ABSTRACT
Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.
Subject(s)
Bridged Bicyclo Compounds , Drug Design , Heptanes , Anions/chemistry , Benzene/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Drug Discovery , Heptanes/chemical synthesis , Heptanes/chemistry , Pentanes/chemical synthesis , Pentanes/chemistry , SolubilityABSTRACT
(S)-5-Methylhept-2-en-4-one is a key flavour compound in hazelnuts. We have performed its chiral-pool-based chemoenzymatic synthesis with 39% overall yield (73% ee). The four-step aldol-based sequence avoids the use of highly reactive and/or toxic reagents, does not require anhydrous conditions and uses only distillation as the purification method. Thus, such methodology represents a green and scalable alternative to only two stereoselective approaches towards this natural product known so far. In addition, we have designed and prepared a set of new (di)enones as achiral synthetic analogues of the title compound. The results of their sensory analyses clearly show that relatively minor structural changes of the natural molecule significantly alter its olfactory properties. Thus, simple (poly)methylation completely changes the original hazelnut aroma of (S)-5-methylhept-2-en-4-one and shifts the odour of its analogues to eucalyptus, menthol, camphor, and sweet aroma.
Subject(s)
Corylus/chemistry , Heptanes/chemical synthesis , Odorants , Smell , Aldehydes/chemistry , Heptanes/chemistry , StereoisomerismABSTRACT
This comprehensive review of filbertone, a principal flavor compound of hazelnut, evaluates the current state of the art of all relevant aspects of the title molecule: its occurrence and properties, laboratory preparation and bulk synthesis, analytical issues regarding stereochemistry and purity, sensory evaluation, and practical uses. Comparisons are made between different synthetic approaches, and a critical assessment of various applications is presented.
Subject(s)
Corylus/chemistry , Heptanes/chemistry , Nuts/chemistry , Heptanes/chemical synthesis , Molecular StructureABSTRACT
The estrogen receptor (ER), a member of the nuclear receptor (NR) family, is involved in the regulation of physiological effects such as reproduction and bone homeostasis. Approximately 70% of human breast cancers are hormone-dependent and ERα-positive, and, thus, ER antagonists are broadly used in breast cancer therapy. We herein designed and synthesized a set of ER antagonists with a 4-heterocycle-4-phenylheptane skeleton.
Subject(s)
Estrogen Receptor Antagonists/pharmacology , Heptanes/pharmacology , Indoles/pharmacology , Pyrroles/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Thiophenes/pharmacology , Dose-Response Relationship, Drug , Drug Design , Estrogen Receptor Antagonists/chemical synthesis , Estrogen Receptor Antagonists/chemistry , Heptanes/chemical synthesis , Heptanes/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Ligands , MCF-7 Cells , Models, Molecular , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Receptors, Estrogen/metabolism , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Tumor Cells, CulturedABSTRACT
The 2-substituted piperidine core is found in drugs (18 FDA-approved drugs), however, their spirocyclic analogues remain unknown. Described here is the synthesis of spirocyclic analogues for 2-substituted piperidines and a demonstration of their validation in drug discovery.
