Upamostat: a serine protease inhibitor for antiviral, gastrointestinal, and anticancer indications.

INTRODUCTION: Serine proteases are involved in many normal metabolic processes but also contribute to diseases of several organ systems, including viral and gastrointestinal diseases and oncology. Upamostat is an orally bioavailable prodrug of WX-UK1, which is most active against trypsins and closely related enzymes. AREAS COVERED: Research over the past two decades suggests several diseases in the three areas noted above which upamostat may be active. Upamostat has been studied clinically against several cancers and for outpatient treatment of COVID-19. Preclinical and clinical pharmacokinetic and metabolism studies demonstrate good bioavailability, sustained tissue levels, and high concentrations of the active moiety, WX-UK1, in stool, potentially important for treatment of gastrointestinal diseases. Clinical studies suggest activity against SARS-CoV-2; results against pancreatic cancer are also encouraging, though studies in both indications are not definitive. The drug was very well tolerated for periods of 2 weeks to several months. EXPERT OPINION: Upamostat is an orally bioavailable serine protease inhibitor with an excellent safety profile and favorable pharmacokinetic properties. It has demonstrated preliminary evidence of efficacy against COVID-19, and nonclinical data suggest potential applicability against other viral illnesses, gastrointestinal diseases, and cancer.

Cryobiology and fertility preservation: a perspective on past, current and future studies.

Cryopreservation has been used over many decades for the maintenance of viable biological specimens. Its expansion into the area of fertility preservation has been a natural outcome of the increased risks to human fertility from diseases, such as cancer and its treatment protocols, including radiation and chemo-therapy, and the general lifestyle trend to later marriages. The use of assisted reproductive techniques (ART) in preserving fertility have benefitted significantly from new scientific approaches, such as cryostorage, in which live cells and tissues are stored at low temperatures and revived when necessary. This review focuses on "cryopreservation science monitoring in reproductive biomedicine" to evaluate knowledge, trends, driving forces, impetus, and emerging technologies in order to draw a future roadmap for this field. Our analysis of the field of cryobiology emphasizes the significance of strategic planning of cryobiology research to support more its extensive use in therapeutics in the future. The Royan Institute (Tehran, Iran) recognises this need and has developed a strategic plan to engage in multidisciplinary research on the application of cryobiology, including cryobioengineering, in disease mitigation. We hoped that this study can help improve the quality and quantity of public discourse and expert awareness of the role for cryopreservation in fertility preservation within ART. DOI: 10.54680/fr23410110112.

Design and fabrication of aspiration microfluidic channel for oocyte characterization.

The development potential for oocytes can be predicted by their mechanical properties. One important parameter that is measured to calculate oocyte hardness is Cortical Tension (CT). In this work, for the first time, we present the design, simulation, and fabrication of a new aspiration microfluidic chip to measure the CT of oocytes and then predict their maturation capability in the Germinal Vesicle (GV) stage. This high-performance technique facilitates oocyte characterization and is a promising alternative to traditional methods such as MicroPipette Aspiration (MPA). The proposed technique involves considerably simpler operation, less specialized equipment, and less technical skill than MPA. The proposed microfluidic channel also promises faster measurements. It is shown that in order to completely continue the growth process of oocytes in GV stage, the CT should be in a certain range: very low or very high CTs lead to unsuccessful growth. The obtained results show that 79% of oocytes with the CT between 1.5 and 3 nN/µm reach the Metaphase II (MII) stage, whereas the growth for 78% of oocytes with the CT less than 1.5 nN/µm or higher than 3 nN/µm stops at the GV or Germinal Vesicle Break Down (GVBD) stages. Another property, kvis, that points to the viscous behavior of oocytes is also measured. It is seen that 80% of GV oocytes with the kvis values between 15 and 30 k Pa s/m reach the MII stage.

The Beneficial Effects of Static Magnetic Field and Iron Oxide Nanoparticles on the Vitrification of Mature Mice Oocytes.

