Ring-fused Analogues Research Articles

Theoretical insight on model linear oligomers and their ring-fused analogs used in organic electronics

Theoretical systematic study compares chemical and electronic structure of six series of linear aromatic oligomers and their ring-fused analogues with various chain length of 5- and 6-membered rings. Chemical structure was described by structural HOMED and one-electron density topology EL aromaticity descriptors. The calculations demonstrated that the diradical electronic ground-state system is energetically preferred for larger six-membered acenes where the electronic structure can be separated into two linear polyene chains. The influence of intermolecular interaction on the aromaticity perturbation in crystals was also analyzed for 20 available X-ray structures. The aromaticity of central ring is lowered for longer molecules in solids. Next, the primary effect of aromatic chain elongation on frontier orbital energies and vertical excitation energies was predicted. The calculated data were correlated with experimental ones and polymer limits on investigated properties were estimated. Quantitative criteria of aromaticity were explored for various linear organic molecules with increasing chain lengths to extrapolate electronic properties at the polymer limit. • Systematic DFT study of linear oligomers and ring-fused analogues. • The aromaticity indices are evaluated. • The structural conditions for diradical system are determined. • Electrochemical band gaps and optical transitions are calculated. • Polymer limits on investigated properties are estimated.

Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of cardiovascular disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (QH536) showed an EC50 of 0.22 μΜ in promoting HMGCR degradation, which was about 2 times more potent than HMG499 (EC50 = 0.43 μM). Interestingly, 29 was different from HMG499, it had no side-effect of inducing cholesterol accumulation in cells. Mechanistic studies disclosed that 29 could significantly decrease statin-induced accumulation of HMGCR protein via ubiquitination and degradation of HMGCR through ubiquitin-proteasome pathway and inhibit the cholesterol biosynthesis in cells. Therefore, these heterocyclic ring-fused analogs could be used as promising leads for the development of new types of agents against CVD. Furthermore, 29 also lowered cholesterol levels and suppressed TGFβ1-induced proliferation of LX-2 hepatic stellate cells in a dose-dependent manner. In particular, 29 not only decreased the NASH associated fibrotic mRNA and protein expression of α-SMA, COL1A1, TIMP1 and TGFβ1 but also suppressed cholesterol levels and inflammatory genes of TNF-α, IL-6 an IL-1β in RAW264.7 macrophage cells, indicating that 29 may bring therapeutic benefit to treat NASH.

Impact of molecular chain length on polarizabilities of model acenes and oligomers

Abstract A systematic quantum chemical study of model linear oligomers and their ring-fused (condensed) analogues based on six-membered and five-membered aromatic units is presented. Static electric polarizabilities were calculated for optimal geometries. The dependence of electronic and vibrational polarizability contributions on the molecular size was discussed and polymer limits were estimated. The presence of a diradical electronic structure in fused six-membered compounds significantly increases the polarizability values.

Sulfonamide-based ring-fused analogues for CAN508 as novel carbonic anhydrase inhibitors endowed with antitumor activity: Design, synthesis, and in vitro biological evaluation

In the present study, we report the design and synthesis of novel CAN508 sulfonamide-based analogues (4, 8a-e, 9a-h and 10a-e) as novel carbonic anhydrase (CA) inhibitors with potential CDK inhibitory activity. A bioisosteric replacement approach was adopted to replace the phenolic OH of CAN508 with a sulfamoyl group to afford compound 4. Thereafter, a ring-fusion approach was utilized to furnish the 5/5 fused imidazopyrazoles 8a-e which were subsequently expanded to 6/5 pyrazolopyrimidines 9a-h and 10a-e. All the synthesized analogues were evaluated for their inhibitory activity toward isoforms hCA I, II, IX and XII. The target tumor-associated isoforms hCA IX and XII were effectively inhibited with KIs ranges 6–67.6 and 10.1–88.6 nM, respectively. Furthermore, all compounds were evaluated for their potential CDK2 and 9 inhibitory activities. Pyrazolopyrimidines 9d, 9e and 10b displayed weak CDK2 inhibitory activity (IC50 = 6.4, 8.0 and 11.6 μM, respectively), along with abolished CDK9 inhibitory activity. This trend suggested that pyrazolopyrimidine derivatives merit further optimization to furnish more effective CDK2 inhibitor lead. On account of their excellent activity and selectivity towards hCA IX and XII, pyrazolopyrimidines 10 were evaluated for their anti-proliferative activity toward breast cancer MCF-7 and MDA-MB-468 cell lines under normoxic and hypoxic conditions. The most potent anti-proliferative agents 10a, 10c and 10d significantly increased cell percentage at sub-G1 and G2-M phases with concomitant decrease in the S phase population in MCF-7 treated cells. Finally, a docking study was undertaken to investigate the binding mode for the most selective hCA IX and XII inhibitors 10a-e, within hCA II, IX and XII active sites.

