The teneurin C-terminal associated peptides (TCAPs) are a novel family of four endogenous peptide... more The teneurin C-terminal associated peptides (TCAPs) are a novel family of four endogenous peptides that have previously shown bioactive properties both in vitro and in vivo. Previously we have shown that repeated intracerebral injections of synthetic TCAP-1 modulate anxiety-like behaviors in three tests of anxiety, although the neural substrates responsible for these effects were previously unknown. In the current study, we examined both c-Fos induction and behavioral responses in the elevated plus maze and open field tests after a single intracerebroventricular dose of TCAP-1 followed by an intracerebroventricular injection of CRF in male Wistar rats. The results indicate that TCAP-1 injection attenuated the CRF-induced increase in c-Fos expression in the limbic system and many of the areas associated with the behavioral responses to stress, including the hippocampus, central and basolateral nuclei of the amygdala, medial prefrontal cortex, and dorsal raphe nucleus. Other areas, such as the paraventricular nucleus of the hypothalamus, bed nucleus of the stria terminalis, medial nucleus of the amygdala, and locus coeruleus, displayed CRF-induced c-Fos levels that were unaffected by TCAP-1. Furthermore, TCAP-1 administration increased stretched-attend postures, a type of risk-assessment behavior, on the elevated plus maze. These results indicate that TCAP-1 may play a potential role in the regulation of stress by blocking CRF-mediated activity in specific stress-sensitive areas of the brain.
The synthesis and structure-activity relationship (SAR) studies of the effect of different polysu... more The synthesis and structure-activity relationship (SAR) studies of the effect of different polysubstitution patterns in the aromatic ring of 5-(acetamidomethyl)oxmlidinone antibacterials (I) on antibacterial activity are presented. Compounds I were prepared by the six-step synthesis described previously (Gregory, W. A.; et al. J. Med. Chem. I 1989, 32, 1673), electrophilic aromatic substitution reactions of 3-substituted compounds, and functional-group interchange reactions of 3,4-disubstituted compounds. Antibacterial evaluation of compounds I against Staphylococcus aureus and Enterococcus faecalis gave the following results. The 2,4-and 2,5disubstituted derivatives have weak or no antibacterial activity. Antibacterial activities of 3,4-disubstituted compounds are comparable to those of the 4-monosubstituted analogues for small 3-substituents (smaller than Br), but decline rapidly for larger 3-substituents. 3,4-Annulated derivatives are comparable in activity to their open-chain analogues. 3,BDisubstituted and 3,4,5and 2,4,6-trisubstituted derivatives are devoid of antibacterial activity. II 0 1 2 Chemistry A six-step synthesis (Scheme I) of 5-(acetamido-methy1)oxamlidinones has been reported previously? The properties of compounds 3-13, which were prepared by this route, are summarized in Table I. The syntheses of compounds 14-17,2 18-19: 20,' and 22-34l have already been described. The 2,4-dinitro derivative 21 was prepared by nitration of the parent phenyloxazolidinone. Compounds with o-fluoro substituents required the specialized routes formulated in Scheme 11. Transition metal-mediated cross-coupling4 of TMS-acetylene with 5 afforded 35, from which the protective group was cleaved to yield 36. Hydration of the triple bond gave the desired acetyl compound 37. The same sequence was employed to convert 6 into difluoro derivative 38.
Expert Opinion on Investigational Drugs, Dec 1, 2002
Integrins are involved in many cellular processes, including some pathological ones associated wi... more Integrins are involved in many cellular processes, including some pathological ones associated with various cancers, both solid tumours and metastases. Since integrins are involved in such critical processes as gene expression, which lead to cellular proliferation, migration, survival and angiogenesis, they represent potential targets for therapeutic intervention. The alpha(v)beta(3) integrin is one of the most widely studied integrins because it is one of the most promiscuous. Published studies provide compelling evidence that small molecule antagonists have the potential to treat both solid tumours and metastases, serve as diagnostic imaging agents and be used for site-directed delivery of drugs to solid tumours. The alpha(v)beta(3) integrin antagonists also inhibit blood vessel formation associated with tumour growth. Therapeutic candidates have included antibodies, cyclic peptides, peptidomimetics and small molecules. A number of potent small-molecule antagonists of the alpha(v)beta(3) integrin have now been identified and are progressing in the clinic. This review focuses on the role of alpha(v)beta(3) in cancer. The rationale for the development of the therapeutic and diagnostic candidates based on the key role of alpha(v)beta(3) is discussed.