This study was conducted to evaluate the effects of static magnetic field (SMF) and nanoparticles (NPs) on the vitrification of cumulus-oocyte-complex (COC). To this end, the non-vitrified (nVit) and vitrified groups (Vit) that contain NPs, with or without SMF were labeled nVit_NPs, nVit_NPs_SMF, Vit_NPs, and Vit_NPs_SMF, respectively. The non-toxic dosages of NPs were first determined to be 0.008% w/v. The survival, apoptosis, and necrosis, mitochondrial activity, fertilization rate, subsequent-derived embryo development, and gene expressions were examined. The viability rates obtained by trypan blue and Anx-PI staining were meaningfully smaller in the Vit groups, compared to the nVit groups. The JC1 red/green signal ratios were reduced considerably in the Vit group, compared to the nVit. Transmission electron microscopy (TEM) was performed to assess the entry of the NPs into the oocytes. TEM images showed that NPs were present in nVit_NPs, and Vit_NPs. Thereafter, the effects of NPs and SMF on in vitro fertilization (IVF) were examined. The difference in blastocyst rates between nVit and Vit_NPs_SMF groups was significant. Finally, Nanog, Cdx2, Oct4, and Sox2 genes were evaluated. There were substantial differences in Cdx2 gene expressions between the Vit_NPs and nVit groups. The expression of Nanog in Vit was significantly higher than those of the Vit_NPs, Vit_NPs_SMF, and nVit groups. The data presented here provide deeper insight into the application of iron oxide nanoparticles in COC vitrification. It appears that using SMF and supplemented CPA by NPs inhibits cryoinjury and promote the embryo development capacity of vitrified-warmed COCs.

Static magnetic field halves cryoinjuries of vitrified mouse COCs, improves their functions and modulates pluripotency of derived blastocysts.

This study was performed with the aim of evaluating the influence of static magnetic field (SMF) of 60 mT on mouse Cumulus Oocytes Complexes (COCs) vitrification. The COCs were vitrified in the presence (Vit_SMF+) and absence of SMF (Vit_SMF-). Along with these groups, non-vitrified or fresh COCS, which exposed (nVit_SMF+) and non-exposed (nVit_SMF-) to magnetic field, were also considered. Survival and viability rates and mitochondrial activity as well as ultrastructure of oocytes were examined by trypan blue Staining (TBS), Annexin-PI Staining, JC1 staining and transition electron microscopy, respectively. Following in vitro fertilization (IVF) and embryo development, gene expression was carried out through qRT-PCR at blastocyst (BL) stage. The survival rate in Vit_SMF+ and Vit_SMF- decreased meaningfully in comparison with nVit_SMF- (P < 0.05), but there was no significant difference between SMF+ and SMF- groups. The mitochondrial activity in Vit_SMF- was significantly reduced compared to the nVit_SMF- group (P < 0.05), however its value in Vit_SMF+ returned to the control level. Ultrastructural study demonstrated that SMF could protect the COCs from cryoinjuries and reduced damaged features in ooplasm of the vitrified oocytes. There was no significant difference in fertilization rate. Although, BL formation was the highest rate in the Vit_SMF+ group, it was just substantially higher than the non-vitrified groups (P < 0.05). The significant changes of Oct4, Cdx2 and Nanog genes expression due to vitrification (Vit_SMF-) or SMF (nVit_SMF+) treatments (P < 0.05) as compared to control (nVit_SMF-), returned to the natural level after using SMF in vitrified derived blastocysts (Vit_SMF+). Totally based on the results, it is clear that static magnetic field improves mitochondrial potential activity and ultrastructure of mouse vitrified COCs. In addition, SMF enhances the embryo cleavage rate to blastocyst stage and modulates pluripotency in blastocyst embryos derived from vitrified COCs.

Rhamnus prinoides (gesho) stem extract prevents co-culture biofilm formation by Streptococcus mutans and Candida albicans.

Streptococcus mutans and Candida albicans exhibit a symbiotic relationship to form polymicrobial biofilms that exacerbate oral infections including early-childhood caries, periodontitis and candidiasis. Rhamnus prinoides (gesho) has traditionally been used for the treatment of a variety of illnesses and was recently found to inhibit Gram-positive bacterial biofilm formation. We hypothesized that Rhamnus prinoides extracts have anti-biofilm activity against S. mutans and C. albicans mono- and dual-species biofilms. Ethanol extracts were prepared from gesho stems and leaves; then anti-biofilm activity was assessed using crystal violet, resazurin and XTT staining. Ethanol extracts significantly inhibited Streptococcus mutans and Candida albicans mono-species biofilm formation up to 97 and 75%, respectively. The stem ethanol extract disrupted S. mutans and C. albicans co-culture synergism, with 98% less polymicrobial biofilm formation than the untreated control. Additionally, this extract inhibited planktonic S. mutans cell growth and decreased biofilm polysaccharide production up to 99%. The reduction in polysaccharide production is likely a contributing factor in the anti-biofilm activity of GSE. These findings indicate that gesho or gesho-derived compounds may have potential as additives to oral hygiene products. SIGNIFICANCE AND IMPACT OF THE STUDY: Oral Streptococcus mutans and Candida albicans biofilms are associated with a variety of illnesses. When occurring together, the resulting infections are especially challenging to treat due to enhanced biofilm formation and antibiotic resistance. More therapeutics that can effectively prevent polymicrobial biofilm formation and disrupt interspecies synergism are needed. Rhamnus prinoides ethanol extracts significantly inhibited dual-species biofilm formation and disrupted interspecies synergism.

