Metal-based new sulfonamides: Design, synthesis, antibacterial, antifungal, and cytotoxic properties

Cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes with 5-chlorosalicyladehyde derived Schiff base sulfonamides have been synthesized and characterized. Structure and bonding nature of all the synthesized compounds have been deduced from physical, analytical, and spectral (IR, (1)H NMR, (13)C NMR, Mass, electronic) data. An octahedral geometry has been proposed for all the metal complexes. The ligands and their metal complexes have been screened for their in vitro antibacterial, antifungal, and cytotoxic properties and results are reported.     

Stability of 100 homo and heterotypic coiled-coil a-a' pairs for ten amino acids (A, L, I, V, N, K, S, T, E, and R)

We present the thermal stability monitored by circular dichroism (CD) spectroscopy at 222 nm of 100 heterodimers that contain all possible coiled-coil a-a' pairs for 10 amino acids (I, V, L, N, A, K S, T, E, and R). This includes the stability of 36 heterodimers for 6 amino acids (I, V, L, N, A, and K) previously described and 64 new heterodimers including the 4 amino acids (S, T, E, and R). We have calculated a double mutant alanine thermodynamic cycle to determine a-a' pair coupling energies to evaluate which a-a' pairs encourage specific dimerization partners. The four new homotypic a-a' pairs (T-T, S-S, R-R, E-E) are repulsive relative to A-A and have destabilizing coupling energies. Among the 90 heterotypic a-a' pairs, the stabilizing coupling energies contain lysine or arginine paired with either an aliphatic or a polar amino acid. The range in coupling energies for each amino acid reveals its potential to regulate dimerization specificity. The a-a' pairs containing isoleucine and asparagine have the greatest range in coupling energies and thus contribute dramatically to dimerization specificity, which is to encourage homodimerization. In contrast, the a-a' pairs containing charged amino acids (K, R, and E) show the least range in coupling energies and promiscuously encourage heterodimerization.     

Myelomonocytic leukemia: clinical, cytological, and cytogenetic studies of acute, subacute, and chronic forms (author's transl)]

44 patients suffering from myelomonocytic leukemia (MML) have been observed over the last four years. They have been subclassified in acute myelomonocytic and acute monoblastic leukemias (AMML, n = 12; AMoL, n = 10), subacute myelomonocytic leukemias (SMML, n = 13), and chronic myelomonocytic leukemias (CMML, n = 9) on the basis of bone marrow cytology(blast and promonocyte counts, maturation of granulopoesis) and cytochemical findings (peroxydase and unspecific esterase reaction). This subclassification has been proved to be of prognostic relevance by its good correlation with the mean survival times (AMML : 4.5 months, AMoL : 2.4 months, SMML : 8 months, CMML : 18 months). The acute forms have been treated in general with combined cytostatic chemotherapy, whereas SMML and CMML have been treated this way only in case of progression to an acute phase. These progressions to an AMML have been observed more often and earlier in subacute forms than in chronic forms. The diagnosis of SMML and CMML is supported by the finding of sea-blue histiocytes in the bone marrow, increased lysozyme levels in serum and urine and by the absence of the Philadelphia-Chromosome.     

Hemoglobin genotype, fertility, and the malaria hypothesis

Epidemiological and clinical studies (Fleming et al. 1985; Perrin et al. 1982) indicate that hemoglobin (Hb) AS individuals have a selective advantage in malarial environments. Thus the high frequency of Hb S in human populations has been attributed to the decreased malarial morbidity and mortality experienced by Hb AS heterozygotes. It has also been suggested that Hb AS women have a higher fertility than that of Hb AA women, thus contributing to the elevated frequency of Hb S in malarial environments (Livingstone 1957). Firschein (1961) demonstrated a significantly greater fertility among Hb AS females, whereas Custodio and Huntsman (1984) documented no fertility differential between Hb AS and Hb AA women. Here I examine the reproductive careers of Hb AA and Hb AS subjects 40 years of age and older from Limon, Costa Rica. The purpose is to determine whether normal homozygotes and heterozygotes have significantly different fertilities. The research shows that these groups do not have significantly different completed family sizes (t = 0.38, ns) or significantly different numbers of pregnancies (t = 0.34, ns), live births (t = 0.36, ns), or abortions (t = 0.20, ns). My results support previous suggestions that differential fertility does not contribute to the maintenance of the Hb S polymorphism.     

