Bicyclic Scaffold Research Articles

A Systems Biology Approach to Dissection of the Effects of Small Bicyclic Peptidomimetics on a Panel of Saccharomyces cerevisiae Mutants

In recent years, an approach called "chemical genetics" has been adopted in drug research to discover and validate new targets and to identify and optimize leads by high throughput screening. In this work, we tested the ability of a library of small peptidomimetics to induce phenotypic effects with functional implications on a panel of strains of the budding yeast Saccharomyces cerevisiae, both wild type and mutants, for respiratory function and multidrug resistance. Further elucidation of the function of these peptidomimetics was assessed by testing the effects of the compound with the most prominent inhibitory activity, 089, on gene expression using DNA microarrays. Pathway analysis showed the involvement of such a molecule in inducing oxidative damage through alterations in mitochondrial functions. Transcriptional experiments were confirmed by increased levels of ROS and activation of mitochondrial membrane potential. Our results demonstrate the influence of a functional HAP1 gene in the performance of S. cerevisiae as a model system.

Design, synthesis, and biological evaluation of novel coxsackievirus B3 inhibitors

The synthesis and SAR study of a novel class of coxsackievirus B3 (CVB3) inhibitors are reported. These compounds could be considered as the 6-chloropurines substituted at position 9 with variously substituted bicyclic scaffolds (bicyclo[2.2.1]heptane/ene—norbornane or norbornene). The synthesis and biological evaluation of 31 target compounds are described. Several of the analogues inhibited CVB3 in the low micromolar range (0.66–2 μM). Minimal or no cytotoxicity was observed.

Abstract 4541: The design, synthesis and evaluation of selective FR α and β substrates with potent GARFTase inhibitory activity as antitumor agents

Abstract Glycinamide ribonucleotide formyl transferase (GARFTase) catalyzes the first of two formyl transfer steps in the de novo purine biosynthetic pathway. Potent inhibitors of GARFTase and de novo purine biosynthesis have shown promise as antitumor drugs. However, a lack of selectivity and toxicity has been a major hurdle for GARFTase inhibitors as cancer chemotherapeutic agents. We recently reported a series of thieno[2,3-d]pyrimidine classical antifolates that are specifically taken up by the folate receptor (FR) and inhibit FR expressing tumor cells at nanomolar IC50 values (IC50= 4.9 nM in human KB tumor cells, IC50= 5.9 nM in human IGROV1 tumor cells,). GARFTase was confirmed as the target. Notably, the thieno[2,3-d]pyrimidine antifolates are unique and distinct from all other classical antifolates evaluated, including pemetrexed (PMX), raltitrexed (RTX), and methotrexate (MTX) in that they are neither substrates for reduced folate carrier (RFC) nor for the proton-coupled folate transporter (PCFT). This characteristic results in selective targeting of FR-expressing cells, without toxicity to normal cells that express RFC. To further investigate the structural requirements of antifolates with respect to FR substrate activity, a series of four 2-amino-4-oxo-6-substituted thieno[2,3-d]pyrimidines with different aryl side chains were synthesized. This afforded potent antitumor agents with increased inhibitory activity against FRα expressing tumor cells (IC50= 2 nM in human KB tumor cells) 2.5- fold more potent than the lead benzoyl compound. In addition, these thieno[2,3-d]pyrimidines were specific for FRα and were not transported by RFC or PCFT and indicated that the nature of the bicyclic scaffold is an important structural determinant for transport specificity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4541.

Expedient synthesis of novel bicyclic peptidomimetic scaffolds

Abstract In the past, bicyclic structures mimicking dipeptides have been designed and successfully used to prepare enzyme inhibitors. We report herein our preliminary results in the design and expedient synthesis of a novel series of diastereomeric N -amino-hexahydro-1 H -isoindolone scaffolds built from three commercially available building blocks in only two steps, with high yields, a single protecting group and a single purification step.

Annelation of perfluorinated heteroaromatic systems by 1,3-dicarbonyl derivatives

Reactions of various perfluorinated heteroaromatic substrates such as tetrafluoro-4-cyanopyridine, tetrafluoropyrazine and tetrafluoropyridazine with 1,3-dicarbonyl systems gave corresponding [5,6]-ring fused furo derivatives. Subsequent reactions of the [5,6] bicyclic scaffolds with nucleophiles gave some highly functionalised heteroaromatic systems.

