Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane.

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.

Scalable Preparation of Enantioenriched (S)-5-methylhept-2-en-4-one. Synthesis and Aroma Properties of Achiral Analogues Thereof.

(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.

Design and synthesis of estrogen receptor ligands with a 4-heterocycle-4-phenylheptane skeleton.

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.

Bicyclo[3.2.0]heptane as a Core Structure for Conformational Locking of 1,3-Bis-Pharmacophores, Exemplified by GABA.

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.

1-Substituted 2-Azaspiro[3.3]heptanes: Overlooked Motifs for Drug Discovery.

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.

Synthesis and antibacterial evaluation of macrocyclic diarylheptanoid derivatives.

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.

Synthesis of Novel Nucleoside Analogues Built on a Bicyclo[4.1.0]heptane Scaffold.

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.

Transnitrosylation directs TRPA1 selectivity in N-nitrosamine activators.

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.

Potent inhibitors of malarial aspartic proteases, the plasmepsins, by hydroformylation of substituted 7-azanorbornenes.

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 6 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 PM IV enzyme. Designing non-peptidic ligands for PM II is a valid route to generate compounds that inhibit the entire family of vacuolar plasmepsins.

Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH4-induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity.

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.

Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists.

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.

Gold(I)-catalysed cycloisomerisation of 1,6-cyclopropene-enes.

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.

Steric effects in the tuning of the diastereoselectivity of the intramolecular free-radical cyclization to an olefin as exemplified through the synthesis of a carba-pentofuranose scaffold.

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)(•) radical in the ß-face. The conversion of 17 → 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.

7-Azabicyclo[2.2.1]heptane as a scaffold for the development of selective sigma-2 (σ2) receptor ligands.

A series of N-substituted 7-azabicyclo[2.2.1]heptanes (12-17 and 22-25) and similarly substituted pyrrolidines (32-36 and 41-44) were synthesized as sterically-reduced, achiral analogs of adamantane- and trishomocubane-derived σ ligands. In vitro competition binding assays against σ receptors revealed that arylalkyl N-substituents conferred selectivity for the σ(2) subtype, while alicyclic or polycarbocyclic substituents imparted high affinity for both subtypes. The σ(2) binding and subtype selectivities of N-arylalkyl-7-azanorbornanes was generally greater than the analogously-substituted pyrrolidines, indicating that steric bulk and conformational restriction around the nitrogen atom are likely important for subtype discrimination.

First total synthesis of prasinic acid and its anticancer activity.

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.

Convergent and stereodivergent synthesis of complex 1-aza-7-oxabicyclo[2.2.1]heptanes.

A convergent and stereodivergent pathway to highly substituted 1-aza-7-oxabicyclo[2.2.1]heptanes is described. It begins with a coupling reaction involving allylic alcohol, aldehyde, and LiHMDS to produce stereodefined primary homoallylic amines. Subsequent N-oxidation and condensation with formaldehyde or glyoxylate defines a convenient entry to densely functionalized homoallylic nitrones whose intramolecular annulation can be controlled to deliver one of two distinct heterocyclic skeletons, each with ≥20:1 stereoselection. Control of the stereochemistry in these reactions results from both control of the nitrone geometry and selective partitioning of the reaction pathway between direct [3 + 2] cycloaddition and tandem [3,3] rearrangement/[3 + 2] cycloaddition.

Synthesis of (S)-7-amino-5-azaspiro[2.4]heptane via highly enantioselective hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropanecarboxylates.

Highly effective asymmetric hydrogenation of protected ethyl 1-(2-aminoaceto)cyclopropane carboxylates in the presence of [RuCl(benzene)(S)-SunPhos]Cl was realized, and high enantioselectivities (up to 98.7% ee) were obtained. This asymmetric hydrogenation provides a key intermediate for the enantioselective synthesis of (S)-7-amino-5-azaspiro[2.4]heptane moiety of quinolone antibacterial agents.

Synthesis and antiviral activity of cyclopropyl-spirocarbocyclic adenosine, (4R,5S,6R,7R)-4-(6-amino-9H-purin-9-yl)-7-(hydroxymethyl)spiro[2.4]heptane-5,6-diol against hepatitis C virus.

An efficient method was developed for the synthesis of 6-exocyclic methylene carbocyclic intermediate 4. The Simmons-Smith cyclopropanation protocol was applied on the 6-exocyclic methylene of intermediate 4 and demonstrated its utility for the synthesis of novel class of a spiro-carbocyclic nucleoside analog 8. The titled compound 8 demonstrated a significant antiviral activity against HCV with EC(50) values of 0.273 and 0.368 µM in genotypes 1A and 1B, respectively.

1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo[4.1.0]heptane: further insights into a class of triple re-uptake inhibitors.

Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.

Syntheses and structure-activity relationship (SAR) studies of 2,5-diazabicyclo[2.2.1]heptanes as novel alpha7 neuronal nicotinic receptor (NNR) ligands.

Biaryl substituted 2,5-diazabicyclo[2.2.1]heptanes have been synthesized and tested for their affinity toward alpha7 neuronal nicotinic receptors (NNRs). SAR studies established that 5-N-methyl substituent, heteroaryl linker and the nature of terminal aryl group are critical for the ligand to achieve potent alpha7 NNR agonist activity.