Stereochemistry and reactivity of the HPA-imine Mannich intermediate

Homophthalic anhydride (HPA) typically reacts rapidly with benzalimines to afford the formal [4+2] adduct, a 1,2,3,4-tetrahydroisoquinolin-1-one-4-carboxylic acid. The stereochemical outcome of this reaction is consistent with an open transition state comprising an iminium species and enolized HPA, leading to a short-lived amino-anhydride intermediate. In the case of N-tert-butylbenzalimine, this Mannich-type intermediate, which would normally cyclize at low temperature to a single isomer of the delta-lactam, is intercepted by base treatment to afford beta-lactam products. A pathway featuring ketene formation followed by ring closure is implicated.     

Design,synthesis, antitubercular and antibacterial activities of pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives and in silico docking studies

Abstract

A novel series pyrrolo[3,2-b]pyridine-3-carboxamide linked 2-methoxypyridine derivatives have been designed, synthesized and confirmed by FT-IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR, MS, and elemental analysis. The synthesized compounds were screened for their antitubercular activity using microplate alamar blue assay method and antibacterial activity. Among the tested compounds, 4- fluorophenyl (8m), 4- chlorophenyl (8n) and 4-methoxyphenyl (8i) showed potent anti-TB activity (3.12?µg/mL) in comparison with reference drug, Pyrazinamide ((3.12?µg/mL). In addition, all compounds were docked into DprE1 (PDB code: 4KW5) to explore their binding interactions at the active site. The compounds exhibited essential key interactions as that of reported DprE1 inhibitors and hence, the synthesized compounds may be considered as molecular scaffolds for antitubercular activity. Compounds, 4-chlorophenyl (8n) and 4-flurophenyl (8m) showed significant antibacterial activity against Escherichia coli and Staphylococcus aureus strains. In silico prediction of toxicities, druglikeness and drug score profiles of the tested compounds are promising.     

Ultra-performance liquid chromatographic determination of manufacturing intermediates and subsidiary colors in D&C Red No. 34 and its lakes

An ultra-performance liquid chromatography (UPLC) method was developed to determine the manufacturing intermediates and subsidiary colors in the monosulfo monoazo color additive D&C Red No. 34 and its lakes. This method is currently used for batch certification of the color additives by the U.S. Food and Drug Administration to ensure that each lot meets published specifications for coloring drugs and cosmetics. The new UPLC method has replaced an HPLC method for determining the intermediates and a TLC method for determining the subsidiary colors. The intermediates are 2-amino-1-naphthalenesulfonic acid (Tobias acid) and 3-hydroxy-2-naphthalenecarboxylic acid (3-hydroxy-2-naphthoic acid). Subsidiary colors are positional isomers of the major dye component or related compounds containing lower numbers of substituent groups. The analytes are identified by comparison of their UPLC retention times and UV or visible absorption spectra with those of standards. Validation studies showed that peak area calibrations for the analytes were generally linear (R > 0.999), and recoveries were 98-103%. The LODs were 0.002-0.02%, and the RSDs at the specification levels were 0.7-2.2%. Survey analyses of 12 samples of certified D&C Red No. 34 straight colors and lakes from six domestic and foreign manufacturers yielded results for the intermediates by UPLC and HPLC that were consistent within experimental error. The UPLC analyses yielded results for the subsidiary colors that were consistently lower than results previously obtained by TLC, which we attribute to limitations of the TLC method. The new UPLC method provides sharper peaks, better peak separation, and faster analysis times than the formerly used HPLC method and is more accurate, much faster, and much less labor-intensive than the formerly used TLC method.     

新型BrФnsted酸性离子液体的合成与表征

制备了五种对水稳定性好、带-SO3H官能团的磺酸类BrФnsted酸离子液体,用核磁共振(NMR)、红外光谱(IR)、电喷雾质谱(ESI-MS)、热重分析(TG)等表征手段对制备的离子液体进行了表征。结果表明,制备的离子液体与预期设计的结构一致,离子液体纯度大于95%;热重分析发现离子液体具有高的热稳定性和较宽的液态范围,其分解温度均高于300℃;五种离子液体均存在四种离子存在形式,H 可以单独以离子形式存在,并不是通常所认为的仅有两种离子存在形式。另外,研究了离子液体在常用溶剂中的溶解性,发现制备的离子液体易溶于水、甲醇,不溶于乙醚、甲苯和乙酸乙酯。     