ChemInform Abstract: Asymmetric Construction of Nitrogen‐Containing [2.2.2] Bicyclic Scaffolds Using N‐(p‐Dodecylphenylsulfonyl)‐2‐pyrrolidinecarboxamide.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and Pharmacological Evaluation of SNC80 Analogues with a Bridged Piperazine Ring

To discover novel delta-opioid receptor ligands derived from SNC80 (1), a series of 6,8-diazabicyclo[3.2.2]nonane derivatives bearing two aromatic moieties was prepared, and the affinity toward delta, mu, and kappa receptors, as well as sigma receptors, was investigated. After removal of the 4-methoxybenzyl and 2,4-dimethoxybenzyl protecting groups, the pharmacophoric N,N-diethylcarbamoylbenzyl residue was attached to the 6,8-diazabicyclo[3.2.2]nonane framework to yield the designed delta receptor ligands. In a first series of compounds the benzhydryl moiety of SNC80 was dissected, and one phenyl ring was attached to the bicyclic framework. In a second series of delta ligands the complete benzhydryl moiety was introduced into the bicyclic scaffold. The determined delta receptor affinities show that compounds based on an (R)-glutamate-derived bicyclic scaffold possess higher delta receptor affinity than their (S)-glutamate-derived counterparts. Furthermore, an intact benzhydryl moiety leads to delta receptor ligands that are more potent than compounds with two separated aromatic moieties. Compound 24, with the same spatial arrangement of substituents around the benzhydryl stereocenter as SNC80, shows the highest delta receptor affinity of this series: K(i)=24 nM. Whereas the highly potent delta ligands reveal good selectivity against mu and kappa receptors, the sigma(1) and/or sigma(2) affinities of some compounds are almost in the same range as their delta receptor affinities, such as compound 25 (sigma(2): K(i)=83 nM; delta: K(i)=75 nM). In [(35)S]GTPgammaS assays the most potent delta ligands 24 and 25 showed almost the same intrinsic activity as the full agonist SNC80, proving the agonistic activity of 24 and 25. The enantiomeric 4-benzylidene derivatives 15 and ent-15 showed selective cytotoxicity toward the 5637 (bladder) and A-427 (small-cell lung) human tumor cell lines.

Diverse backbone-cyclized peptides via codon reprogramming

We report a methodology for the ribosomal synthesis of backbone-cyclized peptides involving genetic code reprogramming to introduce one or more nonproteinogenic amino acids. Expression of linear peptides bearing a cysteine-proline dipeptide sequence followed by glycolic acid results in self-rearrangement to a C-terminal diketopiperadine-thioester, which non-enzymatically generates a cyclized peptide. We demonstrate the ribosomal synthesis of several naturally occurring backbone-cyclized peptides and a library based on a bicyclic scaffold, and we identify bioactive sequences by screening and deconvolution.

Aminocatalysis Cascades of Enones

The authors identified the cinchona alkaloid derived primary amine 1 in combination with acid 2 as a powerful catalyst system for organocatalytic cascade reactions of enones. Employing nitroalkenes as reaction partners, the corresponding cyclohexanones were obtained in high optical purity and in favor of the trans isomer (see A). Depending on the reaction partner, also cyclohexanones containing all-carbon quaternary centers (see B) as well as bicyclic scaffolds (see C) can be constructed with high efficiency.

N-Bridged bicyclic sulfonamides as inhibitors of γ-secretase

The structural modification of a series of [3.3.1] bicyclic sulfonamide based γ-secretase inhibitors is described. Appropriate substitution on the bicyclic scaffold provides a significant increase in the metabolic stability of the compounds resulting in an improved in vivo metabolic profile.

Constrained Peptidomimetics Reveal Detailed Geometric Requirements of Covalent Prolyl Oligopeptidase Inhibitors

Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program fitted, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light on the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.

New classes of potent and bioavailable human renin inhibitors

New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.

Conformational Effects in Diastereoselective Aryne Diels−Alder Reactions: Synthesis of Benzo-Fused [2.2.1] Heterobicycles

It was found that the diastereoselectivity of the Diels-Alder reaction between arynes and substituted furans is highly sensitive to substitution, which affects the reactive conformation. By varying the location of the groups on the diene partner, it is possible to obtain both excellent chemical yields and high stereoselectivity. This methodology offers rapid and convenient access to enantiomerically pure bicyclic scaffolds which are difficult to prepare by other means.