Design, synthesis, and radiosensitizing activities of sugar-hybrid hypoxic cell radiosensitizers

We have designed sugar-hybrid TX-1877 derivatives conjugated with sugar moieties including beta-glucose (beta-Glc), beta-galactose (beta-Gal), alpha-mannose (alpha-Man) and N-acetyl-beta-galactosamine (beta-GalNAc). Compound 1 (TX-1877) was glycosylated with appropriate peracetylated sugars using BF(3)-OEt(2) to give acetylated sugar-hybrids, 5 (TX-2244), 6 (TX-2245), 7 (TX-2246), and 10 (TX-2243). Removal of the acetyl groups afforded the sugar-hybrids having free hydroxyl groups, 11 (TX-2141), 12 (TX-2218), 13 (TX-2217) and 14 (TX-2068). We evaluated their radiosensitizing activities by an in vitro radiosensitization assay. All free hydroxyl hybrids have lower enhancement ratio (ER) values (ER1.43) and lower n-octanol/water partition coefficient (P(oct)) values (P(oct)<1.00x10(-2)) than does 1 (TX-1877, ER=1.75, P(oct): 5.60x10(-2)). All acetylated hybrids have similar P(oct) values (3.55x10(-2)-1.05x10(-1)) to 1 (TX-1877) and have improved ER values (ER>or=1.47) compared to the hybrids having free hydroxyl groups. Among these, 5 (TX-2244) is the most active radiosensitizer (ER=2.30). We found a good correlation (r=0.866) between the magnitude of P(oct) (logP(oct)) and the ER value of 5 (TX-2244), 6 (TX-2245), 7 (TX-2246), 10 (TX-2243) and 1 (TX-1877), suggesting that increasing the hydrophobicity is reflected in increased in vitro radiosensitizing activity. In the present study, we have succeeded in producing sugar-hybrid hypoxic cell radiosensitizers that have an increased radiosensitizing activity that does not depend on increased hydrophobicity.     

Metal-based new sulfonamides: Design,synthesis, antibacterial,antifungal, and cytotoxic properties

Cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes with 5-chlorosalicyladehyde derived Schiff base sulfonamides have been synthesized and characterized. Structure and bonding nature of all the synthesized compounds have been deduced from physical, analytical, and spectral (IR, ¹H NMR, ¹³C NMR, Mass, electronic) data. An octahedral geometry has been proposed for all the metal complexes. The ligands and their metal complexes have been screened for their in vitro antibacterial, antifungal, and cytotoxic properties and results are reported.     

Synthesis, spectroscopic, cytotoxic, and DNA binding studies of binuclear 2,2'-bipyridine-platinum(II) and -palladium(II) complexes of meso-alpha,alpha'-diaminoadipic and meso-alpha,alpha'-diaminosuberic acids.

Four new binuclear complexes of formula [M2(bipy)2(BAA)]Cl2 (where M is Pt(II) or Pd(II), bipy is 2,2'-bipyridine, and BAA is a dianion of meso-alpha-alpha'-diaminoadipic acid (DAA) or meso-alpha,alpha'-diaminosuberic acid (DSA) have been synthesized. These complexes have been characterized by chemical analysis and ultraviolet-visible, infrared, and 1H NMR spectroscopy. The mode of binding of ligands in these complexes has been ascertained by infrared and detailed 1H NMR spectroscopy. These complexes are 1:2 electrolyte in conductivity water. They have also been tested against P388 lymphocytic leukemia cells and their target is DNA molecules. [Pt2(bipy)2(DSA)]Cl2, [Pd2(bipy)2(DSA)Cl2, and [Pd2(bipy)2(DAA)]Cl2 show I.D.50 values comparable or lower than cis-diamminedichloroplatinum(II) and [Pt(bipy)(Ala)]Cl. In addition, binding studies of [Pt2(bipy)2(DSA)]Cl2 and [Pd2(bipy)2(DAA)]Cl2 to calf thymus DNA have been carried out and the mode of binding seems to be hydrogen bonding, as suggested earlier for analogous mononuclear amino acid-DNA complexes.     

Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease

There is increasing evidence that the consumption of flavonoid-rich foods can beneficially influence normal cognitive function. In addition, a growing number of flavonoids have been shown to inhibit the development of Alzheimer disease (AD)-like pathology and to reverse deficits in cognition in rodent models, suggestive of potential therapeutic utility in dementia. The actions of flavonoid-rich foods (e.g., green tea, blueberry, and cocoa) seem to be mediated by the direct interactions of absorbed flavonoids and their metabolites with a number of cellular and molecular targets. For example, their specific interactions within the ERK and PI3-kinase/Akt signaling pathways, at the level of receptors or kinases, have been shown to increase the expression of neuroprotective and neuromodulatory proteins and increase the number of, and strength of, connections between neurons. Concurrently, their effects on the vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Additional mechanisms have been suggested for the ability of flavonoids to delay the initiation of and/or slow the progression of AD-like pathology and related neurodegenerative disorders, including a potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g., oxidative stress and neuroinflammation) or disrupt amyloid β aggregation and effects on amyloid precursor protein processing through the inhibition of β-secretase (BACE-1) and/or activation of α-secretase (ADAM10). Together, these processes act to maintain the number and quality of synaptic connections in key brain regions and thus flavonoids have the potential to prevent the progression of neurodegenerative pathologies and to promote cognitive performance.     

