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In this research, two novel series of dibenzo[ b,f ]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates ( 5a-g ) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate ( 5e ).HighlightsTwo novel series of dibenzo[ b,f ]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. 5e was the most active anti-topo II congener (IC 50 = 6.36 ± 0.36 µM). 5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC 50 = 13.05 ± 0.62 µM). In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm 3 compared to doxorubicin treatment.

Ring closing acyclic parts of a molecular scaffold or the opposite manipulation, opening rings to produce pseudo-ring structures, is an important scaffold hopping manipulation. Analogues derived from biologically active compounds through the utilization of such strategies are often similar in shape and physicochemical properties and, therefore, likely to exhibit similar potency. This review will demonstrate how several different ring closure techniques, such as replacing carboxylic functions by cyclic peptide mimics, incorporating double bonds into aromatic rings, tying back ring substituents to a bicyclic structure, cyclizing adjacent ring substituents to an annulated ring, bridging annulated ring systems to tricyclic scaffolds, and exchanging gem -dimethyl groups by cycloalkyl rings, but also ring opening led to the discovery of highly active agrochemicals.

The intramolecular Heck reaction is a well-established strategy for natural product total synthesis. When constructing large rings, this reaction is also referred to as Heck macrocyclization, which has proved a viable avenue to access diverse naturally occurring macrocycles. Less noticed but likewise valuable, it has created novel macrocycles of non-natural origin that neither serve as nor derive from natural products. This review presents a systematic account of the title reaction in forging this non-natural subset of large rings, thereby addressing a topic rarely covered in the literature. Walking through two complementary sections, namely (1) drug discovery research and (2) synthetic methodology development, it demonstrates that beyond the well-known domain of natural product synthesis, Heck macrocyclization also plays a remarkable role in forming synthetic macrocycles, in particular macrocyclic drugs.

Decomposition of the polycation Al 13 O 4 (OH) 24 (H 2 O) 12 7+ (Al 13 ) promoted by ligand is a vital subject to advance our understanding of natural and artificial occurrence and evolution of aluminum ions, especially in the case of acidic condition that dissolved Al 3+ species can be released from the Al-bearing substances. However, the microscopic pathway of synchronous proton-promoted and ligand-promoted decomposition process for Al 13 is still in the status of ambiguity. Herein, we applied differential mass spectrometry method and DFT calculation to study the initial detailed process of Al 13 decomposition under the presence of proton and salicylic acid (H 2 Sal). Mass results showed that the mononuclear Al 3+ -H 2 Sal complexes dominated the resulting Al species, whereas the monodentate complex Al 13 HSal 6+ decomposition process, and the proton transfer determined the ring closure efficiency. The ring closure reaction is the prerequisite for the collapse of Al 13 decomposition process, and the proton transfer determined the ring closure efficiency. The ring closure reaction is the prerequisite for the collapse of Al 13 structure and detachment of the mononuclear complex. DFT calculations reveal that hydrogen bond plays an important role in inducing the formation of chelated complex accompanying proton transfer. Attachment of protons at the bridging OH - can elongate and weaken the critical bond between targeted Al 3+ and µ 4 -O 2- resulting from delocalization of electron pairs in the oxygen atom. These results demonstrate the detailed mechanism of Al 13 composition promoted by ligand and proton, and provide significant understanding for further application and control of Al 13 ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022. Published by Elsevier B.V.)

Over the past few years, great progress has been made in the development of high-affinity adenosine A 1 and/or A 2A receptor antagonists-promising agents for the potential treatment of Parkinson's disease. Unfortunately, many of these compounds raise structure-related concerns. The present study investigated the effect of ring closures on the rA 1 /A 2A affinity of compounds containing a highly reactive α,β-unsaturated carbonyl system, hence providing insight into the potential of heterocycles to address these concerns. A total of 12 heterocyclic compounds were synthesised and evaluated in silico and in vitro. The test compounds performed well upon qualitative assessment of drug-likeness and were generally found to be free from potentially problematic fragments. Most also showed low/weak cytotoxicity. Results from radioligand binding experiments confirm that heterocycles (particularly 2-substituted 3-cyanopyridines) can replace the promiscuous α,β-unsaturated ketone functional group without compromising A 1 /A 2A affinity. Structure-activity relationships highlighted the importance of hydrogen bonds in binding to the receptors of interest. Compounds 3c (rA 1 K i  = 16 nM; rA 2A K i  = 65 nM) and 8a (rA 1 K i  = 102 nM; rA 2A K i  = 37 nM), which both act as A 1 antagonists, showed significant dual A 1 /A 2A affinity and may, therefore, inspire further investigation into heterocycles as potentially safe and potent adenosine receptor antagonists., (© 2021 John Wiley & Sons Ltd.)

