Unique Ring Research Articles

Operon for biosynthesis of lipstatin, the Beta-lactone inhibitor of human pancreatic lipase.

Lipstatin, isolated from Streptomyces toxytricini as a potent and selective inhibitor of human pancreatic lipase, is a precursor for tetrahydrolipstatin (also known as orlistat, Xenical, and Alli), the only FDA-approved antiobesity medication for long-term use. Lipstatin features a 2-hexyl-3,5-dihydroxy-7,10-hexadecadienoic-β-lactone structure with an N-formyl-l-leucine group attached as an ester to the 5-hydroxy group. It has been suggested that the α-branched 3,5-dihydroxy fatty acid β-lactone moiety of lipstatin in S. toxytricini is derived from Claisen condensation between two fatty acid substrates, which are derived from incomplete oxidative degradation of linoleic acid based on feeding experiments. In this study, we identified a six-gene operon (lst) that was essential for the biosynthesis of lipstatin by large-deletion, complementation, and single-gene knockout experiments. lstA, lstB, and lstC, which encode two β-ketoacyl-acyl carrier protein synthase III homologues and an acyl coenzyme A (acyl-CoA) synthetase homologue, were indicated to be responsible for the generation of the α-branched 3,5-dihydroxy fatty acid backbone. Subsequently, the nonribosomal peptide synthetase (NRPS) gene lstE and the putative formyltransferase gene lstF were involved in decoration of the α-branched 3,5-dihydroxy fatty acid chain with an N-formylated leucine residue. Finally, the 3β-hydroxysteroid dehydrogenase-homologous gene lstD might be responsible for the reduction of the β-keto group of the biosynthetic intermediate, thereby facilitating the formation of the unique β-lactone ring.

ChemInform Abstract: Biomimetic Total Synthesis of (.+‐.)‐Yezo′otogirin A.

The total synthesis of yezo'otogirin A has been achieved via a biosynthetically-inspired strategy. Diastereoselective synthesis of pre-yezo'otogirin A, the proposed biosynthetic pre-cursor of yezo'otogirin A, was accomplished in eight steps from 3-ethoxy-2-cyclohexenone. A biomimetic oxidative radical cyclization was then used to construct the unique tricyclic ring system of yezo'otogirin A. The synthesis showcases the ability of biomimetic radical cyclizations to generate complex natural products from unprotected intermediates.

Triazole-containing monophosphate mRNA cap analogs as effective translation inhibitors.

Synthetic analogs of the 5′ end of mRNA (cap structure) are widely used in molecular studies on mechanisms of cellular processes such as translation, intracellular transport, splicing, and turnover. The best-characterized cap binding protein is translation initiation factor 4E (eIF4E). Recognition of the mRNA cap by eIF4E is a critical, rate-limiting step for efficient translation initiation and is considered a major target for anticancer therapy. Here, we report a facile methodology for the preparation of N2-triazole-containing monophosphate cap analogs and present their biological evaluation as inhibitors of protein synthesis. Five analogs possessing this unique hetero-cyclic ring spaced from the m7-guanine of the cap structure at a distance of one or three carbon atoms and/or additionally substituted by various groups containing the benzene ring were synthesized. All obtained compounds turned out to be effective translation inhibitors with IC50 similar to dinucleotide triphosphate m7GpppG. As these compounds possess a reduced number of phosphate groups and, thereby, a negative charge, which may support their cell penetration, this type of cap analog might be promising in terms of designing new potential therapeutic molecules. In addition, an exemplary dinucleotide from a corresponding mononucleotide containing benzyl substituted 1,2,3-triazole was prepared and examined. The superior inhibitory properties of this analog (10-fold vs. m7GpppG) suggest the usefulness of such compounds for the preparation of mRNA transcripts with high translational activity.

Formation of annular austenitic ring between outer ferrite layer and solid globule in a semi-solid processed SS 304L

The microstructure of an austenitic SS 304L rapidly quenched from its semi-solid state shows a unique annular austenitic ring in between the core of each globule and its ferritic outer layer. On the basis of experimental results and microstructural analysis, it is proposed that the ring is formed as a result of preferential austenitic phase nucleation in a small quantity of liquid entrapped between adjacent solid globules during rapid quenching, in spite of the fact that ferrite is the thermodynamically stable phase for the alloy.

Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice

Multiple sclerosis is a chronic demyelinating disease of the central nervous system leading to progressive cognitive and motor dysfunction, which is characterized by neuroinflammation, demyelination, astrogliosis, loss of oligodendrocytes, and axonal pathologies. Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. In this study, we investigated the effects of cPA on cuprizone-induced demyelination, which is a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, astrocyte and microglial activation, and motor dysfunction. Simultaneous administration of cPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction. These data indicate that cPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis. cPA is a potential lead compound in the development of drugs for the treatment of this devastating disease.

Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: a platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition.

The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein–protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate–catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein–protein interactions.

독창적 반지 설계를 위한 유전자 알고리즘 기반의 변환생성 디자인

독창성은 예술작품 뿐만아니라 장신구, 생활용품 등 다양한 디자인에서 요구된다. 창조적 디자인 작업에 참신한 모티프를 얻기 위해 변환생성 디자인 기법이 활용될 수 있다. 이 논문에서는 유전자 알고리즘을 이용하여 독특한 반지 모델을 만들어 내는 변환생성 디자인 방법을 제안한다. 후보해 표현방법, 연산자, 평가함수 관점에서 제안된 알고리즘에 대해서 소개한다. 제안한 방법은 고객이 자신의 반지 모양에 대한 취향을 선택하도록 하고, 취향을 평가에 반영하도록 하면서 여러 가지 반지 모델을 만들어서 추천하도록 한다. 반지 모델은 3차원 입체로 표현되기 때문에, 고객이 최종적으로 선택한 모델을 3차원 프린터를 통해서 실물로 제작될 수 있다. Creativity is crucial in designing and producing attractive accessaries and daily supplies as well as art works. Generative design can be a paradigm to be used to obtain novel ideas or motifs for creative design works. This paper introduces a generative design method which comes up with unique ring models using genetic algorithm. It presents how the genetic algorithm works in terms of candidate solution coding, operators, and fitness evaluation function. The proposed method allows the customers to express their personal preference and later the preference to be reflected in fitness evaluation. In the final stage of the proposed method, several ring models are suggested for customers to choose on their own. The chosen ring models can be put into physical rings with the help of a 3D printer because the models are expressed in 3D geometric structures.

Cyclic phosphatidic acid and lysophosphatidic acid induce hyaluronic acid synthesis via CREB transcription factor regulation in human skin fibroblasts

Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator and an analog of the growth factor-like phospholipid lysophosphatidic acid (LPA). cPA has a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We showed before that a metabolically stabilized cPA derivative, 2-carba-cPA, relieved osteoarthritis pathogenesis in vivo and induced hyaluronic acid synthesis in human osteoarthritis synoviocytes in vitro. This study focused on hyaluronic acid synthesis in human fibroblasts, which retain moisture and maintain health in the dermis. We investigated the effects of cPA and LPA on hyaluronic acid synthesis in human fibroblasts (NB1RGB cells). Using particle exclusion and enzyme-linked immunosorbent assays, we found that both cPA and LPA dose-dependently induced hyaluronic acid synthesis. We revealed that the expression of hyaluronan synthase 2 messenger RNA and protein is up-regulated by cPA and LPA treatment time dependently. We then characterized the signaling pathways up-regulating hyaluronic acid synthesis mediated by cPA and LPA in NB1RGB cells. Pharmacological inhibition and reporter gene assays revealed that the activation of the LPA receptor LPAR1, Gi/o protein, phosphatidylinositol-3 kinase (PI3K), extracellular-signal-regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding protein (CREB) but not nuclear factor κB induced hyaluronic acid synthesis by the treatment with cPA and LPA in NB1RGB cells. These results demonstrate for the first time that cPA and LPA induce hyaluronic acid synthesis in human skin fibroblasts mainly through the activation of LPAR1-Gi/o followed by the PI3K, ERK, and CREB signaling pathway.

ChemInform Abstract: The Chemistry and Biological Potential of Azetidin‐2‐ones.

AbstractReview: 198 refs.

An orthorhombic polymorph ofN1,N4-diphenyl-3,6-bis(phenylimino)cyclohexa-1,4-diene-1,4-diamine

A new ortho­rhom­bic polymorph of the title compound, C30H24N4, with a density of 1.315 Mg m−3, has been obtained. The mol­ecule is centrosymmetric with the centroid of the cyclo­hexa-1,4-diene ring located on an inversion center. The two unique benzene rings are almost perpendicular to each other [dihedral angle = 86.70 (6)°] and are oriented at dihedral angles of 30.79 (5) and 68.07 (5)° with respect to the central cyclo­hexa­diene ring. In the crystal, π–π stacking is observed between the central cyclo­hexa-1,4-diene-1,4-di­amine unit and a phenyl ring of a neighboring mol­ecule [centroid–centroid distance = 3.7043 (7) Å]. The crystal structure of the triclinic polymorph [Ohno et al. (2014 ▶). Acta Cryst. E70, o303–o304] showed chains running along the b-axis direction through weak C—H⋯π inter­actions.