Volumetric properties for the monosaccharide (D-xylose, D-arabinose, D-glucose, D-galactose)-NaCl-water systems at 298.15 K

Densities have been measured for monosaccharide (D-xylose, D-arabinose, D-glucose and D-galactose)-NaCl-water solutions at 298.15 K. These data have been used to determine the apparent molar volumes of these saccharides and NaCl in the studied solutions. Infinite-dilution apparent molar volumes for the saccharides (V0(phi,S)) in aqueous NaCl and those for NaCl (V0(phi,E)) in aqueous saccharide solutions have been evaluated, together with the standard transfer volumes of the saccharides (delta(t) V0S) from water to aqueous NaCl and of NaCl (delta(t) V0E) from water to aqueous saccharide solutions. It is shown that the delta(t) V0S and delta (t) V0E values are positive and increase with increasing co-solute molalities. Volumetric parameters indicating the interactions of NaCl with saccharides in water have been obtained, respectively, by using transfer volumes of the saccharides and NaCl, and the resulting values are in good agreement with each other within experimental error. The interactions between saccharides and NaCl are discussed in terms of the structural interaction model and the stereochemistry of the saccharide molecules in water.     

Biochemical, structural, genetic, physiological, and pathophysiological features of lipocalin-type prostaglandin D synthase

Lipocalin-type prostaglandin (PG) D synthase (PGDS) catalyzes the isomerization of PGH(2), a common precursor of various prostanoids, to produce PGD(2), a potent endogenous somnogen and nociceptive modulator, in the presence of sulfhydryl compounds. PGDS is an N-glycosylated monomeric protein with an M(r) of 20000-31000 depending on the size of the glycosyl moiety. PGDS is localized in the central nervous system and male genital organs of various mammals and in the human heart and is secreted into the cerebrospinal fluid, seminal plasma, and plasma, respectively, as beta-trace. The PGDS concentrations in these body fluids are useful for the diagnosis of several neurological disorders, dysfunction of sperm formation, and cardiovascular and renal diseases. The cDNA and gene for PGDS have been isolated from several animal species, and the tissue distribution and cellular localization have also been determined. This enzyme is considered to be a dual functional protein; i.e. it acts as a PGD(2)-producing enzyme and also as a lipophilic ligand-binding protein, because the enzyme binds biliverdin, bilirubin (K(d)=30 nM), retinaldehyde, retinoic acid (K(d)=80 nM) with high affinities. X-ray crystallographic analyses revealed that PGDS possesses a beta-barrel structure with a hydrophobic pocket in which an active thiol, Cys(65), the active center for the catalytic reaction, was located facing to the inside of the pocket. Gene-knockout and transgenic mice for PGDS were generated and found to have abnormalities in the regulation of nociception and sleep.     

anti-CRISPR的起源、发展和应用

细菌和古菌等微生物与病毒（噬菌体）之间的生存之战是一场“军备竞赛”。细菌和古菌已经进化出多种先天和适应性的免疫系统来抵御噬菌体的入侵。噬菌体则利用不同的对抗策略来躲避这些噬菌体防御机制。CRISPR-Cas （Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-Associated）系统就是细菌和古菌广泛编码的一种抵御噬菌体等外源遗传元件的获得性免疫系统,与此同时,噬菌体也进化出特异性的anti-CRISPR来抵抗CRISPR-Cas系统的免疫。本文系统综述了anti-CRISPR的发现过程、分类和作用机制,并展望了其潜在的应用。     

Synthesis, characterization, antibacterial and cytotoxic study of platinum (IV) complexes

Platinum (IV) complexes [Pt (L)2Cl2] [where, L= benzyl-N-thiohydrazide (L1), (benzyl-N-thio)-1,3-propanediamine (L2), benzaldehyde-benzyl-N-thiohydrazone (L3) and salicylaldehyde-benzyl-N-thiohydrazone (L4)] have been synthesized. The thiohydrazide, thiodiamine and thiohydrazones can exist as thione-thiol tautomer and coordinate as a bidentate N-S ligand. The ligands were found to act in monobasic bidentate fashion. Analytical data reveal that metal to ligand stoichiometry is 1:2. The complexes have been characterized by elemental analysis, IR, mass, electronic and 1H NMR spectroscopic studies. In vitro antibacterial and cytotoxic studies have been carried out for some complexes. Various kinetic and thermodynamic parameters like order of reaction (n), activation energy (Ea), apparent activation entropy (S#) and heat of reaction (DeltaH) have also been carried out for some complexes.     

New reagents, reactions, and peptidomimetics for drug design.