Exploiting Hydrazones To Improve the Efficiency of 6π-Electrocyclization Reactions of 1-Azatrienes.

The greater geometric lability of hydrazones compared to that of oxime ethers is used as a basis to overcome the reluctance of Z-oxime ether azatrienes to undergo electrocyclization toward the synthesis of borylated (heteroaromatic) pyridines and ring-fused analogues. Such hydrazones now allow access to previously inaccessible tri- and tetrasubstituted 3-borylpyridines in high yields.

Tweaking the Molecular Geometry of a Tetraperylenediimide Acceptor.

Partial flattening of the spatially extended molecular scaffold has been employed as an effective tactic to improve the device performance of a perylenediimide (PDI)-based small-molecule acceptor because the less twisted yet not completely planar molecular geometry is anticipated to improve the molecular packing and thereby attain a more suitable balance between the carrier transport ability and phase domain size. A small-molecule acceptor BF-PDI comprising four α-substituted PDI units attached around a 9,9'-bifluorenylidene (BF) central moiety is designed and studied in polymer solar cells. The BF group is deemed a ring-fused analogue of the tetraphenylethylene (TPE) unit. Due to the less twisted and better conjugated BF skeleton, BF-PDI displays more delocalized lowest unoccupied molecular orbital. By virtue of both the electronic and steric effects, BF-PDI is suggested to bring about superior intermolecular stacking and donor-acceptor phase separation morphology in blend films. Indeed, the experimental results show that BF-PDI displays improved charge transport ability and a higher power-conversion efficiency of 8.05% than that of TPE-PDI. Grazing-incidence wide-angle X-ray diffraction and resonant soft X-ray scattering confirm the more compact and ordered molecular packing as well as smaller domain sizes in the P3TEA/BF-PDI blend.

Greener synthesis using hydrogen peroxide in ethyl acetate of alicyclic ring-fused benzimidazoles and anti-tumour benzimidazolequinones

Environmentally-friendly and cost effective hydrogen peroxide in ethyl acetate was used to prepare in high yields pyrrolo[1,2-a]benzimidazoles from commercial o-(pyrrolidin-1-yl)anilines without the requirement for organic-aqueous extraction and chromatography. Six, seven and eight membered ring-fused analogues were similarly obtained in high yields with methanesulfonic acid required for the pyrido[1,2-a]benzimidazole. Anti-tumour benzimidazolequinone derivatives were obtained in high yield via the cyclization of 3,6-dimethoxy-2-(cycloamino)anilines.

Benzoyl Ring Halogenated Classical 2-Amino-6-methyl-3,4-dihydro-4-oxo-5-substituted Thiobenzoyl-7H-pyrrolo[2,3-d]pyrimidine Antifolates as Inhibitors of Thymidylate Synthase and as Antitumor Agents

In an attempt to circumvent resistance to and toxicity of clinically used folate-based thymidylate synthase (TS) inhibitors that require folylpoly-gamma-glutamate synthetase (FPGS) for their antitumor activity, we designed and synthesized two classical 6-5 ring-fused analogues, N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]-2'-fluorobenzoyl]-l-glutamic acid (4) and N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio]-2'-chlorobenzoyl]-l-glutamic acid (5), as TS inhibitors and antitumor agents. The key intermediates in the synthesis of these classical analogues were the mercaptans 10 and 11, which were obtained from the corresponding nitro compounds 6 and 7 respectively, by reduction of the nitro groups followed by diazotization of the amines. The syntheses of analogues 4 and 5 were achieved via the oxidative addition of the sodium salt of ethyl 2-halo-substituted-4-mercaptobenzoate (16 or 17) to 2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine (18) in the presence of iodine. The esters obtained from the reaction were deprotected and coupled with diethyl-l-glutamate followed by saponification. Compounds 4 and 5 were both more potent inhibitors of human TS (IC(50) values of 54 and 51 nM, respectively) than were PDDF and the clinically used ZD1694 and LY231514. Compounds 4 and 5 were not substrates for human FPGS up to 250 muM. In addition, 4 and 5 were growth inhibitory against CCRF-CEM cells as well as a number of other tumor cell lines in culture, and protection studies established TS as the principal target of these analogues.