Jiadifenlactone A, a novel diseco-prezizaane-type sesquiterpenoid from the fruits of Illicium jiadifengpi

Jiadifenlactone A (1), the first example of cleavage of bond [4, 9] of the seco-prezizaane-type sesquiterpenoid with a unique 9-membered ring moiety, together with its biosynthetic related compound 2, were isolated from the fruits of Illicium jiadifengpi. The structure of 1 and its relative configuration were determined by spectroscopic methods and single-crystal X-ray diffraction analysis. The inhibitory rates of compound 1 on the HBeAg and HBsAg expressions were 37.91±2.78% and 17.21±3.78%, respectively.

The Beginning of Metallurgy in the Southern Levant: A Late 6th Millennium CalBC Copper Awl from Tel Tsaf, Israel

The beginning of metallurgy in the ancient Near East attracts much attention. The southern Levant, with the rich assemblage of copper artifacts from the Nahal Mishmar cave and the unique gold rings of the Nahal Qanah cave, is regarded as a main center of early metallurgy during the second half of the 5th millennium CalBC. However, a recently discovered copper awl from a Middle Chalcolithic burial at Tel Tsaf, Jordan Valley, Israel, suggests that cast metal technology was introduced to the region as early as the late 6th millennium CalBC. This paper examines the chemical composition of this item and reviews its context. The results indicate that it was exported from a distant source, probably in the Caucasus, and that the location where it was found is indicative of the social status of the buried individual. This rare finding indicates that metallurgy was first defused to the southern Levant through exchange networks and only centuries later involved local production. This copper awl, the earliest metal artifact found in the southern Levant, indicates that the elaborate Late Chalcolithic metallurgy developed from a more ancient tradition.

Synthesis and biological activity of Citridone A and its derivatives

Citridone A (1), originally isolated as a potentiator of antifungal miconazole activity from a fungal culture broth, has a phenyl-R-furopyridone structure. Because of its unique ring structure, 11 derivatives were chemically synthesized and their biological activity was evaluated. Derivatives 17, 20 and 21 potentiated miconazole activity against Candida albicans. Furthermore, 1, 14, 20 and 21 were found to inhibit yellow pigment production in methicillin-resistant Staphylococcus aureus.

Synthesis and DNA Cleavage Activity of Bis‐3‐chloropiperidines as Alkylating Agents

Nitrogen mustards are an important class of bifunctional alkylating agents routinely used in chemotherapy. They react with DNA as electrophiles through the formation of highly reactive aziridinium ion intermediates. The antibiotic 593A, with potential antitumor activity, can be considered a naturally occurring piperidine mustard containing a unique 3-chloropiperidine ring. However, the total synthesis of this antibiotic proved to be rather challenging. With the aim of designing simplified analogues of this natural product, we developed an efficient bidirectional synthetic route to bis-3-chloropiperidines joined by flexible, conformationally restricted, or rigid diamine linkers. The key step involves an iodide-catalyzed double cyclization of unsaturated bis-N-chloroamines to simultaneously generate both piperidine rings. Herein we describe the synthesis and subsequent evaluation of a series of novel nitrogen-bridged bis-3-chloropiperidines, enabling the study of the impact of the linker structure on DNA alkylation properties. Our studies reveal that the synthesized compounds possess DNA alkylating abilities and induce strand cleavage, with a strong preference for guanine residues.

Efficient ring perception for the Chemistry Development Kit

BackgroundThe Chemistry Development Kit (CDK) is an open source Java library for manipulating and processing chemical information. A key aspect in handling chemical structures is the determination of the chemical rings. The rings of a structure are used areas including descriptors, stereochemistry, similarity, screening and atom typing. The CDK includes multiple algorithms for determining the rings of a structure on demand. Non-unique descriptions of rings were often used due to the slower performance of the unique alternatives.ResultsEfficient algorithms for handling chemical ring perception have been implemented and optimised in the CDK. The algorithms provide much faster computation of new and existing types of rings. Several optimisation and implementation considerations are discussed which improve real case usage. The performance is measured on several publicly available data sets and in several cases the new implementations were found to be more than an order of magnitude faster.ConclusionsAlgorithmic improvements allow handling of much larger datasets in reasonable time. Faster computation allows more appropriate rings to be utilised in procedures such as aromaticity. Several areas that require ring perception have also seen a noticeable improvement. The time taken to compute the unique rings is now comparable allowing a correct usage throughout the toolkit. All source code is open source and freely available.