Heparin-induced haemorrhagic bullous dermatosis.

BACKGROUND: Heparin-induced haemorrhagic bullous dermatosis (HBD) is a rare but probably underdiagnosed reaction to heparin, with 26 cases reported in the English literature. Currently, there is no consensus regarding the treatment. AIM: To assess our new cases of HBD and review the previously reported cases, in order to draw conclusions about this adverse skin reaction to heparin. METHODS: A PubMed search was performed for articles containing the terms '(heparin-induced AND (blister OR bulla OR bullae)) OR (hemorrhagic bullous dermatosis AND heparin) OR heparin bullous dermatosis'. Descriptive statistical data analysis was performed using Microsoft Excel. RESULTS: We assessed five new cases of HBD. In addition, our literature search revealed 26 previously reported patients. Combining these, we found that the mean ± SD age of patients with HBD was 71.4 ± 14 years. HBD affects men more commonly than women (men 22/31; P = 0.02). Patients develop tense bullae most frequently on the extremities, approximately 8 days (mean ± SD 7.5 ± 6.4 days) after starting treatment with a heparin product, usually enoxaparin. CONCLUSIONS: The typical clinical course is spontaneous resolution within days to weeks irrespective of continuation of heparin therapy. Because of its self-limiting nature, interruption of heparin therapy may not be required.

Follicle Development in Grafted Mouse Ovaries after Vitrification Processes Under Static Magnetic Field.

BACKGROUND: Ovarian cryopreservation has emerged as an important method of fertility preservation. Magnetic field enhanced cryopreservation has been considered in recent times as a promising type of ovarian cryopreservation but the effectiveness of the process is still not clear. OBJECTIVE: The aim of the present study was to investigate the effect of applying 1-mT SMF (static magnetic field) on the vitrification of ovarian tissue and the follow-up investigation of the morphology and functions of vitrified- warmed ovarian tissue after transplantation. MATERIALS AND METHODS: Ovaries of 6-8 week-old female mice from the Naval Medical Research Institute (NMRI) were exposed of the static magnetic field during different steps of the vitrification process. Immunohistological studies were performed on the ovaries. RESULTS: The mean percentage of damaged primordial follicles was lowest in control group and the group with ovaries exposed to magnetic field during the equilibration step. The latter group also had the highest percentage of intact primordial follicles after transplantation. CONCLUSION: Exposure of mice ovaries to static magnetic field during first step of vitrification process (the equilibration step) resulted in greater resistance against injury.

Tissue Engineered Human Amniotic Membrane Application in Mouse Ovarian Follicular Culture.

Since folliculogenesis requires a powerful cell-matrix interaction, natural scaffolds seem to be needed for follicular culture. Human amniotic membrane (HAM) offers promise as a support of in vitro ovarian follicular culture. HAM was decellularized with trypsin and EDTA. DNA and histology assays were performed to determine the elimination rate of genomic components. Cyto-biocompatibility of decellular AM (DAM) was verified by the cell viability (MTT) test. The small parts of intact amniotic membrane (IAM) and DAM were coated on the bottom of 96-well and each well was filled with 150 µL of base medium. Mouse primary-secondary (PS) follicles were separated to three groups: 1-culture in base medium (Control), 2-culture on IAM and 3-culture on DAM. Follicular size, morphology, viability, estradiol production and genes expression were evaluated and IAM group showed better growth and development in follicle culture. The viability rate and estradiol production in both experimental groups were statistically higher than the Control. Gdf9, Bmp15 and Cx37 were found to have higher expression levels in IAM group. Also, maximum apoptotic and survival indexes were determined in Control and IAM groups, respectively. Finally, IAM provides a better protective environment for mouse PS follicular culture that can reduce apoptosis level.