2-Phenylpyrazolo[4,3-d]pyrimidin-7-one as a New Scaffold To Obtain Potent and Selective Human A3 Adenosine Receptor Antagonists: New Insights into the Receptor−Antagonist Recognition

A molecular simplification approach of previously reported 2-arylpyrazolo[3,4-c]quinolin-4-ones was applied to design 2-arylpyrazolo[4,3-d]pyrimidin-7-one derivatives as new human A(3) adenosine receptor antagonists. Substituents with different lipophilicity and steric hindrance were introduced at the 5-position of the bicyclic scaffold (R(5) = H, Me, Et, Ph, CH(2)Ph) and on the 2-phenyl ring (OMe, Me). Most of the synthesized derivatives were highly potent hA(3) adenosine receptor antagonists, the best being the 2-(4-methoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-one (K(i) = 1.2 nM). The new compounds were also highly selective, being completely devoid of affinity toward hA(1), hA(2A), and hA(2B) adenosine receptors. On the basis of the recently published human A(2A) receptor crystallographic information, we propose a novel receptor-driven hypothesis to explain both A(3) AR affinity and A(3) versus A(2A) selectivity profiles of these new antagonists.

Stereoelectronic Effects in Dihapto-Coordinated Complexes of TpW(NO)(PMe3) and Their Manifestation in Diels−Alder Cycloaddition of Arenes

The addition of singly and doubly activated dienophiles to TpW(NO)(PMe3)(5,6-η2-anisole) and TpW(NO)(PMe3)(5,6-η2-1,3-dimethoxybenzene) to generate dihapto-coordinated [2.2.2]bicyclooctadienes and -trienes is explored. The highly functionalized bicyclic scaffolds are isolated from the metal fragment intact. Although moderate yields hinder their synthetic application, a unique stereoelectronic effect is uncovered. Coordination diastereomers of anisoles with the methoxy substituent distal to the PMe3 ligand have faster reaction rates relative to the proximal diastereomer. DFT calculations reveal the metal fragment possesses a dipole that directs positive charge away from the PMe3 ligand, and a polarized cycloaddition transition state is invoked to explain this observation.

Synthesis of a constrained polyfunctional bicyclic iminocyclitol scaffold from l-sorbose via a tandem sequence including stereoselective intramolecular Huisgen cycloaddition

The synthesis of a functionalized (azido, amino, and hydroxy) 8-oxa-3-azabicyclo[3.2.1]octane framework and its conversion into a protected sugar amino acid and a tricyclic framework is described. The sequence includes a one-pot Huisgen 1,3-dipolar cycloaddition, with decomposition to an aziridine and subsequent ring opening by azide. The stereoselectivity observed in the Huisgen cycloaddition reaction is attributed to minimization of allylic strain.

Concise Synthesis of the Bicyclic Scaffold ofN-Methylwelwitindolinone C Isothiocyanate via an Indolyne Cyclization

A concise synthesis of the N-methylwelwitindolinone C isothiocyanate scaffold is disclosed. The approach relies on an indolyne cyclization to construct the [4.3.1]-bicyclic ring system present in the natural product. Subsequent oxidation of the indole core occurs with excellent diastereoselectivity to afford oxindole 2, the structure of which was confirmed by X-ray crystallographic analysis.

Diversity-oriented synthesis of a cytisine-inspired pyridone library leading to the discovery of novel inhibitors of Bcl-2

Four enantiopure cytisine-inspired scaffolds can be accessed via a versatile pyrrolidine template derived from a stereocontrolled [3+2] azomethine ylide–alkene cycloaddition . Differential ester protection allows for the selective formation of either a bridged bicyclic or tricyclic scaffold via pyridone cyclization. Solid-phase diversification of the pyridone scaffolds yielded a diverse library of 15,000 compounds enabling the discovery of a novel class of Bcl-2 inhibitors.

Allosteric Modulation of the Dopamine D2 Receptor by Pro-Leu-Gly-NH2 Peptidomimetics Constrained in Either a Polyproline II Helix or a Type II β-Turn Conformation

Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH(2). The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor.

Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors

We identified a series of structurally novel SCD (Δ9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog ( 8g) had IC 50 value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Δ5 and Δ6 desaturases.