The chemistry and biological potential of azetidin-2-ones

Azetidin-2-ones, commonly referred as β-lactams, represent a unique ring system, with interesting chemistry and great biological potential. Besides its well known antibiotic activity, this ring system exhibits a wide range of activities, attracting the attention of researchers. The biological and pharmacological profile of azetidin-2-ones is reviewed here comprehensively with several examples under fourteen different activity heads. The chemistry and methods of synthesis have also been discussed.

Cyclic phosphatidic acid relieves osteoarthritis symptoms.

BackgroundCyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. Natural cPA and its chemically stabilized cPA derivative, 2-carba-cPA (2ccPA), inhibit chronic and acute inflammation, and 2ccPA attenuates neuropathic pain. Osteoarthritis (OA) is a degenerative disease frequently associated with symptoms such as inflammation and joint pain. Because 2ccPA has obvious antinociceptive activity, we hypothesized that 2ccPA might relieve the pain caused by OA. We aimed to characterize the effects of 2ccPA on the pathogenesis of OA induced by total meniscectomy in the rabbit knee joint.ResultsIntra-articular injection of 2ccPA (twice a week for 42 days) significantly reduced pain and articular swelling. Histopathology showed that 2ccPA suppressed cartilage degeneration in OA. We also examined the effects of 2ccPA on the inflammatory and catabolic responses of human OA synoviocytes and chondrosarcoma SW1353 cells in vitro. 2ccPA stimulated synthesis of hyaluronic acid and suppressed production of the metalloproteinases MMP-1, -3, and -13. However, it had no effect on the production of interleukin (IL)-6, an inflammatory cytokine. The suppressive effect of 2ccPA on MMP-1 and -3 production in synoviocytes and on MMP-13 production in SW1353 cells was not mediated by the lysophosphatidic acid receptor, LPA1 receptor (LPA1R).ConclusionsOur results suggest that 2ccPA significantly reduces the pain response to OA by inducing hyaluronic acid production and suppressing MMP-1, -3, and -13 production in synoviocytes and chondrocytes.

A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors

The first-in-human phase 1 trial examined the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic profile, and antitumor activity of TLC388, a novel camptothecin with a unique lactone ring modification, in patients with advanced solid tumors. TLC388 was administered intravenously to patients with metastatic chemotherapy refractory solid tumors on days 1, 8, and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8, and 15 of cycles 1 and 2. Fifty-four patients were enrolled at doses ranging from 1.5 to 60.0 mg/m(2) over 12 cohorts. Treatment was generally well-tolerated and no cumulative toxicity observed. Two of six patients treated at 60.0 mg/m(2) developed DLTs of grade 3 neutropenia causing dose delay and grade 3 febrile neutropenia. The next lower dose, 50.0 mg/m(2), was declared as MTD. Treatment-related grade 3-4 hematologic toxicities included neutropenia (19 %), leukopenia (15 %), anemia (9 %), and thrombocytopenia (7 %). Grade 3-4 nonhematologic toxicities included diarrhea (2 %) and hyponatremia (4 %). Pharmacokinetics of both diastereomers (S,R and S,S) of TLC388, a mixture of two diastereomers, was dose independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m(2) for S,R and 996 (1333) L/m(2) for S,S, and 2174 (2526) L/h-m(2) for S,R and 2670 (2988) L/h-m(2) for S,S, respectively. The half-life values averaged 0.67 (1.15) hours for S,R and 0.64 (1.11) hours for S,S. The best overall response was stable disease in 21 (39 %) patients. Prolonged (≥ 6 months) stable disease was noted in eight patients. TLC388 at 50 mg/m(2) on the current treatment schedule is generally safe and well tolerated.

On Approximating the Translational Velocity of Vortex Rings

A method is presented whereby the translational velocity of a vortex ring can be approximated from the total circulation, impulse, and kinetic energy of the vortex system. Assuming a uniform vorticity density, these bulk quantities define a unique stable vortex ring configuration, and the translational velocity can be inferred from this configuration and the system scaling. Here, the accuracy of this approximation is presented for vortex rings formed from starting jets, and the translational velocity is also characterized as it relates to the driving parameters. The translational velocity is well approximated for a wide range of experimentally generated vortex rings. It is observed that starting jets with a converging radial velocity create vortex rings with a significantly higher translational velocity. The converging radial velocity was observed to increase translational velocity by as much as 30% over parallel jet flows with identical volume flux and nozzle diameter, but the exact increase is specific to the nozzle arrangement and driving conditions.

Classification of factorial generalized down–up algebras

We determine when a generalized down–up algebra is a Noetherian unique factorisation domain or a Noetherian unique factorisation ring.