Subject(s)
Aza Compounds/chemical synthesis , Drug Discovery , Heptanes/chemical synthesis , Piperidines/chemistry , Spiro Compounds/chemical synthesis , Aza Compounds/chemistry , Heptanes/chemistry , Molecular Structure , Spiro Compounds/chemistryABSTRACT
The synthesis and X-ray crystal structures of syn and anti 4-N-Boc-aminobicyclo[3.2.0]heptane-1-carboxylic acids are described. The placement of the N-Boc-amino groups in the two stereoisomers in either pseudo-equatorial or pseudo-axial positions renders the molecules conformationally locked, with N-Boc-protected γ-aminobutyric acid (GABA) embedded within the bicyclic core. Despite the different conformations of the urethane and distinct crystal packing, the bicyclic core units of the two stereoisomers adopt virtually identical structures. They correspond to in silico models of the parent bicyclic core and a systematic array of disubstituted derivatives. The study documents an intrinsic property of the bicyclo[3.2.0]heptane core to favor adoption of a boat-like conformation, which is largely unaffected by various substitution patterns. The structural concepts are useful in the design of molecules with spatial and directional fixation of pharmacophoric groups.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Heptanes/chemistry , gamma-Aminobutyric Acid/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Crystallography, X-Ray , Heptanes/chemical synthesis , Hydrogen Bonding , Models, Molecular , Molecular Conformation , Stereoisomerism , gamma-Aminobutyric Acid/chemical synthesisABSTRACT
Bacterial infections, caused by Mycobacterium tuberculosis and other problematic bacterial pathogens, continue to pose a significant threat to global public health. As such, new chemotype antibacterial agents are desperately needed to fuel and strengthen the antibacterial drug discovery and development pipeline. As part of our antibacterial research program to develop natural product-inspired new antibacterial agents, here we report synthesis, antibacterial evaluation, and structure-activity relationship studies of an extended chemical library of macrocyclic diarylheptanoids with diverse amine, amide, urea, and sulfonamide functionalities. Results of this study have produced macrocyclic geranylamine and 4-fluorophenethylamine substituted derivatives, exhibiting moderate to good activity against M. tuberculosis and selected Gram-positive bacterial pathogens.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antitubercular Agents/chemical synthesis , Heptanes/chemistry , Amines/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Gram-Positive Bacteria/drug effects , Heptanes/chemical synthesis , Heptanes/pharmacology , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Structure-Activity Relationship , Sulfonamides/chemistry , Urea/chemistryABSTRACT
A new class of carbocyclic nucleoside analogues built on a bicyclo[4.1.0]heptane scaffold, a perspective novel pseudosugar pattern, have been conceived as anti-HSV agents on the basis of initial protein-ligand docking studies. The asymmetric synthesis of a series of these compounds incorporating different nucleobases has been efficiently completed starting from 1,4-cyclohexanedione.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Cyclohexanones/chemistry , Heptanes/chemical synthesis , Nucleosides/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Heptanes/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Nucleosides/chemistry , StereoisomerismABSTRACT
Two diazabicyclic analogues of ranolazine, (S,S,S)-5 and (S,S,R)-5, and their epimeric mixture were synthesized. Furthermore, their vasomotor effects on rat aorta rings precontracted with phenylephrine were analyzed. These compounds showed vasodilating effects significantly greater than ranolazine. The vasodilating activities of these analogues have two components, one that depends on the endothelium, due to the release of NO, and another one due to a direct effect on the vascular smooth muscle. The compounds [(S,S,S)(S,S,R)]-5 and (S,S,R)-5 induce, in a manner similar to ranolazine, the release of a prostanoid from the cyclooxygenase pathway, whose vasoconstrictor effect is masked by the predominant vasodilation induced by these compounds.
Subject(s)
Acetanilides/chemical synthesis , Acetanilides/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Vasoconstrictor Agents/chemical synthesis , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Acetanilides/chemistry , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacology , Cyclization , Heptanes/chemical synthesis , Heptanes/chemistry , Heptanes/pharmacology , Inhibitory Concentration 50 , Muscle, Smooth, Vascular/drug effects , Piperazines/chemistry , Ranolazine , Rats , Vasoconstrictor Agents/chemistryABSTRACT
S-Nitrosylation, the addition of a nitrosyl group to cysteine thiols, regulates various protein functions to mediate nitric oxide (NO) bioactivity. Recent studies have demonstrated that selectivity in protein S-nitrosylation signaling pathways is conferred through transnitrosylation, a transfer of the NO group, between proteins via interaction. We previously demonstrated that sensitivity to activation by synthetic NO-releasing agents via S-nitrosylation is a common feature of members of the transient receptor potential (TRP) family of Ca(2+)-permeable cation channels. However, strategies to confer subtype selectivity to nitrosylating agents targeted to TRP channels are yet to be developed. Here, we show selective activation of TRPA1 channels by novel NO donors derived from the ABBH (7-azabenzobicyclo[2.2.1]heptane) N-nitrosamines, which exhibit transnitrosylation reactivity to thiols without releasing NO. The NNO-ABBH1 (N-nitroso-2-exo,3-exo-ditrifluoromethyl-7-azabenzobicyclo[2.2.1]heptane) elicits S-nitrosylation of TRPA1 proteins, and dose-dependently induces robust Ca(2+) influx via both recombinant and native TRPA1 channels, but not via other NO-activated TRP channels. TRPA1 activation by NNO-ABBH1 is suppressed by specific cysteine mutations but not by NO scavenging, suggesting that cysteine transnitrosylation underlies the activation of TRPA1 by NNO-ABBH1. This is supported by the correlation of N-NO bond reactivity and TRPA1-activating potency in a congeneric series of ABBH N-nitrosamines. Interestingly, nonelectrophilic derivatives of ABBH also activate TRPA1 selectively, but less potently, compared with NNO-ABBH1. Thus, ABBH N-nitrosamines confer subtype selectivity on S-nitrosylation in TRP channels through synergetic effects of two chemical processes: cysteine transnitrosylation and molecular recognition of the nonelectrophilic moiety.
