Interaction between 3-(p-tolylamino)-1,5-azulenequinone and the deoxyguanosine residue in various oligonucleotides upon photolysis.

Eight single-stranded oligodeoxyribonucleotides 32P-labeled at the 5'-end were synthesized; they were annealed with the complementary oligodeoxyribonucleotides to form the corresponding double-stranded helices. These duplexes possessed standard Watson-Crick base pairs, locally perturbed sites of a base mismatch, or a bulge. Further, 5'-32P-labeled oligodeoxyribonucleotides with a hairpin loop were also synthesized. Cleavage of these single- and double-stranded oligodexyribonucleotides selectively at the deoxyguanosine residue was accomplished by use of 3-(p-tolylamino)-1,5-azulenequinone 1 upon irradiation with 350 nm UV light. The single strands were cleaved more efficiently than the double-helices. For the helices containing a deoxyguanosine residue at a bulge, at a hairpin loop or toward the end, the cleaving efficiency was increased. Computation results indicate that two possibilities exist for agent 1 to form two "Watson-Crick type" hydrogen bonds with guanine in single-stranded oligodeoxyribonucleotides; yet, only one possibility exists in duplexes.

Design, synthesis, and SAR of novel carbapenem antibiotics with high stability to Xanthomonas maltophilia oxyiminocephalosporinase type II.

Racemic cis-6-(phenylacetamido)carbapenem (21), 2-hydroxycarbonyl-cis-6-(phenylacetamido)carbapenem (22), 2-methoxycarbonyl-cis-6-(phenylacetamido)carbapenem (30), 2-methoxycarbomethyl-cis-6-(phenylacetamido)carbapenem (33), 2-hydroxyethyl-cis-6-(phenylacetamido)carbapenem (34), and 2-acetoxyethyl-cis-6-(phenylacetamido)carbapenem (35) were synthesized. Formation of the carbapenem nuclei in 21, 22, and 30 involved dehydrophosphonation of the corresponding 2-diphenylphosphono-6-(phenylacetamido)carbapenam precursors 14, 15, and 28 using trimethylsilyl triflate and 1,8-diazabicyclo[5.4.0]undec-7-ene in THF. Syntheses of carbapenems 33-35 involved a Wittig reaction of carbapenam 14 with methyl glyoxylate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. For the antibacterial activities against Staphylococcus aureus FDA 209P, S. aureus 95, Escherichia coli ATCC 39188, Klebsiellapneumoniae NCTC 418, Pseudomonas aeruginosa 1101-75, and P. aeruginosa 18S-H, carbapenems (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 were found comparable with imipenem ((+)-3), yet they were notably more potent than (+)-3 against Xanthomonas maltophilia GN 12873. On the other hand, unlike (+)-3, carbapenems (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 were stable to X. maltophilia oxyiminocephalosporinase type II. Their beta-lactamase inhibitory properties, however, were found to be more comparable with those of penicillin G ((+)-4) than to those of imipenem ((+)-3). A combination of imipenem ((+)-3) with (+/-)-21, (+/-)-22, (+/-)-30, and (+/-)-33-35 resulted in synergistic antibacterial activity against X. maltophilia GN 12873. Results from the biological tests were correlated with the distribution of the electron density at C(2)=C(3) of carbapenems upon reaction with transpeptidases or beta-lactamases.

Enthalpy and enzyme activity of modified histidine residues of adenosine deaminase and diethyl pyrocarbonate complexes.

Kinetic and thermodynamic studies have been made on the effect of diethyl pyrocarbonate as a histidine modifier on the active site of adenosine deaminase in 50 mM sodium phosphate buffer pH 6.8, at 27 degrees C using UV spectrophotometry and isothermal titration calorimetry (ITC). Inactivation of adenosine deaminase by diethyl pyrocarbonate is correlated with modification of histidyl residues. The number of modified histidine residues complexed to active site of adenosine deaminase are equivalent to 4. The number and energy of histidine binding sets are determined by enthalpy curve, which represents triple stages. These stages are composed of 3,1 and 1 sites of histidyl modified residues at diethyl pyrocarbonate concentrations, 0.63, 1.8, 3.3 mM. The heat contents corresponding to the first, second and third sets are found to be 18000, 22000 and 21900 kJ mol(-1) respectively.

Syntheses of new isodethiaazacephems as potent antibacterial agents.

New isodethiaazacephems (+/-)-3, (+/-)-4, and (+/-)-10 as well as the 4-sulfonylated isodethiaazacepham (+/-)-5 were synthesized by chemical methods and found to possess biological activity against five pathogenic microorganisms in vitro. The mesylate and the triflate functionalities in (+/-)-3 and (+/-)-4, acting as effective leaving groups, enhanced remarkably the biological activity in comparison with the parent 3-hydroxyisodethiaazacephem (+/-)-10. The mode of action related to (+/-)-3 and (+/-)-4 can be explained by a [1,4]-elimination process.

Cephalosporin 3'-phloroglucide esters and 7-(phloroglucidamido) cephalosporins as novel antibacterial agents.

