Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway

Hobbs, Heather; Bravi, Gianpaolo; Campbell, Ian B.; Convery, M.A.; Davies, H. G.; Inglis, Graham G. A.; Pal, Siladitya; Peace, Simon; Redmond, Joanna M.; Summers, Declan

doi:10.1021/acs.jmedchem.9b00348

Cited by 19 publications

(13 citation statements)

References 46 publications

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“…The phosphoinositide-3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway is involved in a number of cellular processes such as proliferation, metabolism, autophagy, differentiation, and survival . Therefore, Hobbs et al synthesized compound 12 , characterized by the presence of a 3-oxabicyclo[4.1.0]heptane all-carbon quaternary morpholine surrogate, as a multitarget (PI3K/AKT/MTOR) inhibitor . The X-ray structure of 12 revealed coplanarity between the pyrimidine ring and the 3-oxabicyclo[4.1.0]heptane moiety.…”

Section: Matched Molecular Pairs Of Quaternary Versus Secondary/terti...mentioning

confidence: 99%

“…54 Therefore, Hobbs et al synthesized compound 12, characterized by the presence of a 3-oxabicyclo[4.1.0]heptane all-carbon quaternary morpholine surrogate, as a multitarget (PI3K/AKT/MTOR) inhibitor. 55 The X-ray structure of 12 revealed coplanarity between the pyrimidine ring and the 3-oxabicyclo[4.1.0]heptane moiety. The authors postulated that the oxygen atom in a 3oxabicyclo[4.1.0]heptane ring is oriented optimally to engage in a key hydrogen bonding interaction with the target enzymes.…”

Section: Development Of G-protein-coupled Bile Acidmentioning

confidence: 99%

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Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

2020

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A quaternary carbon bears four other carbon substituents or combination of four non-hydrogen substituents at four vertices of a tetrahedron. The spirocyclic quaternary carbon positioned at the center of a bioactive molecule offers conformational rigidity, which in turn reduces the penalty for conformational entropy. The quaternary carbon is a predominant feature of natural product structures and has been associated with more effective and selective binding to target proteins compared to planar compounds with a high sp 2 count. The presence of a quaternary carbon stereocenter allows the exploration of novel chemical space to obtain new molecules with enhanced three-dimensionality. These characteristics, coupled to an increasing awareness to develop sp 3 -rich molecules, boosted utility of quaternary carbon stereocenters in bioactive compounds. It is hoped that this Perspective will inspire the chemist to utilize quaternary carbon stereocenters to enhance potency, selectivity, and other drug-like properties.

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Section: Matched Molecular Pairs Of Quaternary Versus Secondary/terti...mentioning

confidence: 99%

Section: Development Of G-protein-coupled Bile Acidmentioning

confidence: 99%

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

2020

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“…Several morpholine-containing pharmacophores have been identified as responsible for the selective interaction with specific molecular targets, such as aryl-morpholines interacting with PI3K kinase family or morpholine–azaindoles with cannabinoid receptors . They are structurally similar to endogenous neurotransmitters (as in the case of aryl-morpholines) and it has been demonstrated that they play a key role in improving the crossing of the blood-brain barrier.…”

Section: Introductionmentioning

confidence: 99%

“…Just to give some examples, doxapram (1976), 26 phendimetrazine (1979), 27 moclobemide (1992), 28 reboxetine (1997), 29 and aprepitant (2003) 30−32 are drugs with applications in several CNS diseases, mainly as anxiolytics and/or antidepressants. Several morpholine-containing pharmacophores have been identified as responsible for the selective interaction with specific molecular targets, such as aryl-morpholines interacting with PI3K kinase family 33 or morpholine−azaindoles with cannabinoid receptors. 34 They are structurally similar to endogenous neurotransmitters (as in the case of arylmorpholines) and it has been demonstrated that they play a key role in improving the crossing of the blood-brain barrier.…”

Section: ■ Introductionmentioning

confidence: 99%

Occurrence of Morpholine in Central Nervous System Drug Discovery

Lenci

Calugi

Trabocchi

2021

ACS Chem. Neurosci.

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Developing drugs for the central nervous system (CNS) requires fine chemical modifications, as a strict balance between size and lipophilicity is necessary to improve the permeability through the blood-brain barrier (BBB). In this context, morpholine and its analogues represent valuable heterocycles, due to their conformational and physicochemical properties. In fact, the presence of a weak basic nitrogen atom and of an oxygen atom at the opposite position provides a peculiar pK a value and a flexible conformation to the ring, thus allowing it to take part in several lipophilic−hydrophilic interactions, and to improve blood solubility and brain permeability of the overall structure. In CNS-active compounds, morpholines are used (1) to enhance the potency through molecular interactions, (2) to act as a scaffold directing the appendages in the correct position, and (3) to modulate pharmacokinetic/ pharmacodynamic (PK/PD) properties. In this perspective, selected morpholinecontaining CNS drug candidates are discussed to reveal the active pharmacophores accountable for the (1) modulation of receptors involved in mood disorders and pain, (2) bioactivity toward enzymes and receptors responsible for neurodegenerative diseases, and (3) inhibition of enzymes involved in the pathology of CNS tumors. The medicinal chemistry/pharmacological activity of morpholine derivatives is discussed, in the effort to highlight the importance of morpholine ring interactions in the active site of different targets, particularly reporting binding features retrieved from PDB data, when available.

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“…[67,68] Even tertiary cyclopropane-containing trifluoroborates are sufficiently reactive; an example can be provided by potassium 3-oxabicyclo [4.1.0]heptan-6-yltrifluoroborate (53), which was used in the cross-coupling with pyrimidine derivative 54 (Scheme 15 A). [69] This transformation was used by GSK scientists to introduce the 3-oxabicyclo[4.1.0]heptane motif as a morpholine isostere without a nitrogen atom and to develop novel inhibitors of the PI3 K-AKT-mTOR signaling pathway. A similar process involving azabicyclo[n.1.0]alkane-derived trifluoroborates 56 was used by Pfizer chemists in the synthesis of clinical candidates for the pain treatment.…”

Section: Suzuki-miyaura Cross-couplingmentioning

confidence: 99%

Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

Volochnyuk

Gorlova

Grygorenko

2021

Chemistry A European J

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This review discusses recent advances in the chemistry of saturated boronic acids, boronates, and trifluoroborates. Applications of the title compounds in the design of boron-containing drugs are surveyed, with special emphasis on α-amino boronic derivatives. A general overview of saturated boronic compounds as modern tools to construct C(sp 3 )À C and C(sp 3 )-heteroatom bonds is given, including recent developments in the Suzuki-Miyaura and Chan-Lam cross-couplings, single-electron-transfer processes including metallo-and organocatalytic photoredox reactions, and transformations of boron "ate" complexes. Finally, an attempt to summarize the current state of the art in the synthesis of saturated boronic acids, boronates, and trifluoroborates is made, with a brief mention of the "classical" methods (transmetallation of organolithium/magnesium reagents with boron species, anti-Markovnikov hydroboration of alkenes, and the modification of alkenyl boron compounds) and a special focus on recent methodologies (boronation of alkyl (pseudo)halides, derivatives of carboxylic acids, alcohols, and primary amines, boronative CÀ H activation, novel approaches to alkene hydroboration, and 1,2-metallate-type rearrangements).

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Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway

Cited by 19 publications

References 46 publications

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon

Occurrence of Morpholine in Central Nervous System Drug Discovery

Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

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