Subject(s)
Aza Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Calcium Channels/metabolism , Heptanes/pharmacology , Nerve Tissue Proteins/metabolism , Nitric Oxide Donors/pharmacology , Nitrosamines/pharmacology , Transient Receptor Potential Channels/metabolism , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , HEK293 Cells , Heptanes/chemical synthesis , Heptanes/chemistry , Humans , Nitric Oxide Donors/chemical synthesis , Nitric Oxide Donors/chemistry , Nitrosamines/chemical synthesis , Nitrosamines/chemistry , Patch-Clamp Techniques , TRPA1 Cation ChannelABSTRACT
Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.
Subject(s)
Aza Compounds/chemistry , Heptanes/chemistry , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Spiro Compounds/chemistry , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation, Preclinical , Half-Life , Heptanes/chemical synthesis , Heptanes/pharmacokinetics , Orexin Receptors , Rats , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Structure-Activity RelationshipABSTRACT
(2E,4E,6E,8E,10E,12E,14E)-2,15-Diiodo-6,11-dimethylhexadeca-2,4,6,8,10,12,14-heptaene, prepared by homometathesis, has been used in palladium-catalyzed Suzuki and Stille cross-coupling reactions with the appropriate partners to construct the C2-symmetric carotenoids ß,ß-carotene, lycopene, synechoxanthin and 4,4'-diapo-ψ,ψ-carotene-4,4'-dial.
Subject(s)
Carotenoids/chemical synthesis , Heptanes/chemistry , Hydrocarbons, Iodinated/chemistry , Carotenoids/chemistry , Catalysis , Heptanes/chemical synthesis , Hydrocarbons, Iodinated/chemical synthesis , Molecular Structure , Palladium/chemistryABSTRACT
2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines were employed for the one-step stereoselective construction of both endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH(4)-induced reductive cyclization protocol. Antiplasmodial assessment of these 1-azabicyclo[2.2.1]heptanes revealed moderate to good activities in the micromolar range, with the exo-isomers being the most promising structures. Furthermore, the proposed mode of action was supported by ligand docking studies, pointing to a strong binding interaction with the enzyme plasmepsin II.
Subject(s)
Antimalarials/chemical synthesis , Antimalarials/pharmacology , Aziridines/chemistry , Heptanes/chemical synthesis , Heptanes/pharmacology , Aluminum Compounds/chemistry , Antimalarials/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Cyclization , Heptanes/chemistry , Humans , Ligands , Lithium Compounds/chemistry , Molecular Docking Simulation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The increasing prevalence of multidrug-resistant strains of the malarial parasite Plasmodium falciparum requires the urgent development of new therapeutic agents with novel modes of action. The vacuolar malarial aspartic proteases plasmepsin (PM) I, II, and IV are involved in hemoglobin degradation and play a central role in the growth and maturation of the parasite in the human host. We report the structure-based design, synthesis, and in vitro evaluation of a new generation of PM inhibitors featuring a highly decorated 7-azabicyclo[2.2.1]heptane core. While this protonated central core addresses the catalytic Asp dyad, three substituents bind to the flap, the S1/S3, and the S1' pockets of the enzymes. A hydroformylation reaction is the key synthetic step for the introduction of the new vector reaching into the S1' pocket. The configuration of the racemic ligands was confirmed by extensive NMR and X-ray crystallographic analysis. In vitro biological assays revealed high potency of the new inhibitors against the three plasmepsins (IC(50) values down to 6â nM) and good selectivity towards the closely related human cathepsins D and E. The occupancy of the S1' pocket makes an essential contribution to the gain in binding affinity and selectivity, which is particularly large in the case of the PMâ IV enzyme. Designing non-peptidic ligands for PM II is a valid route to generate compounds that inhibit the entire family of vacuolar plasmepsins.
