper, we report our investigation on lysozyme modifications upon treatment with selected benzoquinones (BQs), utilizing fluorescence spectroscopy including anisotropy determination, UV-Vis spectroscopy, and SDS-PAGE. Lysozyme was reacted with substituted BQs in order to examine substituent effects on protein modifications. In addition, we evaluated lysozyme modifications induced by 1,4-benzoquinone in concentration-, pH-, temperature-, and time-dependent studies. Our study shows that all BQs can readily modify lysozyme in a complex manner through adduct formation, oligomerization, polymeric aggregation, and/or fibrilization. Electrochemical properties of selected BQs were monitored using cyclic voltammetry in phosphate buffered aqueous solution, and it was found that quinone reduction potentials correlate well with their reactivity trend toward lysozyme.

Inactivation of bovine plasma amine oxidase by 1,1,1-trihalo-3-aminopropanes.

In this paper, we report the inactivation of copper containing bovine plasma amine oxidase (BPAO) by a series of saturated alkylamines containing halogen atoms at γ-position, which are 1,1,1-trihalo-3-aminopropane, 1,1,1-trifluoro-2-hydroxy-3-aminopropane, 1,1,1-trichloro-2-hydroxy-3-aminopropane, and 1,1,1-trichloro-2-(2-phenethyloxy)-3-aminopropane. The trihalo-2-hydroxypropylamine analogs exhibited a time-dependent inactivation behavior of BPAO, with 1,1,1-trifluoro-2-hydroxy-3-aminopropane as the most efficient inactivator. The incorporation of a OH group at ß-position increased inactivation efficiency by 10-fold within the trifluoro analogs, and the incorporation of a phenethyloxy group at ß-position exhibited a higher efficiency by 3-fold within the trichloro analogs based on I75 values. All four compounds were found to be irreversible inactivators for BPAO.

Prophylactic versus Early Rescue Surfactant Treatment in Preterm Infants Born at Less than 30 Weeks Gestation or with Birth Weight Less than or Equal 1,250 Grams.

Prophylactic surfactant is known to be effective to reduce chronic lung disease in preterm infants compared with rescue surfactant treatment. In Korea, early prophylactic surfactant therapy was introduced in 2011. However, recently, the increased utilization of antenatal steroids and early stabilization through continuous positive airway pressure (CPAP) in the delivery room may have changed the risks and benefits of prophylactic surfactant therapy of infants at high risk of respiratory distress syndrome (RDS). We compared the effects and safety of prophylactic surfactant therapy (within 30 minutes after birth) and early selective surfactant therapy (within 3 hours after birth) in preterm infants born at < 30 weeks gestation or with birth weight ≤ 1,250 g. The clinical data of 193 infants in period 1 (from 2008 to 2010, early selective surfactant therapy group) were collected retrospectively; those of 191 infants in period 2 (from 2012 to 2014, prophylactic surfactant therapy group) were collected prospectively. Compared to period 1, the rate of intubation and surfactant use were significantly increased in period 2. The use of multiple doses of surfactant in period 2 was significantly increased compared with period 1. Despite more invasive and aggressive management in period 2, there was no difference in the duration of mechanical ventilation, the incidence of bronchopulmonary dysplasia (BPD) or death, and the risk of other adverse neonatal outcomes between the 2 groups. In conclusion, the benefit of prophylactic surfactant therapy in infants treated under current practices is no longer clear compared to early selective surfactant therapy.

Longitudinal bone growth is impaired by direct involvement of caffeine with chondrocyte differentiation in the growth plate.

We showed previously that caffeine adversely affects longitudinal bone growth and disrupts the histomorphometry of the growth plate during the pubertal growth spurt. However, little attention has been paid to the direct effects of caffeine on chondrocytes. Here, we investigated the direct effects of caffeine on chondrocytes of the growth plate in vivo and in vitro using a rapidly growing young rat model, and determined whether they were related to the adenosine receptor signaling pathway. A total of 15 male rats (21 days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180 mg kg-1  day-1 for 4 weeks. After sacrifice, the tibia processed for the analysis of the long bone growth and proliferation of chondrocytes using tetracycline and BrdU incorporation, respectively. Caffeine-fed animals showed decreases in matrix mineralization and proliferation rate of growth plate chondrocytes compared with the control. To evaluate whether caffeine directly affects chondrocyte proliferation and chondrogenic differentiation, primary rat chondrocytes were isolated from the growth plates and cultured in either the presence or absence of caffeine at concentrations of 0.1-1 mm, followed by determination of the cellular proliferation or expression profiles of cellular differentiation markers. Caffeine caused significant decreases in extracellular matrix production, mineralization, and alkaline phosphatase activity, accompanied with decreases in gene expression of the cartilage-specific matrix proteins such as aggrecan, type II collagen and type X. Our results clearly demonstrate that caffeine is capable of interfering with cartilage induction by directly inhibiting the synthetic activity and orderly expression of marker genes relevant to chondrocyte maturation. In addition, we found that the adenosine type 1 receptor signaling pathway may be partly involved in the detrimental effects of caffeine on chondrogenic differentiation, specifically matrix production and mineralization, as evidenced by attenuation of the inhibitory effects of caffeine by blockade of this receptor. Thus, our study provides novel information on the integration of caffeine and adenosine receptor signaling during chondrocyte maturation, extending our understanding of the effect of caffeine at a cellular level on chondrocytes of the growth plate.