Antimicrobial Agents and Chemotherapy, Mar 1, 1983
The antibacterial activity of octenidine dihydrochloride (WIN 41464-2) against intact preformed i... more The antibacterial activity of octenidine dihydrochloride (WIN 41464-2) against intact preformed in vitro plaques of four indigenous oral plaque-forming microorganisms, Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus, and Actinomyces naeslundii, was studied. Both absolute (plaque bactericidal index) and relative (chlorhexidine coefficient) indices of antiplaque efficacy were established. Octenidine dihydrochloride compared favorably with chlorhexidine digluconate with respect to overall antiplaque potency in this in vitro plaque bactericidal model. These data indicate that prudent selection of treatment concentration and duration and frequency of exposure should provide an effective means to aid in controlling dental caries and Actinomyces-associated disease in vivo.
Antimicrobial Agents and Chemotherapy, Aug 1, 1988
The mode of action of DuP 721 was investigated. This compound was active primarily against gram-p... more The mode of action of DuP 721 was investigated. This compound was active primarily against gram-positive bacteria, including multiply resistant strains of staphylococci. Although inactive against wild-type Escherichia coli, DuP 721 did inhibit E. coli when the outer membrane was perturbed by genetic or chemical means. Pulse-labeling studies with E. coli PLB-3252, a membrane-defective strain, showed that DuP 721 inhibited amino acid incorporation into proteins. The 50% inhibitory concentration of DuP 721 for protein synthesis was
Octenidine, a bispyridine antimicrobial compound, has evidenced significant antiplaque activity w... more Octenidine, a bispyridine antimicrobial compound, has evidenced significant antiplaque activity when used in solution in both animal and human model systems. The present study was designed to evaluate concurrently the antiplaque and antigingivitis potential of a dentifrice formulation containing octenidine. In addition to an antimicrobial agent, the product was formulated to exhibit abrasive and foaming chracteristics similar to those of current commercial dentifrices. Adult female cynomolgus monkeys, five per group, received once daily oral treatments with either the octenidine dentifrice formulation or a placebo formulation. Both formulations were delivered as a suspension which was gently dispersed by manipulation of the cheeks. Direct delivery using a toothbrush was purposely avoided in order to permit the assessment of antimicrobial and antiplaque efficacy in the absence of direct mechanical action. The development of plaque and gingivitis was observed to be suppressed in the presence of the octenidine dentifrice formulation over the 21-day experimental period. By contrast, animals receiving the placebo formulation evidenced a signficant increase in dental plaque levels and extensive gingival inflammation.
ChemInform Abstract Reaction of the phenyl isocyanates (I) with the epoxides (II) yields the oxaz... more ChemInform Abstract Reaction of the phenyl isocyanates (I) with the epoxides (II) yields the oxazolidinones (III). Transformation of the bromo derivative (IIIb) to the azido compound, followed by reduction and acetylation gives the acetaminomethyl derivative (VI). Aniline (VII) reacts with glycidol (VIII) to form the racemic diol (±)-(IX) which is optically resolved by means of mandelic acid. Ring closure of (R)-(IX) with the carbonate (X) produces the optically active oxazolidinone (XI) which is converted into substitution products such as (XII)-(XV). These are tested for their antibacterial activities.