In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB 4receptor antagonist with anti-inflammatory activity

Summary Leukotriene B 4(LTB 4) and 12-(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-[R]-HETE) have been postulated to contribute to the pathophysiology of inflammatory diseases. SB 201993, (E)-3 [[[[6-(2-carboxyethenyl)-5-[lsqb;8-(4-methoxyphenyl)octyl] oxy]-2-pyridinyl] methyl] thio] methyl] benzoic acid, identified from a chemical series designed as ring-fused analogs of LTB 4, was evaluated as an antagonist of LTB 4- and 12-(R)-HETE-induced responses in vitro and for anti-inflammatory activity in vivo. SB 201993 competitively antagonized ‘ 3-H’-LTB 4binding to intact human neutrophils (K i= 7.6 NM) and to membranes of RBL 2H3 cells expressing the LTB 4receptor (RBL 2H3-LTB 4R; IC 50= 154 nM). This compound demonstrated competitive antagonism of LTB 4- and 12-(R)-HETE-induced Ca 2+mobilization responses in human neutrophils (IC 50s of 131 nM and 105 nM, respectively) and inhibited LTB 4-induced Ca 2+mobilization in human cultured keratinocytes (IC 50= 61 nM), RBL 2H3-LTB 4R cells (IC 50= 255 nM) and mouse neutrophils (IC 50= 410 nM). SB 201993 showed weak LTD 4-receptor binding affinity (K i= 1.9 μM) and inhibited 5-lipoxygenase (IC 50of 3.6 mM), both in vitro and ex vivo. In vivo, SB 201993 inhibited LTB 4-induced neutrophil infiltration in mouse skin and produced dose-related, long lasting topical anti-inflammatory activity against the fluid and cellular phases of arachidonic acid-induced mouse ear inflammation (ED 50of 580 μg/ear and 390 μg/ear, respectively). Similarly, anti-inflammatory activity was also observed in the murine phorbol ester-induced cutaneous inflammation model (ED 50of 770 and 730 mg/ear, respectively, against the fluid and cellular phases). These results indicate that SB 201993 blocks the actions of LTB 4and 12-(R)-HETE and inhibits a variety of inflammatory responses; and thus may be a useful compound to evaluate the role of these mediators in disease models.

Synthesis, X-Ray Crystal Structure and Tubulin- Binding Properties of a Benzofuran Analogue of the Potent Cytotoxic Agent Combretastatin A4

The benzofuran (4), a ring-fused analogue of the potent antimitotic agent combretastatin A4 (1), has been prepared by a convergent route involving 5-endo-dig iodocyclization of o-hydroxytolan (5) as the key step. Compound (4), which has been characterized crystallographically as well as spectroscopically, is inactive as a tubulin-binding agent.

5-Arylthio-substituted 2-amino-4-oxo-6-methylpyrrolo[2,3-d]pyrimidine antifolates as thymidylate synthase inhibitors and antitumor agents.

Classical antifolate inhibitors of thymidylate synthase (TS) often require the reduced folate uptake system in order to exert their antitumor effects. In addition, these analogues are polyglutamylated via the enzyme folylpoly-gamma-glutamate synthetase (FPGS), which prevents analogue efflux from the cell and usually increases their inhibitory potency against TS. Impaired function of the reduced folate uptake system and that of FPGS are potential sources of resistance to such antifolates. We designed and synthesized a classical 6-5 ring-fused analogue N-[4-[(2-amino-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3- d]pyrimidin-5-yl)thio]-benzoyl]-L-glutamic acid (5) and a nonclassical 6-5 ring-fused analogue 2-amino-6-methyl-5-(pyridin-4-ylthio)-3,4-dihydro-4-oxo-7H-pyrrolo [2,3- d]pyrimidine (6) as TS inhibitors and antitumor agents. The syntheses of analogues 5 and 6 were achieved via the oxidative addition of the sodium salt of ethyl 4-mercaptobenzoate or 4-mercaptopyridine to 2-(pivaloylamino)-6-methyl-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyri midine (17) in the presence of iodine. For the synthesis of 5 the ester obtained from the reaction was deprotected and coupled with diethyl L-glutamate followed by saponification. Compound 5 was a potent inhibitor of human and bacterial TS with IC50 values of 42 and 21 nM, respectively. Compound 6 was 10-fold less potent than 5 against human TS but more than 4700-fold less potent than 5 against Lactobacillus casei TS. The classical analogue 5 was neither a substrate nor an inhibitor of human FPGS derived from CCRF-CEM cells. Compound 5 was cytotoxic to CCRF-CEM and FaDu tumor cell lines as well as to an FPGS-deficient subline of CCRF-CEM. Thymidine protection studies established that TS was the primary target of 5.

