Ethynyl hydrogen bonds and iodoethynyl halogen bonds: a case of synthon mimicry

Aakeröy, Christer B.; Welideniya, Dhanushi; Desper, John

doi:10.1039/c6ce02201d

Cited by 20 publications

(6 citation statements)

References 27 publications

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“…Activated iodine has shown the ability of forming interactions with the π-electron density of a triple bond which can act as a halogen bond acceptor [46][47][48]. In the complex [Cu(L3) 2 ], mainly halogen· · · π interactions and halogen· · · oxygen interactions are observed due to the absence of a competitive halogen bond acceptor solvent.…”

Section: Discussionmentioning

confidence: 99%

The Role of Halogen Bonding in Controlling Assembly and Organization of Cu(II)-Acac Based Coordination Complexes

et al. 2017

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Abstract:In order to explore the use of non-covalent interactions in the deliberate assembly of metal-supramolecular architectures, a series of β-diketone based ligands capable of simultaneously acting as halogen-bond donors and chelating ligands were synthesized. The three ligands, L1, L2, and L3, carry ethynyl-activated chlorine, bromine, and iodine atoms, respectively and copper(II) complexes of all three ligands were crystallized from different solvents, acetonitrile, ethyl acetate, and nitromethane in order to study specific ligand-solvent interaction. The free ligands L2 and L3, with more polarizable halogen atoms, display C-X· · · O halogen bonds in the solid state, whereas the chloro-analogue (L1) does not engage in halogen bonding. Both acetonitrile and ethyl acetate act as halogen-bond acceptors in Cu(II)-complexes of L2 and L3 whereas nitromethane is present as a 'space-filling' guest without participating in any significant intermolecular interactions in Cu(II)-complexes of L2. L3, which is decorated with an iodoethynyl moiety and consistently engages in halogen-bonds with suitable acceptors. This systematic structural analysis allows us to rank the relative importance of a variety of electron-pair donors in these metal complexes.

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Section: Discussionmentioning

confidence: 99%

The Role of Halogen Bonding in Controlling Assembly and Organization of Cu(II)-Acac Based Coordination Complexes

et al. 2017

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“…Br and Cl (especially when associated with an electron-withdrawing group like the 4-F in 13d) are capable of forming halogen bonds while F can't [40]. The ethynyl group (as a 'supramolecular halogen' [41]) is capable of forming a hydrogen bond equivalent to the halogen bond [42]. Based on these assumptions, we can hypothesize that the activity against EGFR requires the formation of a halogen bond in the hydrophobic pocket I.…”

Section: (D) Compounds With Poor Egfr Inhibition (18-21%) and Poor Her2mentioning

confidence: 99%

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

Milik

Abdel-Aziz

Lasheen

et al. 2018

European Journal of Medicinal Chemistry

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In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.

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“…Access to calculated molecular electrostatic potential surface maps on molecules with multiple acceptors and donors provides valuable information for estimating the most probable binding preferences for a target molecule in co-crystallization experiments (Perera et al, 2016;Aakerö y et al, 2013Aakerö y et al, , 2015. Both the mimic and erlotinib contain the same type of potential hydrogen-bond acceptors and both are equipped with an ethynyl group and an N-H moiety which are capable of acting as hydrogen-bond donors (Engle et al, 2011;Aakerö y et al, 2017). Electrostatic potentials were calculated via density functional theory (B3LYP) (Tirado-Rives & Jorgensen, 2008) using 6-31G*basis set in vacuum with Spartan 0 08 (Wavefunction, 2008) software.…”

Section: Molecular Electrostatic Potential Calculations Of Em and Erlmentioning

confidence: 99%

Using structural mimics for accessing and exploring structural landscapes of poorly soluble molecular solids

Perera

Sinha

Aakeröy

2018

Acta Crystallogr Sect B

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The importance of using structural mimics for mapping out the structural landscape of a poorly soluble active pharmaceutical ingredient was investigated using erlotinib as an example. A mimic was synthesized by preserving the main molecular functionalities responsible for creating the most probable structural arrangements in the solid state. Calculated molecular electrostatic potentials on both erlotinib and the mimic showed very comparable values indicating that the latter would be able to form hydrogen bonds of similar probability and strength as those of erlotinib. In order to establish the binding preference in cocrystallization experiments, the mimic molecule was co-crystallized with US Food and Drug Administration approved dicarboxylic acids. The crystal structures of the mimic and of four co-crystals thereof were obtained. The mimic forms hydrogen bonds in a way that closely resembles those found in the crystal structure of erlotinib. The four co-crystals display self-consistent hydrogen-bond interactions. Thermal and solubility data for the co-crystals demonstrate that by making systematic and controllable changes to the solid forms of the mimic, it is also possible to alter the behaviour and properties of the new solid forms. The use of a suitable structural mimic can allow for a systematic structural examination of a compound that is otherwise not amenable to such investigations by facilitating the elucidation and mapping out of a closely related structural landscape.

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Ethynyl hydrogen bonds and iodoethynyl halogen bonds: a case of synthon mimicry

Abstract: The common electrostatic features of ethynyl and iodoethynyl hydrogen- and halogen-bond donors, respectively, lead to synthon mimicry which can be employed in synthetic crystal engineering for the construction of identical supramolecular assemblies in the solid-state.

Cited by 20 publications

References 27 publications

The Role of Halogen Bonding in Controlling Assembly and Organization of Cu(II)-Acac Based Coordination Complexes

The Role of Halogen Bonding in Controlling Assembly and Organization of Cu(II)-Acac Based Coordination Complexes

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

Using structural mimics for accessing and exploring structural landscapes of poorly soluble molecular solids

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