The Journal of Allergy and Clinical Immunology, Feb 1, 2019
RATIONALE: Mast cell activation syndrome (MCAS) has been increasingly diagnosed. In preparation f... more RATIONALE: Mast cell activation syndrome (MCAS) has been increasingly diagnosed. In preparation for a National Institutes of Health workshop, The Mastocytosis Society, Inc. (TMS) conducted a large-scale survey to characterize this population. METHODS: Upon IRB approval, patient/caregiver-reported (medical records not reviewed) data (N 5 1701) were collected through an online Qualtrics survey platform, August 17-25, 2018, from those reporting physician-diagnosed MCAS (n 5 1574) and/or hereditary a-tryptasemia (n 5 61). Data gathered included demographics, diagnoses/comorbidities, diagnostic criteria, symptoms, quality of life (QoL), and perceptions of research and care. RESULTS: Participants' ages ranged from 0-85 (M 5 43.0, SD 5 16.2), 87.8% female; 82.1% received MCAS treatment in the US. Most commonly reported co-occurring conditions were dysautonomia (47.5%) and connective-tissue disorder(s) (41.0%). Of respondents reporting an MCAS diagnosis, 21.5% reported no rise in mast cell mediators, while 24.8% reported elevated baseline serum tryptase, 26.0% N-methylhistamine, and 21.8% prostaglandins. Most used H1 blockers (91.9%), H2 blockers (71.5%), and/or mast-cell stabilizers (55.9%). Moderate/severe symptoms affecting multiple body systems were wide ranging: 45.5% moderately/severely affected by anaphylaxis, 69.4% food-restricted, and 40.1% able to eat < _20 foods. Symptoms impacted QoL, with 87.6% reporting moderate/severe life interruption; 66.1% reporting daily interruption, 84.7% moderately/severely affected by unpredictability of onset, and 48.1% often/very frequently requiring assistance with routine care needs. 68.0% reported fair/poor health, with M 5 17.9 (SD 5 10.6) poor physical health, M 5 11.8 (SD 5 10.2) poor mental health, and M 5 15.1 (SD 5 10.9) activity-limited days in the past month. CONCLUSIONS: Survey data presents a profile of reported MCAS as more chronically disabling than has been widely recognized, with patients in need of improved, more readily available care.
The hollow fiber assay, a unique in vivo model, permits the simultaneous evaluation of compound e... more The hollow fiber assay, a unique in vivo model, permits the simultaneous evaluation of compound efficacy against multiple cell lines in two physiological compartments. This assay has been used to characterize in vivo activity of cytotoxic compounds. The purpose of the present study was to characterize and optimize this assay for compounds with a defined mechanism of action, specifically cell cycle inhibition. Two human tumor cell lines and one normal human cell line were loaded into polyvinylidene fluoride hollow fibers at two or more cell concentrations and grown in mice for 3-10 days. The data demonstrate the importance of characterizing the initial loading density of various cell lines in the evaluation of compounds. All studies were performed with cells in the linear part of the cell growth curves. Initial loading densities of 1-2 x 10(4) cells/fiber gave the greatest opportunity for growth in the three human cell lines tested (HCT116 colon carcinoma, NCI-H460 non-small cell carcinoma, and AG 1523 normal fibroblast). Utilizing the MTT assay, standard curves were constructed to correlate the final number of cells with optical density (OD) readings at 540 nm in order to calculate cell numbers in the fibers. Insights into the mechanism of action of cisplatin have been gained using Western blot analysis of the cell cycle markers PCNA (a protein present throughout the cell cycle) and Rb (a protein that acts as a tumor suppressor gene product) from the hollow fiber cells. In cisplatin-treated NCI-H460 cells both PCNA and Rb phosphorylation decreased, suggesting the arrest of the cells prior to the S phase. Standard therapeutic agents, cisplatin, racemic flavopiridol, cyclophosphamide and mitomycin C, were evaluated independently in the hollow fiber assay and the xenograft model. The data demonstrate that compounds active in the hollow fiber assay are also active in the xenograft.
Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The gen... more Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism in rats. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 in the C2C12 mouse skeletal cell line shows that TCAP stimulates an LPHN-dependent cytosolic Ca2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism that regulates the energy...