Effect of therapeutic ultrasound on folliculogenesis, angiogenesis and apoptosis after heterotopic mouse ovarian transplantation.

One of the challenges in ovarian transplantation is ischemia-reperfusion damage. When transitional tissue faces an acute and critical condition in terms of blood supply (immediately after organ transplantation), treatment with low-intensity pulsed ultrasound (LIPUS) seems to be very beneficial. The aim of this study was to evaluate the effects of ultrasound therapy on heterotopic transplanted mouse ovarian tissue. Adult female Naval Medical Research Institute mice were divided into three groups. In the experimental groups, the transplanted ovary was exposed 5 min daily to ultrasound with an intensity of 0.3 W/cm(2), frequency of 3 MHz and pulse mode of 1:4. The grafted ovaries were assessed with the usual histology and immunohistochemistry techniques. Results indicate that more CD31 angiogenic factor was expressed in irradiated animals than in control animals, and ultrasound therapy resulted in better follicular preservation, especially after 14 d. In conclusion, therapeutic ultrasound may accelerate and increase re-angiogenesis and can help to promote ovarian follicular growth.

Effects of different cryoprotectant combinations on primordial follicle survivability and apoptosis incidence after vitrification of whole rat ovary.

This study was aimed at obtaining best vitrification conditions for preservation of primordial follicles after vitrification of whole ovarian tissue of rats. Ovaries of prepubertal ~5-week old female Wistar rats were divided randomly into 7 groups: Control (non-vitrified), V1 (EG+DMSO), V2 (EG+PROH), V3 (DMSO+PROH), V4 (EG+DMSO+Sucrose), V5 (EG+PROH+Sucrose) and V6 (DMSO+PROH+Sucrose). Control and vitrified-warmed samples were sectioned serially and stained either with HE or anti and pro active caspase-3 kit. The number of intact follicles in different stages of development was lower and the number of atretic and apoptotic follicles was higher in vitrification groups than those of the control group. Cryoprotectant combinations in V4 group showed better follicular preservation especially for primordial follicle. V3, V4 and V5 were best cryoprotectant mixtures, after the control group, according to the number of atretic follicles but the incidence of apoptotic primordial follicles was lowest in V3, V4 and V6. Incidence of apoptosis and the number of atretic follicles were lowest in V3 and V4 groups, and there was better primordial follicle preservation and survivability in VIV group. Thus, the combination of EG + DMSO with sucrose appears to be better suited for vitrification of whole ovarian tissue of rats.

Mind-mapping for lung cancer: towards a personalized therapeutics approach.

There were over 220,000 people diagnosed with lung cancer and over 160,000 people dying of lung cancer during 2010 alone in the United States. In order to arrive at better control, prevention, diagnosis, and therapeutics for lung cancer, we must be able to personalize the approach towards the disease. Mind-mapping has existed for centuries for physicians to properly think about various "flows" of personalized medicine. We include here the epidemiology, diagnosis, histology, and treatment of lung cancer-in particular, non-small cell lung cancer. As we have new molecular signatures for lung cancer, this is further detailed. This review is not meant to be a comprehensive review, but rather its purpose is to highlight important aspects of lung cancer diagnosis, management, and personalized treatment options.

Influence of arterial compliance on presence and extent of ischaemia during stress echocardiography.

OBJECTIVE: To seek an association between total arterial compliance (TAC) and the extent of ischaemia at stress echocardiography. DESIGN: Cohort study. SETTING: Regional cardiac centre. METHODS: 255 consecutive patients (147 men; mean (SD) age 58 (8)) presenting for stress echocardiography for clinical indications were studied. Wall motion score index (WMSI) was calculated and ischaemia was defined by an inducible or worsening wall motion abnormality. Peak WMSI was used to reflect the extent of dysfunction (ischaemia or scar), and DeltaWMSI was indicative of extent of ischaemia. TAC was assessed at rest by simultaneous radial applanation tonometry and pulsed wave Doppler in all patients. RESULTS: Ischaemia was identified by stress echocardiography in 65 patients (25%). TAC was similar in the groups with negative and positive echocardiograms (1.08 (0.41) v 1.17 (0.51) ml/mm Hg, not significant). However, the extent of dysfunction was associated with TAC independently of age, blood pressure, risk factors, and use of a beta blocker. Moreover, the extent of ischaemia was determined by TAC, risk factors, and use of a beta blocker. CONCLUSION: While traditional cardiovascular risk factors are strong predictors of ischaemia on stress echocardiography, TAC is an independent predictor of the extent of ischaemia.