Comparison between inhibition of protein kinase C and antagonism of calmodulin by tamoxifen analogues

A variety of analogues of tamoxifen were tested for inhibition of protein kinase C (PKC) activity in MCF-7 breast cancer cells. These results were compared with the calmodulin antagonism exhibited by the analogues as measured by inhibition of calmodulin-dependent cyclic AMP phosphodiesterase. The same structural features that enhanced PKC inhibition also led to an increase in calmodulin antagonism, namely 4-iodination and elongation of the basic side-chain. The most potent analogue has a 4-iodine substituent and eight carbon atoms in its basic side-chain with ic 50 values of 38 μM for PKC inhibition and 0.3 μM for calmodulin antagonism, which compares with 92 and 6.8 μM, respectively, for tamoxifen. Some Selectivity was achieved with a ring-fused analogue that retained the potency of tamoxifen as a PKC inhibitor, but lacked calmodulin antagonism.

Evidence that tamoxifen binds to calmodulin in a conformation different to that when binding to estrogen receptors, through structure-activity study on ring-fused analogues

A ring-fused analogue of tamoxifen, which had previously been shown to have practically identical estrogen receptor (ER) affinity and antitumour potency against estrogen responsive cells as tamoxifen, failed to inhibit calmodulin-dependent cyclic AMP phosphodiesterase. The substitution of an extra methyl group into the ring-fusef analogue, at a position which the ethyl group of tamoxifen can occupy in one of its conformations, restored the calmodulin inhibition. Also, the replacement of the tamoxifen ethyl group by methyl diminishes calmodulin inhibition. Direct interaction of these tamoxifen analogues with calmodulin was demonstrated through the use of the fluorescent probe, 2- p-toluidinyl-napthalene-6-sulfonic acid (TNS). These findings lead to the conclusion that tamoxifen binds to calmodulin in a conformation not accessible to the fused analogue and therefore likely to be different to that which binds to the ER. Also, the results on the ring-fused analogues indicate that the calmodulin binding cannot be essential for antitumour activity.

Conformationally Constrained Analogs of Anatoxin. Chirospecific Synthesis of s-Trans Carbonyl Ring-Fused Analogs

Anatoxin is the most potent agonist known for the nicotinic acetylcholine receptor (nAChR). Although it possesses a semirigid structure, it can adopt four distinctly different conformations. Further conformationally constrained analogues of anatoxin should help to refine and discriminate among the current models for activation of this receptor. This report describes three s-trans ring-fused analogues which have been synthesized starting from D-glutamic acid and 3-hydroxyacetophenone. All of them have in common a 3-oxo-13-azatricyclo[8.2.1.0 2,7 ] tridecane structure. They represent the first fully constrained antaogues of anatoxin and are designed to serve as probes of the bioactive conformation of anatoxin at the acetylcholine nicotinic receptor site

ChemInform Abstract: SYNTHESIS OF TRICYCLIC CEPHALOSPORINS

AbstractMit Acrolein (II) reagiert das Ylid (Ia) zur Verbindung (III); dagegen cyclisiert das Sulfoxid (Ib) zur Verbindung (IV), die über (Va) und (Vb) in das Nocardicin‐De?vat (VI) übergeführt wird.

Synthesis of tricyclic cephalosporins

Cephalosporin 3′-triphenylphosphonium ylide (1) reacted with acrylaldehyde to give the C-3,C-4 tricyclic compound (3), while the sulphoxide of the ylide (1) upon similar treatment gave the C-2,C-3 tricyclic compound (4) which was converted into the ring-fused analogue (7) of nocardicin; desulphurization of this compound afforded the nocardicin nucleus (10)

2-(Aminomethyl)phenols, a new class of saluretic agents. 5. Fused-ring analogues.

A number of bicyclic ring-fused analogues of 2-(aminomethyl)phenol were synthesized and tested orally in rats and intravenously in dogs for saluretic and diuretic effects. Of the 15 alicylic, aromatic, and heterocyclic ring-fused compounds tested, only 2-(aminomethyl)-4-chloro-1-naphthalenol hydrochloride (2) and 7-(aminomethyl)-6-hydroxy-5,8-dimethyl-1,2,3,4-tetrahydronaphthalene hydrochloride (6) displayed a high order of activity.