Background: Ig-Like Transcript 2 (ILT2, LILRB1) is an inhibitory receptor prominently expressed o... more Background: Ig-Like Transcript 2 (ILT2, LILRB1) is an inhibitory receptor prominently expressed on resting macrophages, monocytes, and dendritic cells (DCs), with variable expression on CD4+ T cells, CD8+ T cells, B cells, NK cells, and NKT cells in the tumor microenvironment. Interaction of ILT2 with its ligands, HLA-G and classical MHC class I molecules, is reported to impair cytotoxic activity of NK and effector T cells, attenuate B cell function, inhibit antigen-presentation by dendritic cells, and promote immunosuppressive activity of myeloid cells. Further, high ILT2 expression has been associated with poor prognosis in several human malignancies. As a result, ILT2 has been proposed as a therapeutic target to promote antitumor immunity and to overcome resistance to checkpoint blockade. Here, we report that AGEN1571, a fully human anti-ILT2 monoclonal IgG4κ antibody, reversed ILT2-mediated immunosuppression and promoted activation of NK, NKT, T cells, and myeloid cells in a ser...
Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The gen... more Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals, form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 shows that TCAP stimulates an LPHN-mediated cytosolic Ca2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism likely to regulate the energy requirements and performance of skeletal ...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000
Tumor growth is dependent on the balance between cell proliferation and cell death, and these eve... more Tumor growth is dependent on the balance between cell proliferation and cell death, and these events occur heterogenously within an individual tumor. We present a methodology that provides integrative information about cell kinetics, cell death, and cell growth within individual tumors in animals treated with cytotoxic chemotherapeutic agents. Using HCT-116 and NCI-H460 cells, human colonic adenocarcinoma and non-small cell lung cells, respectively, traditional xenograft studies were performed. The tumor-bearing animals were treated with cyclophosphamide (Cytoxan), gemcitabine (Gemzar), or mitomycin C, and extensive analysis of the tumors was studied. Cell kinetics were evaluated by measuring the apoptotic and proliferation indices. The ability to image an entire tumor section using "tiling" by creating a large montage from many high-resolution images makes it possible to identify regional differences within areas of tumor and to demonstrate differences in these tumor regi...
Small molecule MetAP2 inhibitor TNP-470 previously showed clinical anti-tumor activity, however C... more Small molecule MetAP2 inhibitor TNP-470 previously showed clinical anti-tumor activity, however CNS side effects and poor drug-like properties limited its development. SDX-7320 is a polymer-drug conjugate of a novel MetAP2 inhibitor (SDX-7539), intended to improve biodistribution (limit CNS penetration) and pharmacokinetics relative to small molecule MetAP2 inhibitors. SDX-7320 has recently completed a phase I trial in late-stage cancer patients (NCT02743637). SDX-7320 was previously shown to inhibit the growth of syngeneic EO771 triple-negative breast cancers (TNBC) accelerated by obesity/metabolic dysfunction (“metabo-oncology”). In addition SDX-7320 synergized with the PI3Kα inhibitor alpelisib (Piqray®) to block the growth of ER+/Her2- MCF-7 xenografts. Here, we show that SDX-7320 inhibits the growth of MCF-7 xenografts alone and in combination with the CDK4/6 inhibitor Palbociclib (Ibrance®). Nude mice were implanted with slow release estrogen pellets and then injected with MCF...
Mutations in the PI3K pathway have been observed in about 40% of ER+/Her2- breast cancer patients... more Mutations in the PI3K pathway have been observed in about 40% of ER+/Her2- breast cancer patients. Amplification as well as mutation of the catalytic p110α subunit of PI3K results in activation of this pathway within tumors, conferring a growth advantage due to increased transmission of intracellular growth signals. Recently a selective inhibitor of p110α, Piqray®(alpelisib) has been approved by the FDA (in combination with the estrogen receptor degrader/antagonist Faslodex/fulvestrant) for the treatment of ER+/Her2- breast cancers harboring mutation(s) in the p110α subunit of PI3K. Small molecule MetAP2 inhibitors have previously shown clinical anti-tumor activity. SDX-7320 is a polymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) backbone. This is intended to alter biodistribution (limit CNS penetration) and improve pharmacokinetics relative to small molecule, fumagillin-derived Met...
We report the discovery of a class of pyrazole-based compounds that are potent inhibitors of the ... more We report the discovery of a class of pyrazole-based compounds that are potent inhibitors of the dihydroorotate dehydrogenase of Helicobacter pylori but that do not inhibit the cognate enzymes from Gram-positive bacteria or humans. In culture these compounds inhibit the growth of ...