Pulse pressure vs. total arterial compliance as a marker of arterial health.

BACKGROUND: Brachial pulse pressure (BPP) is a predictor of outcome in epidemiologic studies, but brachial and aortic pulse pressure (AoPP) may not correspond and both are influenced by multiple parameters including arterial properties and cardiac output. We sought to what extent pulse pressure (PP) measurements reflected direct measurement of arterial properties, assessed as total arterial compliance (TAC). METHODS: We studied 123 patients (76 men; age 55 +/- 11); 31 normal controls, 46 patients with coronary artery disease and 46 patients with hypertension. PP was determined from brachial cuff pressure and TAC was measured by simultaneous radial applanation tonometry and pulsed wave Doppler of the LV outflow. AoPP was calculated using a transfer function from the radial waveform. RESULTS: There was a significant difference between BPP and AoPP (57 +/- 16 vs. 45 +/- 14; P < 0.0001), although TAC correlated with BPP (r = -0.72; P = 0.01) and AoPP (r = -0.66; P = 0.01). In a multiple linear regression, the difference between BPP and AoPP was predicted by cardiac output (CO) (P = 0.002) and gender (P = 0.03). Bland-Altman analysis showed the best correspondence between BPP and AoPP in the middle tertile (CO 4.7 to 5.7 L min(-1)) with less correlation in the low and high tertiles. The same analysis by gender showed a higher difference in women than men (14 +/- 6 vs. 10 +/- 5; P < 0.0001). The difference between BPP and AoPP showed the best correlation in the control group and the worst in the hypertension group. CONCLUSION: BPP correlates with TAC in men with normal cardiac function. However, in women, in patients at the low and high extremes of function, and in patients with preclinical and overt cardiovascular disease, there appears to be incremental value in measuring TAC.

Effect of tissue Doppler on the accuracy of novice and expert interpreters of dobutamine echocardiography.

The subjective interpretation of dobutamine echocardiography (DBE) makes the accuracy of this technique dependent on the experience of the observer, and also poses problems of concordance between observers. Myocardial tissue Doppler velocity (MDV) may offer a quantitative technique for identification of coronary artery disease, but it is unclear whether this parameter could improve the results of less expert readers and in segments with low interobserver concordance. The aim of this study was to find whether MDV improved the accuracy of wall motion scoring in novice readers, experienced echocardiographers, and experts in stress echocardiography, and to identify the optimal means of integrating these tissue Doppler data in 77 patients who underwent DBE and angiography. New or worsening abnormalities were identified as ischemia and abnormalities seen at rest as scarring. Segmental MDV was measured independently and previously derived cutoffs were applied to categorize segments as normal or abnormal. Five strategies were used to combine MDV and wall motion score, and the results of each reader using each strategy were compared with quantitative coronary angiography. The accuracy of wall motion scoring by novice (68 +/- 3%) and experienced echocardiographers (71 +/- 3%) was less than experts in stress echocardiography (88 +/- 3%, p <0.001). Various strategies for integration with MDV significantly improved the accuracy of wall motion scoring by novices from 75 +/- 2% to 77 +/- 5% (p <0.01). Among the experienced group, accuracy improved from 74 +/- 2% to 77 +/- 5% (p <0.05), but in the experts, no improvement was seen from their baseline accuracy. Integration with MDV also improved discordance related to the basal segments. Thus, use of MDV in all segments or MDV in all segments with wall motion scoring in the apex offers an improvement in sensitivity and accuracy with minimal compromise in specificity.

Noninvasive tests of vascular function and structure: why and how to perform them.