Ultrasound-triggered drug targeting of tumors in vitro and in vivo

The new modality of drug targeting of tumors that we are currently developing is based on drug encapsulation in polymeric micelles, followed by the localized release at the tumor site triggered by focused ultrasound. The rationale behind this approach is that drug encapsulation in micelles decreases systemic concentration of drug, diminishes intracellular drug uptake by normal cells, and provides passive drug targeting of tumors, thus reducing unwanted drug interactions with healthy tissues. Ultrasound irradiation is used to release drug from micelles at the tumor site and to enhance the intracellular drug uptake by tumor cells. An important advantage of ultrasound is that it is noninvasive, can penetrate deep into the interior of the body, can be focused and carefully controlled. Here we describe factors involved in the ultrasound interaction with viable cells in the absence and presence of drug carriers and anti-cancer drugs. We present in vivo effects of 1 MHz ultrasound on drug biodistribution, intratumoral distribution, and survival rates of immuno-compromised athymic nu/nu mice bearing ovarian carcinoma tumors.     

Unifying the Aminohexopyranose‐ and Peptidyl‐Nucleoside Antibiotics: Implications for Antibiotic Design

In search of new anti‐tuberculars compatible with anti‐retroviral therapy we re‐identified amicetin as a lead compound. Amicetin's binding to the 70S ribosomal subunit of Thermus thermophilus (Tth) has been unambiguously determined by crystallography and reveals it to occupy the peptidyl transferase center P‐site of the ribosome. The amicetin binding site overlaps significantly with that of the well‐known protein synthesis inhibitor balsticidin S. Amicetin, however, is the first compound structurally characterized to bind to the P‐site with demonstrated selectivity for the inhibition of prokaryotic translation. The natural product‐ribosome structure enabled the synthesis of simplified analogues that retained both potency and selectivity for the inhibition of prokaryotic translation.     

Unifying the Aminohexopyranose- and Peptidyl-Nucleoside Antibiotics: Implications for Antibiotic Design

In search of new anti-tuberculars compatible with anti-retroviral therapy we re-identified amicetin as a lead compound. Amicetin's binding to the 70S ribosomal subunit of Thermus thermophilus (Tth) has been unambiguously determined by crystallography and reveals it to occupy the peptidyl transferase center P-site of the ribosome. The amicetin binding site overlaps significantly with that of the well-known protein synthesis inhibitor balsticidin S. Amicetin, however, is the first compound structurally characterized to bind to the P-site with demonstrated selectivity for the inhibition of prokaryotic translation. The natural product-ribosome structure enabled the synthesis of simplified analogues that retained both potency and selectivity for the inhibition of prokaryotic translation.     

Wave reflections from slotted tunnel portals

Various modifications to tunnel portals may be employed to reduce the sudden pressure jump which occurs as a train passes through the entrance or exit. Tunnel entrance gives rise to pressure waves which may travel down the length of the tunnel and reflect back to cause ear discomfort to the passengers. Various distortions are introduced to the shape of these waves if they reflect off a modified tunnel portal. A linearized analysis of a pressure impulse and a pressure step reflecting off a portal consisting of a long slotted section is presented. A closed-form solution is obtained. It is shown in both cases that the infinitely steep rise of the incident wave is reflected as a pressure rise of finite slope, and the pressure amplitude may exceed that of the input for some points in time. The apparent mass of flow through a narrow slot is calculated. It is shown that the magnitude of pressure waves produced by tunnel entry may be sufficiently large that significant non-linear acoustic effects may be present.     

Theoretical study of the gas-phase Fe(CO)5 catalyzed water gas shift reaction: a new mechanism proposed

A novel mechanism for the gas-phase Fe(CO)(5) and base catalyzed water gas shift reaction has been examined. The reaction pathway described here is predicted at the B3LYP/6-31++G(d,p) level to be energetically competitive with the classic mechanism. The reaction path explored here involves the energetically barrierless formation of (CO)(4)FeCOOH(-) (the catalyst of the system) decarboxylation induced by the addition of CO to give (CO)(4)FeCHO, and evolution of H(2) upon addition of H(2)O to the (CO)(4)FeCHO intermediate. The energetic barriers predicted for the last two steps are 21.2 and 42.0 kcal/mol, respectively, using the B3LYP method.