The teneurin C-terminal associated peptides (TCAPs) are a novel family of four endogenous peptide... more The teneurin C-terminal associated peptides (TCAPs) are a novel family of four endogenous peptides that have previously shown bioactive properties both in vitro and in vivo. Previously we have shown that repeated intracerebral injections of synthetic TCAP-1 modulate anxiety-like behaviors in three tests of anxiety, although the neural substrates responsible for these effects were previously unknown. In the current study, we examined both c-Fos induction and behavioral responses in the elevated plus maze and open field tests after a single intracerebroventricular dose of TCAP-1 followed by an intracerebroventricular injection of CRF in male Wistar rats. The results indicate that TCAP-1 injection attenuated the CRF-induced increase in c-Fos expression in the limbic system and many of the areas associated with the behavioral responses to stress, including the hippocampus, central and basolateral nuclei of the amygdala, medial prefrontal cortex, and dorsal raphe nucleus. Other areas, such as the paraventricular nucleus of the hypothalamus, bed nucleus of the stria terminalis, medial nucleus of the amygdala, and locus coeruleus, displayed CRF-induced c-Fos levels that were unaffected by TCAP-1. Furthermore, TCAP-1 administration increased stretched-attend postures, a type of risk-assessment behavior, on the elevated plus maze. These results indicate that TCAP-1 may play a potential role in the regulation of stress by blocking CRF-mediated activity in specific stress-sensitive areas of the brain.
The synthesis and structure-activity relationship (SAR) studies of the effect of different polysu... more The synthesis and structure-activity relationship (SAR) studies of the effect of different polysubstitution patterns in the aromatic ring of 5-(acetamidomethyl)oxmlidinone antibacterials (I) on antibacterial activity are presented. Compounds I were prepared by the six-step synthesis described previously (Gregory, W. A.; et al. J. Med. Chem. I 1989, 32, 1673), electrophilic aromatic substitution reactions of 3-substituted compounds, and functional-group interchange reactions of 3,4-disubstituted compounds. Antibacterial evaluation of compounds I against Staphylococcus aureus and Enterococcus faecalis gave the following results. The 2,4-and 2,5disubstituted derivatives have weak or no antibacterial activity. Antibacterial activities of 3,4-disubstituted compounds are comparable to those of the 4-monosubstituted analogues for small 3-substituents (smaller than Br), but decline rapidly for larger 3-substituents. 3,4-Annulated derivatives are comparable in activity to their open-chain analogues. 3,BDisubstituted and 3,4,5and 2,4,6-trisubstituted derivatives are devoid of antibacterial activity. II 0 1 2 Chemistry A six-step synthesis (Scheme I) of 5-(acetamido-methy1)oxamlidinones has been reported previously? The properties of compounds 3-13, which were prepared by this route, are summarized in Table I. The syntheses of compounds 14-17,2 18-19: 20,' and 22-34l have already been described. The 2,4-dinitro derivative 21 was prepared by nitration of the parent phenyloxazolidinone. Compounds with o-fluoro substituents required the specialized routes formulated in Scheme 11. Transition metal-mediated cross-coupling4 of TMS-acetylene with 5 afforded 35, from which the protective group was cleaved to yield 36. Hydration of the triple bond gave the desired acetyl compound 37. The same sequence was employed to convert 6 into difluoro derivative 38.
Expert Opinion on Investigational Drugs, Dec 1, 2002
Integrins are involved in many cellular processes, including some pathological ones associated wi... more Integrins are involved in many cellular processes, including some pathological ones associated with various cancers, both solid tumours and metastases. Since integrins are involved in such critical processes as gene expression, which lead to cellular proliferation, migration, survival and angiogenesis, they represent potential targets for therapeutic intervention. The alpha(v)beta(3) integrin is one of the most widely studied integrins because it is one of the most promiscuous. Published studies provide compelling evidence that small molecule antagonists have the potential to treat both solid tumours and metastases, serve as diagnostic imaging agents and be used for site-directed delivery of drugs to solid tumours. The alpha(v)beta(3) integrin antagonists also inhibit blood vessel formation associated with tumour growth. Therapeutic candidates have included antibodies, cyclic peptides, peptidomimetics and small molecules. A number of potent small-molecule antagonists of the alpha(v)beta(3) integrin have now been identified and are progressing in the clinic. This review focuses on the role of alpha(v)beta(3) in cancer. The rationale for the development of the therapeutic and diagnostic candidates based on the key role of alpha(v)beta(3) is discussed.
