RESUMO
As an underrepresented functional group in bioorganic and medicinal chemistry, the hydroxylamine unit has historically received little attention from the synthetic community. Recent developments, however, suggest that hydroxylamines may have broader applications such that a review covering recent developments in the synthesis of this functional group is timely. With this in mind, this review primarily covers developments in the past 15 years in the preparation of di- and trisubstituted hydroxylamines. The mechanism of the reactions and key features and shortcomings are discussed throughout the review.
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Magnesium dialkylamides react with alcohol-derived 2-methyl-2-tetrahydropyranyl alkyl peroxides (MTHPs) in tetrahydrofuran at 0 °C to give N,N,O-trisubstituted hydroxylamines suitable for medicinal chemistry purposes in good to excellent yields. A wide range of secondary alkyl and aryl amines and primary and secondary alcohol-derived MTHPs are compatible with the described reaction which, coupled with the enormous diversity of commercially available alcohols and secondary amines, suggests broad applicability of the reaction in fragment-based library design.
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The palladium/Lewis acid cocatalyzed ring-opening reaction of various C1-substituted unsymmetrical oxabenzonorbornadienes (OBD) with oxime nucleophiles was investigated. The effects of various C1 substituents were explored. Moderate to excellent yields and excellent regioselectivities were obtained for electron-withdrawing groups. The presence of electron-donating alkyl groups leads to isomerization of the corresponding OBD to afford the substituted naphthol derivatives. Additionally, a mechanism for the formation of C2 regioisomeric ring-opened products has been proposed.
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Metastases to the brain remain a significant problem in lung cancer, as treatment by most small-molecule targeted therapies is severely limited by efflux transporters at the blood-brain barrier (BBB). Here, we report the discovery of a selective, orally bioavailable, epidermal growth factor receptor (EGFR) inhibitor, 9, that exhibits high brain penetration and potent activity in osimertinib-resistant cell lines bearing L858R/C797S and exon19del/C797S EGFR resistance mutations. In vivo, 9 induced tumor regression in an intracranial patient-derived xenograft (PDX) murine model suggesting it as a potential lead for the treatment of localized and metastatic non-small-cell lung cancer (NSCLC) driven by activating mutant bearing EGFR. Overall, we demonstrate that an underrepresented functional group in medicinal chemistry, the trisubstituted hydroxylamine moiety, can be incorporated into a drug scaffold without the toxicity commonly surmised to accompany these units, all while maintaining potent biological activity and without the molecular weight creep common to drug optimization campaigns.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Barreira Hematoencefálica/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Hidroxilamina/metabolismo , Hidroxilamina/uso terapêutico , Hidroxilaminas/metabolismo , Hidroxilaminas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/químicaRESUMO
We describe an atypical amine bioisostere, the trisubstituted hydroxylamine, that upon incorporation into an approved dual cSRC/BCR-ABL1 kinase inhibitor yields 9, a compound that retains potent biological activity and couples it with improved drug efflux and hERG affinity at the expense of only a 2 atomic mass unit increase in molecular weight. Contrary to the common expectation for hydroxylamines in medicinal chemistry, 9 is well tolerated in vivo and lacks the mutagenicity and genotoxicity so often ascribed to lesser substituted hydroxylamines. A matched molecular pair (MMP) analysis suggests that the beneficial properties conferred by the N-alkyl to N-noralkoxy switch arises from a reduction in basicity of the piperazine unit. Overall, these results lend additional support to the use of trisubstituted hydroxylamines as bioisosteres of N-alkyl groups that are not involved in key polar interactions.
RESUMO
The influence of substitution of an N,N,O-trisubstituted hydroxylamine (-NR-OR'-) unit for a hydrocarbon (-CHR-CH2-), ether (-CHR-OR'-), or amine (-NR-CHR'-) moiety on lipophilicity and other ADME parameters is described. A matched molecular pair analysis was conducted across five series of compounds, which showed that the replacement of carbon-carbon bonds by N,N,O-trisubstituted hydroxylamines typically leads to a reduction in logP comparable to that achieved with a tertiary amine group. In contrast, the weakly basic N,N,O-trisubstituted hydroxylamines have greater logD 7.4 values than tertiary amines. It is also demonstrated that the N,N,O-trisubstituted hydroxylamine moiety can improve metabolic stability and reduce human plasma protein binding relative to the corresponding hydrocarbon and ether units. Coupled with recent synthetic methods for hydroxylamine assembly by N-O bond formation, these results provide support for the re-evaluation of the N,N,O-trisubstituted hydroxylamine moiety in small-molecule optimization schemes in medicinal chemistry.
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Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.
Assuntos
COVID-19 , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Animais , Inibidores de Proteases , SARS-CoV-2 , Ubiquitina/metabolismoRESUMO
The reaction of magnesium amides with tert-butyl 2,6-dimethyl perbenzoate in tetrahydrofuran at 0 °C provides a method for the synthesis O-tert-butyl-N,N-disubstituted hydroxylamines by direct N-O bond formation with a broad functional group tolerance. Less sterically hindered magnesium amides require ortho,ortho-disubstitution on the perester electrophile component, whereas sterically encumbered magnesium amides perform comparably with either tert-butyl perbenzoate or tert-butyl 2,6-dimethyl perbenzoate. A reaction mechanism is presented to account for the observed reactivity.