Al/P- and Ga/P-based frustrated Lewis pairs (FLPs) reacted with an azirine under mild conditions under cleavage of the heterocycle on two different positions. Opening of the C-C bond yielded an unusual nitrile-ylide adduct in which a C-N moiety coordinated to the FLP backbone. Cleavage of a C-N bond afforded the thermodynamically favored enamine adduct with the N atom bound to P and Al or Ga atoms. Ring closure was observed upon treatment of an Al/P FLP with electronically unsaturated substrates (4-(1-cyclohexenyl)-1-aza-but-1-en-3-ynes) and yielded by C-N bond formation hexahydroquinoline derivatives, which coordinated to the FLP through P-C and Al-C bonds. Diphenylcyclopropenone showed a diverse reactivity, which depending on steric shielding and the polarizing effect of Al or Ga atoms afforded different products. An AltBu 2 /P FLP yielded an adduct with the C=O group coordinated to P and Al. The dineopentyl derivative gave an equilibrium mixture consisting of a similar product and a simple adduct with O bound to Al and a three-coordinate P atom. Both compounds co-crystallize. The Ga/P FLP only formed the simple adduct with the same substrate. Rearrangement resulted in all cases in C 3 -ring cleavage and migration of a mesityl group from P to a former ring C atom by C-C bond formation. Diphenylthiocyclopropenone (evidence for the presence of P=C bonds) and an imine derivative afforded similar products., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Heterocyclic nucleus plays a fundamental role in the medicinal chemistry and serves as a key template for the development of various therapeutic agents including broad spectrum antibacterial drugs. In an effort to develop new antibacterial agents, a bicyclic twelve-membered heterocyclic nucleus derived from coumarin was prepared by an uncomplicated method. The rate of ring closure for this nucleus, which was given the name coumacine, in addition to two of its derivatives was monitored spectroscopically and this rate followed zero order kinetics. The chemical structures of the synthesized products were established by detecting their physicochemical properties and analyzing their IR, 1 H NMR and 13 C NMR spectra. The in vitro antibacterial activity of coumacines was evaluated via agar dilution method against different standard aerobic and anaerobic bacterial strains using ciprofloxacin and metronidazole as positive controls, respectively; the results indicated that coumacine I has an excellent broad spectrum antibacterial activity against the tested bacterial strains with percentage of growth inhibition approximating to those of positive controls.

A 1,2,4-triazole motif is present in numerous commercialized and investigational bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of convenient combinatorial approaches toward this molecular core. Herein, we present a synthetic strategy suitable for the quick preparation of a library of structurally diverse 1,2,4-triazoles in a one-pot setting. The key steps include the formation of thioureas followed by S-alkylation using 1,3-propane sultone and consecutive ring closure leading to the desired 1,2,4-triazoles. Parallel synthesis yields thousands of 1,2,4-triazoles in a cost- and time-efficient manner from commercially available chemicals.

Established strategies for discovering selective kinase inhibitors are target-centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. Here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Previously synthesized 9-aryl-5H-imidazo[2,1-d][1,2,5]triazepin-6(7H)-ones have been used as starting materials for the synthesis of three new tricyclic ring systems, where an imidazotriazepine is condensed with an imidazole, triazole or tetrazole ring. These novel compounds could be potential drug candidates for central nervous system diseases because of their closely related structure to known tricyclic derivatives with anticonvulsant activity.

In the present paper, we report an expedient total synthesis of triciribine, a tricyclic 7-deazapurine nucleoside and protein kinase B (AKT ) inhibitor, in 35% overall yield. Our synthesis route features a highly regioselective substitution of 1- N -Boc-2-methylhydrazine and a trifluoroacetic acid catalyzed one-pot transformation which combined the deprotection of the tert -butylcarbonyl (Boc) group and ring closure reaction together to give a tricyclic nucleobase motif.

Classic cytotoxic drugs remain indispensable instruments in antitumor therapy due to their effectiveness and a more prevalent insensitivity toward tumor resistance mechanisms. Herein we describe the favorable properties of 6-(N,N-dimethyl-2-aminoethoxy)-11-(3,4,5-trimethoxyphenyl)pyrido[3,4-c][1,9]phenanthroline (P8-D6), a powerful inducer of apoptosis caused by an equipotent inhibition of human topoisomerase I and II activities. A broad-spectrum effect against human tumor cell lines at nanomolar concentrations, as well as strong antileukemic effects, were shown to be superior to those of marketed topoisomerase-targeting drugs and dual topoisomerase inhibitors in clinical trials. The facile four-step synthesis, advantageous drugability properties, and initial in vivo data encourage the application of P8-D6 in appropriate animal tumor models and further drug development., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The preparation of cyclic macromolecules has always represented a challenging task for polymer science, mainly because of difficulties in connecting chain extremities together. Initiated by the pioneering studies of Jacobson and Stockmayer, preparative pathways to cyclic polymers have been considerably improved within the last two decades thanks to the advent of both controlled polymerizations and efficient coupling reactions in organic chemistry. This Review aims to provide a critical up-to-date overview and illustrate the considerable efforts that have been made in the past few years to improve the availability of macrocycles for industrial and academic investigations through the use of the ring-closure approach. Particular attention is paid to methods for the preparation of monocycles over more complex architectures, since the latter are usually derived from the former., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hydroboration of the conjugated enynes 1 a and 1 b with Piers' borane [HB(C6F5)2] gave the respective dienylboranes trans-2 c and trans-2 d. Their photolysis resulted in the formation of the dihydroborole products 3 c and 3 d. Both were converted to their pyridine adducts 5 c and 5 d, respectively. Compounds 3 c and 5 c,d were characterized by X-ray diffraction. The reaction of the bis(enynyl)boranes 6 a and 6 b with B(C6F5)3 resulted in the formation of the dihydroboroles 7 a and 7 b, respectively. This reaction is thought to proceed by 1,1-carboboration of one of the enynyl substituents at boron to generate the dienylborane intermediates 8 a/8 b, followed by thermally induced bora-Nazarov ring-closure and subsequent stabilizing 1,2-pentafluorophenyl group migration from boron to carbon. Compound 7 a was characterized by X-ray diffraction and solid-state (11)B NMR spectroscopy., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new and unexpected Rh(I)-catalyzed cycloisomerization of 1,6-enynes is reported. Several different alkyne substitution patterns were evaluated under the reaction conditions, including a deuterated derivative that provides some insight into the reaction mechanism.