Antimicrobial Agents and Chemotherapy, Mar 1, 1983
The antibacterial activity of octenidine dihydrochloride (WIN 41464-2) against intact preformed i... more The antibacterial activity of octenidine dihydrochloride (WIN 41464-2) against intact preformed in vitro plaques of four indigenous oral plaque-forming microorganisms, Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus, and Actinomyces naeslundii, was studied. Both absolute (plaque bactericidal index) and relative (chlorhexidine coefficient) indices of antiplaque efficacy were established. Octenidine dihydrochloride compared favorably with chlorhexidine digluconate with respect to overall antiplaque potency in this in vitro plaque bactericidal model. These data indicate that prudent selection of treatment concentration and duration and frequency of exposure should provide an effective means to aid in controlling dental caries and Actinomyces-associated disease in vivo.
Antimicrobial Agents and Chemotherapy, Aug 1, 1988
The mode of action of DuP 721 was investigated. This compound was active primarily against gram-p... more The mode of action of DuP 721 was investigated. This compound was active primarily against gram-positive bacteria, including multiply resistant strains of staphylococci. Although inactive against wild-type Escherichia coli, DuP 721 did inhibit E. coli when the outer membrane was perturbed by genetic or chemical means. Pulse-labeling studies with E. coli PLB-3252, a membrane-defective strain, showed that DuP 721 inhibited amino acid incorporation into proteins. The 50% inhibitory concentration of DuP 721 for protein synthesis was
Octenidine, a bispyridine antimicrobial compound, has evidenced significant antiplaque activity w... more Octenidine, a bispyridine antimicrobial compound, has evidenced significant antiplaque activity when used in solution in both animal and human model systems. The present study was designed to evaluate concurrently the antiplaque and antigingivitis potential of a dentifrice formulation containing octenidine. In addition to an antimicrobial agent, the product was formulated to exhibit abrasive and foaming chracteristics similar to those of current commercial dentifrices. Adult female cynomolgus monkeys, five per group, received once daily oral treatments with either the octenidine dentifrice formulation or a placebo formulation. Both formulations were delivered as a suspension which was gently dispersed by manipulation of the cheeks. Direct delivery using a toothbrush was purposely avoided in order to permit the assessment of antimicrobial and antiplaque efficacy in the absence of direct mechanical action. The development of plaque and gingivitis was observed to be suppressed in the presence of the octenidine dentifrice formulation over the 21-day experimental period. By contrast, animals receiving the placebo formulation evidenced a signficant increase in dental plaque levels and extensive gingival inflammation.
ChemInform Abstract Reaction of the phenyl isocyanates (I) with the epoxides (II) yields the oxaz... more ChemInform Abstract Reaction of the phenyl isocyanates (I) with the epoxides (II) yields the oxazolidinones (III). Transformation of the bromo derivative (IIIb) to the azido compound, followed by reduction and acetylation gives the acetaminomethyl derivative (VI). Aniline (VII) reacts with glycidol (VIII) to form the racemic diol (±)-(IX) which is optically resolved by means of mandelic acid. Ring closure of (R)-(IX) with the carbonate (X) produces the optically active oxazolidinone (XI) which is converted into substitution products such as (XII)-(XV). These are tested for their antibacterial activities.