Subject(s)
Antimalarials/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aza Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Formaldehyde/chemistry , Heptanes/chemical synthesis , Plasmodium falciparum/enzymology , Protease Inhibitors/chemistry , Antimalarials/chemical synthesis , Antimalarials/metabolism , Antimalarials/pharmacology , Aspartic Acid Endopeptidases/chemistry , Aspartic Acid Endopeptidases/metabolism , Aza Compounds/chemistry , Aza Compounds/pharmacology , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacology , Heptanes/chemistry , Heptanes/pharmacology , Humans , Models, Molecular , Plasmodium falciparum/drug effects , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , StereoisomerismABSTRACT
The first total synthesis of prasinic acid is being reported along with its biological evaluation. The ten step synthesis involved readily available and cheap starting materials and can easily be transposed to large scale manufacturing. The crucial steps of the synthesis included the formation of two different aromatic units (7 and 9) and their coupling reaction. The synthetic prasinic acid exhibited moderate antitumor activity (IC(50) 4.3-9.1 µM) in different lines of cancer cells.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzoates/chemical synthesis , Benzoates/pharmacology , Heptanes/chemical synthesis , Heptanes/pharmacology , Antineoplastic Agents/chemistry , Benzoates/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Heptanes/chemistry , Humans , Inhibitory Concentration 50 , Molecular StructureABSTRACT
Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba-pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereochemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the α-face) with that of the 8(R)-CH(2)(â¢) radical in the ß-face. The conversion of 17 â 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely.
Subject(s)
Alkenes/chemistry , Free Radicals/chemistry , Heptanes/chemical synthesis , Pentoses/chemistry , Carbohydrate Conformation , Cyclization , Magnetic Resonance Spectroscopy , StereoisomerismABSTRACT
New 3-azabicyclo[3.2.0]heptane derivatives were synthesized using a multicomponent reaction. Racemic compounds were efficiently resolved by kinetic resolution with immobilized lipase B of Candida antarctica (Novozym 435). The obtained compounds demonstrated greater binding affinity at D(2L) and D(3) dopamine receptors compared to D(1) binding sites, and individual enantiomers of the same compound possessed distinct affinities.
Subject(s)
Fungal Proteins/metabolism , Heptanes/chemical synthesis , Heptanes/metabolism , Lipase/metabolism , Receptors, Dopamine/metabolism , Animals , Biocatalysis , Chemistry Techniques, Synthetic , Heptanes/chemistry , Humans , Kinetics , Ligands , Models, Molecular , Molecular Conformation , RatsABSTRACT
Thermolysis of a benzene solution of N-[4-(p-(methoxybenzyl)seleno)cyclohexanoyl]-N,S-dimethyldithiocarbonate affords the hitherto unknown 7-selenabicyclo[2.2.1]heptane in 48% conversion and in 20% yield after chromatography. G3(MP2)-RAD calculations predict a rate constant of 5 × 10(4) s(-1) at 80 °C (3.8 × 10(6) s(-1) at 200 °C) for the intramolecular homolytic substitution process involved in this cyclization.
Subject(s)
Bridged Bicyclo Compounds/chemistry , Heptanes/chemistry , Selenium/chemistry , Benzene/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Cyclization , Heptanes/chemical synthesis , TemperatureABSTRACT
The chemistry underlying how diazabicycloheptanes are assembled is described, subdivided according to chemical structure of two types, the 3,6 diazabicyclo[3.1.1]heptane and the 2,5-diazabicyclo[2.2.1]heptane ring system. Detailed information on myriad of activities of compounds derived from the two scaffolds are reported.
Subject(s)
Aza Compounds/chemistry , Bridged-Ring Compounds/chemistry , Heptanes/chemistry , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/metabolism , Analgesics/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Bacteria/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Heptanes/chemical synthesis , Heptanes/pharmacology , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/metabolism , Protein BindingABSTRACT
The gold(I)-catalysed cycloisomerisation of appropriately substituted 1,6-cyclopropene-enes proceeds through regioselective electrophilic ring opening of the three-membered ring to generate an alkenyl gold carbenoid that achieves the intramolecular cyclopropanation of the remote olefin. This strategy allows straightforward, highly efficient and diastereoselective access to a variety of substituted 3-oxa- and 3-azabicyclo[4.1.0]heptanes, as well as to bicyclo[4.1.0]heptan-3-ol derivatives. Since the isopropylidene group in the resulting cycloisomerisation products can be subjected to ozonolysis, 3,3-dimethylcyclopropenes behave as interesting surrogates for α-diazoketones.