Peripubertal Caffeine Exposure Impairs Longitudinal Bone Growth in Immature Male Rats in a Dose- and Time-Dependent Manner.

This study investigated the dose- and time-dependent effects of caffeine consumption throughout puberty in peripubertal rats. A total of 85 male SD rats were randomly divided into four groups: control and caffeine-fed groups with 20, 60, or 120 mg/kg/day through oral gavage for 10, 20, 30, or 40 days. Caffeine decreased body weight gain and food consumption in a dose- and time-dependent manner, accompanied by a reduction in muscle and body fat. In addition, it caused a shortening and lightening of leg bones and spinal column. The total height of the growth plate decreased sharply at 40 days in the controls, but not in the caffeine-fed groups, and the height of hypertrophic zone in the caffeine-fed groups was lower than in the control. Caffeine increased the height of the secondary spongiosa, whereas parameters related to bone formation, such as bone area ratio, thickness and number of trabeculae, and bone perimeter, were significantly reduced. Furthermore, serum levels of IGF-1, estradiol, and testosterone were also reduced by the dose of caffeine exposure. Our results demonstrate that caffeine consumption can dose- and time-dependently inhibit longitudinal bone growth in immature male rats, possibly by blocking the physiologic changes in body composition and hormones relevant to bone growth.

High doses of caffeine reduce in vivo osteogenic activity in prepubertal rats.

Caffeine adversely affects endochondral ossification during fetal skeletal growth, and results in increased incidence of delayed and abnormal fetal skeletal development. Chronic caffeine intake also decreases growth hormone secretion. Thus, it is conceivable that caffeine may disrupt bone growth during the peripubertal period. This study aimed to investigate the impact of high-caffeine consumption on bone growth throughout puberty. A total of 51 male rats (21 days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180 mg kg(-1)  day(-1) for 4 weeks. After death, the final length and weight of leg bones were measured, and the tibia processed for histomorphometric analysis. Caffeine caused a significant decrease in body mass gain. This was accompanied with proportional decreases in lean body mass and body fat. In addition, bone mass and osteogenic activity in vivo were assessed using dual-energy X-ray absorptiometry and (18) F-NaF positron emission tomography. The results showed significant decreases of bone mass and in vivo osteogenic activity in the caffeine-fed groups. Rats fed with caffeine showed a significantly shorter and lighter tibia and femur and the vertebral column compared with controls. In addition, caffeine does not increase the width of the growth plates (GPs), it slows the rate at which the GP closes due to a slower rate of growth. These results demonstrated that caffeine altered osteogenic activity, leading to delayed peripubertal longitudinal bone growth and maturation. Given that osteogenic cells undergo dynamic changes in metabolic activity and that the pubertal growth spurt is mainly stimulated by growth hormone/insulin-like growth factor-1 and sex steroids during pubertal development, caffeine could suppress ossification by interfering with both physiological changes in hormonal secretion and osteogenic activity during this critical period. Further study will be needed to investigate the cellular/molecular mechanism by which caffeine affects osteogenesis using in vitro experimental models.

A comparison study on ribonuclease A modifications induced by substituted p-benzoquinones.

In this paper, we present our investigation on ribonuclease A (RNase) modifications induced by 1,4-benzoquinone (PBQ), 2-methyl-1,4-benzoquinone (MBQ), and 2-chloro-1,4-benzoquinone (CBQ). The goal of the study was to evaluate quinone-induced protein modifications as well as substituent effects, utilizing several techniques such as SDS-PAGE, fluorescence spectroscopy, microscopy, and LC-ESI(+)-QTOF-MS. SDS-PAGE experiments revealed that all quinones modify RNase through oligomerization as well as polymeric aggregation; with CBQ functioning as the most efficient quinone while MBQ was least efficient. The fluorescence emission was found to be less intense and the anisotropy values were found to be slightly higher for the modified RNase compared to the unmodified RNase. UV-Vis spectroscopy indicated that all three quinones formed adducts in which they were covalently linked to RNase. Confocal imaging analysis showed that the presence of CBQ resulted in massive RNase aggregation, while PBQ-treated RNase formed much smaller aggregates. MBQ-treated RNase exhibited micrographic features that closely resembled those of the unmodified RNase. LC-ESI(+)-QTOF-MS studies indicated the nature of PBQ- and CBQ-induced RNase modifications are complex mainly due to simultaneously occurrence of both adduct formation and oligomerization. Kinetic studies on quinone reactivity toward lysine revealed the rank order of CBQ>PBQ≫MBQ, based on the second-order rate constants. We also utilized scanning electron microscopy in order to investigate the effect of modified RNase on the biomineralization of salts.

Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists.

Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.

Cultural modulation of the neural correlates of emotional pain perception: the role of other-focusedness.

Cultures vary in the extent to which they emphasize group members to habitually attend to the needs, perspectives, and internal experiences of others compared to the self. Here we examined the influence that collectivistic and individualistic cultural environments may play on the engagement of the neurobiological processes that underlie the perception and processing of emotional pain. Using cross-cultural fMRI, Korean and Caucasian-American participants passively viewed scenes of others in situations of emotional pain and distress. Regression analyses revealed that the value of other-focusedness was associated with heightened neural response within the affective pain matrix (i.e. anterior cingulate cortex and insula) to a greater extent for Korean relative to Caucasian-American participants. These findings suggest that mindsets promoting attunement to the subjective experience of others may be especially critical for pain-related and potentially empathic processing within collectivistic relative to individualistic cultural environments.

Modifications of ribonuclease A induced by p-benzoquinone.

The nature of ribonuclease A (RNase) modifications induced by p-benzoquinone (pBQ) was investigated using several analysis methods. SDS-PAGE experiments revealed that pBQ was efficient in producing oligomers and polymeric aggregates when RNase was incubated with pBQ. The fluorescence behavior and anisotropy changes of the modified RNase were monitored for a series of incubation reactions where RNase (0.050 mM) was incubated with pBQ (0.050, 0.25, 0.50, 1.50 mM) at 37 °C in phosphate buffer (pH 7.0, 50 mM). The modified RNase exhibited less intense fluorescence and slightly higher anisotropy than the unmodified RNase. UV-Vis spectroscopy indicated that pBQ formed covalent bonds to the modified RNase. Confocal imaging analysis confirmed the formation of the polymeric RNase aggregates with different sizes upon exposure of RNase to high concentrations of pBQ. The interaction between the modified RNase and salts affecting biomineralization of salts was also investigated by scanning electron microscopy. Overall, our results show that pBQ can induce formation of both RNase adducts and aggregates thus providing a better understanding of its biological activity.

Cultural influences on neural basis of intergroup empathy.

Cultures vary in the extent to which people prefer social hierarchical or egalitarian relations between individuals and groups. Here we examined the effect of cultural variation in preference for social hierarchy on the neural basis of intergroup empathy. Using cross-cultural neuroimaging, we measured neural responses while Korean and American participants observed scenes of racial ingroup and outgroup members in emotional pain. Compared to Caucasian-American participants, Korean participants reported experiencing greater empathy and elicited stronger activity in the left temporo-parietal junction (L-TPJ), a region previously associated with mental state inference, for ingroup compared to outgroup members. Furthermore, preferential reactivity within this region to the pain of ingroup relative to outgroup members was associated with greater preference for social hierarchy and ingroup biases in empathy. Together, these results suggest that cultural variation in preference for social hierarchy leads to cultural variation in ingroup-preferences in empathy, due to increased engagement of brain regions associated with representing and inferring the mental states of others.

Inactivation of bovine plasma amine oxidase by haloallylamines.

Various 2- and 3-haloallylamines were synthesized and evaluated as inhibitors of the quinone-dependent bovine plasma amine oxidase (BPAO). 3-Haloallylamines, which were previously found to be good inhibitors of the flavin-dependent mitochondrial monoamine oxidase (MAO), exhibited a time-dependent inactivation of BPAO, with the 2-phenyl analogs being more potent than the 2-methyl analogs. No plateau of enzyme activity loss was observed, suggestive of a lack of competitive partitioning to normal turnover. The (E)- and (Z)-2-phenyl-3-fluoro analogs were the most potent (low microM IC(50)s), with the corresponding 3-bromo and 3-chloro analogs being >10-fold less potent. In each case, the Z-isomers were more potent than the E-isomers, the reverse of the configurational inhibitory preference observed with MAO. In contrast to the 2-phenyl analogs, 3-phenyl-2(or 3)-chloroallylamines displayed a partitioning behavior, consistent with these being both substrates and inactivators of BPAO.