A novel stereocontrolled approach has been developed for the syntheses of tashiromine and epitashiromine alkaloids from cyclooctene β-amino acids. The synthetic concept is based on the azetidinone opening of a bicyclic β-lactam, followed by oxidative ring opening through ring C-C double bond and reductive ring-closure reactions of the cis- or trans-cyclooctene β-amino acids.

A concise enantioselective synthesis of the advanced intermediate 5 for the synthesis of pumiliotoxins (Gallagher's intermediate) is described. The synthesis started from the regio- and trans-diastereoselective (dr = 98:2) reductive 3-butenylation of (R)-3-(tert-butyldimethylsilyloxy)glutarimide 14. After O-desilylation and Dess-Martin oxidation, the resulting keto-lactam 10 was subjected to a highly trans-stereoselective addition of the methylmagnesium iodide to give carbinol 11 as sole diastereomer. An efficient ring closure procedure consisting of ozonolysis and reductive dehydroxylation provided the indolizidine derivative 5, which completed the formal enantioselective total synthesis of pumiliotoxins 251D and 237A.

Soft scorpionates have thus far been seen mainly as a family of ligands. Their chemistry is extended here to the production of novel cationic macrocycles using dihaloalkanes. By replacing the dihaloalkanes with mild oxidising agents (NO(+), I2) we obtain two unique polycyclic heterocycles. The mechanism which leads to the formation of these polycyclic heterocycles is investigated using ab initio DFT calculations., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A high-yielding general synthesis of imidazophosphor ester based tetrazolo[1,5-b]pyridazines is described. A conjugated reaction between 3,6-diazidopyridazine and different types of phosphonyl carbanion reagents followed by intramolecular cyclization afforded the target products, by using sodium ethanolate solution as a reaction medium. Among the products, five compounds, at a dose of 50 mg per kilogram body weight, showed a notable antinociceptive and anti-inflammatory activity without toxic side-effects.

Linear free-energy relationships, like Hammett correlations, are fundamental in physical organic chemistry for the elucidation of reaction mechanisms. In this work, we show that Hammett correlations exist for the ring closure of six different model systems of vinylheptafulvenes (VHFs) to their corresponding dihydroazulenes (DHAs). These first-order reactions were easily followed by UV/Vis absorption spectroscopy on account of the significantly different absorption characteristics between VHFs and DHAs. Opposing effects displayed by substituent groups at two different positions are conveniently accounted for by simply subtracting the two Hammett σ values of each group. The linear correlations readily allow us to obtain unknown and approximate Hammett σ values for previously uninvestigated substituents. We also show that they can provide alternative values to the standard ones. We present values for a variety of substituent groups ranging from alkynes, sulfones, sulfoxides, and different heteroaromatics. The electronic effects exerted by substituent groups on VHFs are also reflected in their absorption maxima. Thus, we have established an empirical relationship between the absorption maximum of the VHF and the Hammett σ values of its substituents. This fine-tuning of electronic properties is particularly important for the ongoing efforts of using the DHA/VHF molecular switch in molecular electronics devices., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first synthesis of 2,3,6,7-tetrabromoanthracene is presented, starting from benzene in a straightforward four step synthesis.

Loop closure in proteins has been studied actively for over 25 years. Using spherical geometry and polynomial equations, several loop-closure problems in proteins are solved exactly by reducing them to the determination of the real roots of a polynomial. Loops of seven, eight, and nine atoms are treated explicitly, including the tripeptide and disulfide-bonded loop-closure problems. The number of valid loop closures can be evaluated by the method of Sturm chains, which counts the number of real roots of a polynomial. Longer loops can be treated by three methods: by sampling enough dihedral angles to reduce the problem to a soluble loop-closure problem; by applying the loop-closure algorithm hierarchically; or by decimating the chain into independently moving rigid elements that can be reconnected using loop-closure algorithms. Applications of the methods to docking, homology modeling and NMR problems are discussed. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 819-844, 1999., (Copyright © 1999 John Wiley & Sons, Inc.)