It has been a major focus in our laboratories to prepare novel reagents and peptidomimetic structures for drug design. We have designed and prepared novel guanidinylation reagents that can be employed in solution or as solid phase reagents. We and others have utilized the reagent 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) for amide bond formation to couple sterically hindered structures. These couplings proceed with remarkably strong resistance to racemization. In the area of peptidomimetics, we have incorporated novel building blocks to create biologically active compounds. These building blocks include thioether and alkylamine bridges, beta-methylated, and beta,beta-dimethylated amino acid residues. These mimetic structures have been incorporated into specific target molecules such as opioids to obtain cyclic peptidomimetics with potent and selective biological activity.     

Emerging lysophospholipid mediators,lysophosphatidylserine, lysophosphatidylthreonine,lysophosphatidylethanolamine and lysophosphatidylglycerol

It is now widely accepted that lysophospholipids (LPLs), a product of the phospholipase A reaction, function as mediators through G-protein-coupled receptors. Notably, recent studies of lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) have revealed their essential roles in vivo. On the other hand, other LPLs such as lysophosphatidylserine (LPS), lysophosphatidylthreonine (LPT), lysophosphatidylethanolamine (LPE), lysophosphatidylinositol (LPI) and lysophosphatidylglycerol (LPG) have been reported to show lipid mediator-like responses both in vivo (LPS and LPT) and in vitro (LPS, LPT, LPE and LPG), while very little is known about their receptor, synthetic enzyme and patho-physiological roles. In this review, we summarize the actions of these LPLs as lipid mediators including LPS, LPT, LPE and LPG.     

Bryozoan frontal shields: the type species of Desmacystis, Rhamphostomella, Rhamphosmittina, Rhamphostomellina, and new genus Arctonula

Frontal shields have been examined in the type species of several genera of ascophorine cheilostomates. Desmacystis (Desmacystidae) is not an'anascan'as previously thought, but has a cryptocystal shield which is here interpreted to be derived from an umbonuloid shield by foreshortening, possibly from a rhamphostomellan ancestor. Rhamphostomella (type species Rscabra ) and Rhamphosmittina (type species R. bassleero ) (both in the family Porellidae Vigneaux, here raised from subfamily rank) also have umbonuloid shields. Arctomula , new genus, is established for Lepralia arctica M. Sars and transferred from the Umbonulidae to the Exochellidac. Rhamphostomellina (type species R. posidoniue ) has a lepralioid shield. It is here included in the family Celleporidae.     

Probing the conformations of eight cloned DNA dodecamers; CGCGAATTCGCG, CGCGTTAACGCG, CGCGTATACGCG, CGCGATATCGCG, CGCAAATTTGCG, CGCTTTAAAGCG, CGCGGATCCGCG and CGCGGTACCGCG.

The self complementary DNA dodecamers d(CGCGAATTCGCG), d(CGCGTTAACGCG), d(CGCGTATACGCG), d(CGCGATATCGCG), d(CGCAAATTTGCG), d(CGCTTTAAAGCG), d(CGCGGATCCGCG) and d(CGCGGTACCGCG) have been cloned into the Smal site of plasmid pUC19. Radiolabelled polylinker fragments containing these inserts have been digested with nucleases and chemical agents, probing the structure of the central AT base pairs. The sequences AATT and AAATTT are relatively resistant to digestion by DNase I, micrococcal nuclease and hydroxyl radicals, consistent with the suggestion that they possess a narrow minor groove. Nuclease digestion of TTAA is much more even, and comparable to that at mixed sequence DNA. TpA steps in ATAT, TATA and GTAC are cut less well by DNAse I than in TTAA. DNasel cleavage of surrounding bases, especially CpG is strongly influenced by the nature of the central sequence.     

Synthesis,Characterization, and Evaluation of Five Coordinated Copper(II) Complexes as Antibacterial,Artificial Nuclease,and Sod Mimics

The copper(II) complexes with ciprofloxacin (CFLH), levofloxacin (LFLH), norfloxacin (NFLH), and neutral bidentate ligands have been synthesized and characterized. The complexes have been evaluated for their antibacterial activity against selective species. Complexes have been also checked for their interacting behavior with DNA, and were found to have two different modes of interaction, classical and partial intercalation. Tested complexes were found to be better antioxidants with their IC₅₀ values ranging from 0.51 to 0.97 μM.     

HTLV-I,infective dermatitis,and tropical spastic paraparesis

Since human T-cell lymphotropic virus (HTLV-I) was identified in 1980 as causing human disease, it has been etiologically associated with adult T-cell lymphoma/leukemia (ATL) and tropical spastic paraparesis (TSP). More recently, several new diseases have been reported in association with this virus, including infective dermatitis of Jamaican children, which we reported in 1990. Studies on infective dermatitis have shown that these children have abnormalities of immune function, and some develop other HTLV-I associated disorders, including TSP. This paper reviews the work done on infective dermatitis to date, and explores the association with TSP.