Two series of new phloroglucide derivatives were synthesized that possessed antibacterial activities. The first series includes cephalosporin 3'-phloroglucide esters 19 and 20, which were obtained by condensation of cephalosporin 16 with bioactive phloroglucides 14 and 15, respectively. They exhibited a dual mode of antibacterial action. In comparison with cephalosporins 26 and 27, bearing an acetoxy unit at the C-3' position, the bifunctional cephalosporins 19 and 20 showed a broadened spectrum of activity. Results from the consistent valence force field (CVFF) calculations indicate that the most stable conformational isomer of phenolic acid 14, holding a cis-syn-syn geometry, possessed a cavity. It provides an ideal environment to accommodate metal ions of holoenzymes. Phenolic keto acid 15, however, possessed a trans-anti-syn conformation, which allowed chelation between metal ions and the phenolic hydroxyl groups as well as the carbonyl functionalities. Our biological results show that the cavity formed in phloroglucides plays an important role. The second series includes 7-(phloroglucidamido)cephalosporins 24 and 25, which were synthesized by condensation of cephalosporin 21 with 14 and 15, respectively. Results from the CVFF calculations indicate that cephalosporin 24 also possessed a cavity. Unlike cephalosporin 3'-phloroglucide esters 19 and 20, cephalosporins 24 and 25 were found resistant to beta-lactamases from Staphylococcus aureus 95 and Pseudomonas aeruginosa 18S-H. These new compounds, however, showed notable activities against S. aureus FDA 209P, S. aureus 95, Candida albicans, P. aeruginosa 1101-75, and P. aeruginosa 18S-H.

Synthesis and biological evaluation of an electronically activated isooxacephem.

New isooxacephem (+/-)-3-ethyl 2-hydrogen (6RS,7RS)-8-oxo-7-(phenylacetamido)-4-oxa-1-azabicyclo [4.2.0]oct-2-ene-2, 3-dicarboxylate (8) was synthesized from (+/-)-dibenzyl 2-[cis-2-oxo-3-(phenylacetamido)-4-styryl-1-azetidinyl]-2-[t- butyldimethylsiloxy(methoxycarbonyl)methyl]malonate (1) in six steps. This bicyclic beta-lactam was found to possess notable biological activities against several pathogenic microorganisms in vitro, including Staphylococcus aureus 95, S. aureus FDA 209P, Escherichia coli ATCC 39188, Salmonella typhi O-901, Pseudomonas aeruginosa 18S-H, P. aeruginosa 1101-75, and Klebsiella pneumoniae NCTC 418. The electronic activation of the beta-lactam moiety by an ester group plays a prominent role in the biological activity of this novel isooxacephem.

Design, synthesis, and structure-activity relationship of novel dinucleotide analogs as agents against herpes and human immunodeficiency viruses.

A new acyclic nucleoside phosphonate (13) containing an adenine moiety was synthesized, which acted as an excellent inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows it to exert great synergistic effect on certain antiviral agents (e.g., ara-A, 37). Phosphonate 13 was not phosphorylated by the bovine brain guanylate kinase nor by 5-phosphoribosyl 1-pyrophosphate synthetase. Syntheses of biologically active nucleotide phosphonate 40 and its phosphonoamidate derivative 42 were accomplished, which showed remarkable activity against herpes viruses and exhibited low host cell toxicity. 3'-Azido-nucleoside phosphonate 20 and 3'-fluoronucleoside phosphonate 32, as well as the corresponding dinucleotide analogs 47 and 48, and their respective phosphonoamidates 53-56 were also synthesized as new compounds, among which phosphonoamidates 53-56 showed potent activity against human immunodeficiency virus. Phosphonoamidates 55 and 56 bearing a methyl D-alaninate moiety exhibited less cellular toxicity than 53 and 54 bearing a methyl L-alaninate moiety. Nucleotide phosphonate 40 as well as dinucleotide phosphonates 47 and 48 were found susceptible to degradation by phosphodiesterases. Their respective phosphonoamidates 42 and 53-56, however, were completely resistant to snake venom and spleen enzymes.

Transverse holographic optical interconnect design.

The design of A new type of planar optical interconnect, the transverse holographic waveguide, is described. With this type of interconnect a one-dimensional input light distribution is converted into a one-dimensional output light distribution by holographic patterning along the direction of the optical wave propagation.

Designed enediynes: a new class of DNA-cleaving molecules with potent and selective anticancer activity.

The rational design and biological actions of a new class of DNA-cleaving molecules with potent and selective anticancer activity are reported. These relatively simple enediyne-type compounds were designed from basic chemical principles to mimic the actions of the rather complex naturally occurring enediyne anticancer antibiotics, particularly dynemicin A. Equipped with locking and triggering devices, these compounds damage DNA in vitro and in vivo on activation by chemical or biological means. Their damaging effects are manifested in potent anticancer activity with remarkable selectivities. Their mechanism of action involves intracellular unlocking and triggering of a Bergman reaction, leading to highly reactive benzenoid diradicals that cause severe DNA damage. The results of these studies demonstrate the potential of these de novo designed molecules as biotechnology tools and anticancer agents.

Numerically stable algorithm for discrete-ordinate-method radiative transfer in multiple scattering and emitting layered media.

We summarize an advanced, thoroughly documented, and quite general purpose discrete ordinate algorithm for time-independent transfer calculations in vertically inhomogeneous, nonisothermal, plane-parallel media. Atmospheric applications ranging from the UV to the radar region of the electromagnetic spectrum are possible. The physical processes included are thermal emission, scattering, absorption, and bidirectional reflection and emission at the lower boundary. The medium may be forced at the top boundary by parallel or diffuse radiation and by internal and boundary thermal sources as well. We provide a brief account of the theoretical basis as well as a discussion of the numerical implementation of the theory. The recent advances made by ourselves and our collaborators-advances in both formulation and numerical solution-are all incorporated in the algorithm. Prominent among these advances are the complete conquest of two illconditioning problems which afflicted all previous discrete ordinate implementations: (1) the computation of eigenvalues and eigenvectors and (2) the inversion of the matrix determining the constants of integration. Copies of the FORTRAN program on microcomputer diskettes are available for interested users.