BACKGROUND: Early atherosclerosis involves the endothelium of many arteries. Information about peripheral arterial anatomy and function derived from vascular imaging studies such as brachial artery reactivity (BAR) and carotid intima media thickness (IMT) may be pertinent to the coronary circulation. The prevention and early treatment of atherosclerosis is gaining more attention, and these tests might be used as indications or perhaps guides to the effectiveness of therapy, but their application in clinical practice has been limited. This review seeks to define the anatomy and pathophysiology underlying these investigations, their methodology, the significance of their findings, and the issues that must be resolved before their application. METHODS: The literature on BAR and IMT is extensively reviewed, especially in relation to clinical use. RESULTS: Abnormal flow-mediated dilation is present in atherosclerotic vessels, is associated with cardiovascular risk factors, and may be a marker of preclinical disease. Treatment of known atherosclerotic risk factors has been shown to improve flow-mediated dilation, and some data suggest that vascular responsiveness is related to outcome. Carotid IMT is associated with cardiovascular risk factors, and increased levels can predict myocardial infarction and stroke. Aggressive risk factor management can decrease IMT. CONCLUSIONS: BAR and IMT are functional and structural markers of the atherosclerotic process. The clinical use of BAR has been limited by varying reproducibility and the influence by exogenous factors, but IMT exhibits less variability. A desirable next step in the development of BAR and IMT as useful clinical tools would be to show an association of improvement in response to treatment with improvement in prognosis.

Does renal failure cause an atherosclerotic milieu in patients with end-stage renal disease?

PURPOSE: Atherosclerotic vascular disease is the main cause of morbidity and mortality in patients with end-stage renal disease, but the independent contribution of renal failure rather than associated risk factors is unclear. We sought to examine the relative contribution of these factors to the severity of atherosclerosis by measuring intima-medial thickness and brachial artery reactivity in uremic patients and controls. SUBJECTS AND METHODS: Cardiovascular risk factors, including lipid and homocysteine levels, were evaluated in 213 patients (69 on hemodialysis, 60 on peritoneal dialysis, and 82 nonuremic controls). High-resolution B-mode ultrasonography with automated off-line analysis was used to measure the intima-medial thickness in the common carotid artery and to measure the lumen diameter of the brachial artery at rest, during reactive hyperemia, and after sublingual nitroglycerine. The correlations of risk factors with intima-medial thickness and brachial reactivity were examined using a general linear regression model. RESULTS: Patients with renal failure had a greater mean (+/- SEM) maximum intima-medial thickness than controls (0.83 +/- 0.02 mm versus 0.70 +/- 0.02 mm, P < 0.05), but the brachial artery response to reactive hyperemia was not significantly different between the renal failure patients and the control group (4.7% +/- 6.1% versus 6.1% +/- 8.6% dilatation, P > 0.05). The uremic state was an independent predictor of intima-medial thickness (r2 = 0.16, P < 0.001) but not of brachial artery reactivity (P = 0.99). CONCLUSION: The atherosclerotic burden in patients with renal failure, as indicated by an increased intima-medial thickness, may reflect effects of uremia that are independent of cardiovascular risk factors.

Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis.

BACKGROUND: Understanding the molecular mechanisms of complex cellular processes requires unbiased means to identify and to alter conditionally gene products that function in a pathway of interest. Although random mutagenesis and screening (forward genetics) provide a useful means to this end, the complexity of the genome, long generation time and redundancy of gene function have limited their use with mammalian systems. We sought to develop an analogous process using small molecules to modulate conditionally the function of proteins. We hoped to identify simultaneously small molecules that may serve as leads for the development of therapeutically useful agents. RESULTS: We report the results of a high-throughput, phenotype-based screen for identifying cell-permeable small molecules that affect mitosis of mammalian cells. The predominant class of compounds that emerged directly alters the stability of microtubules in the mitotic spindle. Although many of these compounds show the colchicine-like property of destabilizing microtubules, one member shows the taxol-like property of stabilizing microtubules. Another class of compounds alters chromosome segregation by novel mechanisms that do not involve direct interactions with microtubules. CONCLUSIONS: The identification of structurally diverse small molecules that affect the mammalian mitotic machinery from a large library of synthetic compounds illustrates the use of chemical genetics in dissecting an essential cellular pathway. This screen identified five compounds that affect mitosis without directly targeting microtubules. Understanding the mechanism of action of these compounds, along with future screening efforts, promises to help elucidate the molecular mechanisms involved in chromosome segregation during mitosis.

Phosphorus-based combinatorial libraries: use of amino acid derivatives as synthons.

Phosphorus has been used as a scaffold to prepare combinatorial libraries of phosphoramidates in which one of the diversity elements resulted from derivatives of amino acids. A small library was prepared for analytical and characterization purposes, followed by a larger library of approximately 8800 compounds. Libraries were assembled on solid supports using the conventional pool-and-divide method, followed by cleavage from the supports at the end of the synthesis. Mass spectrometry was used to confirm that library synthesis had been successful. Individual compounds were also prepared to study the stability of compounds of this type.