The Journal of Allergy and Clinical Immunology, Feb 1, 2019
RATIONALE: Mast cell activation syndrome (MCAS) has been increasingly diagnosed. In preparation f... more RATIONALE: Mast cell activation syndrome (MCAS) has been increasingly diagnosed. In preparation for a National Institutes of Health workshop, The Mastocytosis Society, Inc. (TMS) conducted a large-scale survey to characterize this population. METHODS: Upon IRB approval, patient/caregiver-reported (medical records not reviewed) data (N 5 1701) were collected through an online Qualtrics survey platform, August 17-25, 2018, from those reporting physician-diagnosed MCAS (n 5 1574) and/or hereditary a-tryptasemia (n 5 61). Data gathered included demographics, diagnoses/comorbidities, diagnostic criteria, symptoms, quality of life (QoL), and perceptions of research and care. RESULTS: Participants' ages ranged from 0-85 (M 5 43.0, SD 5 16.2), 87.8% female; 82.1% received MCAS treatment in the US. Most commonly reported co-occurring conditions were dysautonomia (47.5%) and connective-tissue disorder(s) (41.0%). Of respondents reporting an MCAS diagnosis, 21.5% reported no rise in mast cell mediators, while 24.8% reported elevated baseline serum tryptase, 26.0% N-methylhistamine, and 21.8% prostaglandins. Most used H1 blockers (91.9%), H2 blockers (71.5%), and/or mast-cell stabilizers (55.9%). Moderate/severe symptoms affecting multiple body systems were wide ranging: 45.5% moderately/severely affected by anaphylaxis, 69.4% food-restricted, and 40.1% able to eat < _20 foods. Symptoms impacted QoL, with 87.6% reporting moderate/severe life interruption; 66.1% reporting daily interruption, 84.7% moderately/severely affected by unpredictability of onset, and 48.1% often/very frequently requiring assistance with routine care needs. 68.0% reported fair/poor health, with M 5 17.9 (SD 5 10.6) poor physical health, M 5 11.8 (SD 5 10.2) poor mental health, and M 5 15.1 (SD 5 10.9) activity-limited days in the past month. CONCLUSIONS: Survey data presents a profile of reported MCAS as more chronically disabling than has been widely recognized, with patients in need of improved, more readily available care.
The hollow fiber assay, a unique in vivo model, permits the simultaneous evaluation of compound e... more The hollow fiber assay, a unique in vivo model, permits the simultaneous evaluation of compound efficacy against multiple cell lines in two physiological compartments. This assay has been used to characterize in vivo activity of cytotoxic compounds. The purpose of the present study was to characterize and optimize this assay for compounds with a defined mechanism of action, specifically cell cycle inhibition. Two human tumor cell lines and one normal human cell line were loaded into polyvinylidene fluoride hollow fibers at two or more cell concentrations and grown in mice for 3-10 days. The data demonstrate the importance of characterizing the initial loading density of various cell lines in the evaluation of compounds. All studies were performed with cells in the linear part of the cell growth curves. Initial loading densities of 1-2 x 10(4) cells/fiber gave the greatest opportunity for growth in the three human cell lines tested (HCT116 colon carcinoma, NCI-H460 non-small cell carcinoma, and AG 1523 normal fibroblast). Utilizing the MTT assay, standard curves were constructed to correlate the final number of cells with optical density (OD) readings at 540 nm in order to calculate cell numbers in the fibers. Insights into the mechanism of action of cisplatin have been gained using Western blot analysis of the cell cycle markers PCNA (a protein present throughout the cell cycle) and Rb (a protein that acts as a tumor suppressor gene product) from the hollow fiber cells. In cisplatin-treated NCI-H460 cells both PCNA and Rb phosphorylation decreased, suggesting the arrest of the cells prior to the S phase. Standard therapeutic agents, cisplatin, racemic flavopiridol, cyclophosphamide and mitomycin C, were evaluated independently in the hollow fiber assay and the xenograft model. The data demonstrate that compounds active in the hollow fiber assay are also active in the xenograft.
Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The gen... more Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism in rats. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 in the C2C12 mouse skeletal cell line shows that TCAP stimulates an LPHN-dependent cytosolic Ca2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism that regulates the energy...
Background: Ig-Like Transcript 2 (ILT2, LILRB1) is an inhibitory receptor prominently expressed o... more Background: Ig-Like Transcript 2 (ILT2, LILRB1) is an inhibitory receptor prominently expressed on resting macrophages, monocytes, and dendritic cells (DCs), with variable expression on CD4+ T cells, CD8+ T cells, B cells, NK cells, and NKT cells in the tumor microenvironment. Interaction of ILT2 with its ligands, HLA-G and classical MHC class I molecules, is reported to impair cytotoxic activity of NK and effector T cells, attenuate B cell function, inhibit antigen-presentation by dendritic cells, and promote immunosuppressive activity of myeloid cells. Further, high ILT2 expression has been associated with poor prognosis in several human malignancies. As a result, ILT2 has been proposed as a therapeutic target to promote antitumor immunity and to overcome resistance to checkpoint blockade. Here, we report that AGEN1571, a fully human anti-ILT2 monoclonal IgG4κ antibody, reversed ILT2-mediated immunosuppression and promoted activation of NK, NKT, T cells, and myeloid cells in a ser...
Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The gen... more Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals, form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 shows that TCAP stimulates an LPHN-mediated cytosolic Ca2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism likely to regulate the energy requirements and performance of skeletal ...
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000
Tumor growth is dependent on the balance between cell proliferation and cell death, and these eve... more Tumor growth is dependent on the balance between cell proliferation and cell death, and these events occur heterogenously within an individual tumor. We present a methodology that provides integrative information about cell kinetics, cell death, and cell growth within individual tumors in animals treated with cytotoxic chemotherapeutic agents. Using HCT-116 and NCI-H460 cells, human colonic adenocarcinoma and non-small cell lung cells, respectively, traditional xenograft studies were performed. The tumor-bearing animals were treated with cyclophosphamide (Cytoxan), gemcitabine (Gemzar), or mitomycin C, and extensive analysis of the tumors was studied. Cell kinetics were evaluated by measuring the apoptotic and proliferation indices. The ability to image an entire tumor section using "tiling" by creating a large montage from many high-resolution images makes it possible to identify regional differences within areas of tumor and to demonstrate differences in these tumor regi...
Small molecule MetAP2 inhibitor TNP-470 previously showed clinical anti-tumor activity, however C... more Small molecule MetAP2 inhibitor TNP-470 previously showed clinical anti-tumor activity, however CNS side effects and poor drug-like properties limited its development. SDX-7320 is a polymer-drug conjugate of a novel MetAP2 inhibitor (SDX-7539), intended to improve biodistribution (limit CNS penetration) and pharmacokinetics relative to small molecule MetAP2 inhibitors. SDX-7320 has recently completed a phase I trial in late-stage cancer patients (NCT02743637). SDX-7320 was previously shown to inhibit the growth of syngeneic EO771 triple-negative breast cancers (TNBC) accelerated by obesity/metabolic dysfunction (“metabo-oncology”). In addition SDX-7320 synergized with the PI3Kα inhibitor alpelisib (Piqray®) to block the growth of ER+/Her2- MCF-7 xenografts. Here, we show that SDX-7320 inhibits the growth of MCF-7 xenografts alone and in combination with the CDK4/6 inhibitor Palbociclib (Ibrance®). Nude mice were implanted with slow release estrogen pellets and then injected with MCF...
Mutations in the PI3K pathway have been observed in about 40% of ER+/Her2- breast cancer patients... more Mutations in the PI3K pathway have been observed in about 40% of ER+/Her2- breast cancer patients. Amplification as well as mutation of the catalytic p110α subunit of PI3K results in activation of this pathway within tumors, conferring a growth advantage due to increased transmission of intracellular growth signals. Recently a selective inhibitor of p110α, Piqray®(alpelisib) has been approved by the FDA (in combination with the estrogen receptor degrader/antagonist Faslodex/fulvestrant) for the treatment of ER+/Her2- breast cancers harboring mutation(s) in the p110α subunit of PI3K. Small molecule MetAP2 inhibitors have previously shown clinical anti-tumor activity. SDX-7320 is a polymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) backbone. This is intended to alter biodistribution (limit CNS penetration) and improve pharmacokinetics relative to small molecule, fumagillin-derived Met...
We report the discovery of a class of pyrazole-based compounds that are potent inhibitors of the ... more We report the discovery of a class of pyrazole-based compounds that are potent inhibitors of the dihydroorotate dehydrogenase of Helicobacter pylori but that do not inhibit the cognate enzymes from Gram-positive bacteria or humans. In culture these compounds inhibit the growth of ...
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Papers by Andrew Slee