Highly Oxygenated Cyclobutane Ring in Biomolecules: Insights into Structure and Activity DOI Creative Commons
Valery M. Dembitsky

Oxygen, Journal Year: 2024, Volume and Issue: 4(2), P. 181 - 235

Published: May 22, 2024

This review explores the unique structural and functional characteristics of natural products featuring highly oxygenated cyclobutane rings, with a specific focus on oxetane 1,2-dioxetane motifs. It presents structures biological activities compounds containing these highlighting their contribution to molecular stability pharmacological potency. Through detailed case studies recent research findings, it has been demonstrated that oxygen-rich rings enhance diversity efficacy products, potentially offering new avenues for drug development. Notably, are predominantly synthesized by microorganisms can also be found in extracts from fungi, plants, certain marine invertebrates. Compounds primarily noted strong antineoplastic properties, among other activities. In contrast, most 1,2-dioxetanes exhibit potent antiprotozoal effects. is important note often serve as intermediate oxidation reactions, characterized instability propensity decompose into compounds.

Language: Английский

Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation DOI

Edna Mao,

Cesar N. Prieto Kullmer, Holt A. Sakai

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(8), P. 5067 - 5073

Published: Feb. 16, 2024

The replacement of a functional group with its corresponding bioisostere is widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties candidates while maintaining potency. However, incorporation bioisosteres typically requires lengthy de novo resynthesis potential candidates, which represents bottleneck in their broader evaluation. An alternative would be directly convert into at late stage. Herein, we report realization this approach through conversion aliphatic alcohols difluoromethylated analogues via merger benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)–CF2H bond formation. utility method showcased variety complex compounds.

Language: Английский

Citations

22
Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction DOI Creative Commons
Joseph M. Phelps, Roopender Kumar, James D. Robinson

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(13), P. 9045 - 9062

Published: March 15, 2024

Methods for the synthesis of α-branched alkylamines are important due to their ubiquity in biologically active molecules. Despite development many methods amine preparation, C(sp3)-rich nitrogen-containing compounds continue pose challenges synthesis. While carbonyl reductive amination (CRA) between ketones and is cornerstone method alkylamine synthesis, it sometimes limited by sterically demanding condensation step dialkyl amines more restricted availability compared aldehydes. We recently reported a "higher-order" variant this transformation, alkylative (CAA), which utilized halogen atom transfer (XAT)-mediated radical mechanism, enabling streamlined complex alkylamines. efficacy visible-light-driven approach, displayed scalability issues, competitive was problem certain substrate classes, limiting applicability. Here, we report change reaction regime that expands CAA platform through realization an extremely broad zinc-mediated reaction. This new strategy enabled elimination CRA, simplified purification, improved scope. Furthermore, harnessed carboxylic acid derivatives as alkyl donors facilitated α-trialkyl tertiary amines, cannot be accessed via CRA. Zn-mediated can carried out at variety scales, from 10 μmol setup microtiter plates high-throughput experimentation, gram-scale medicinally-relevant compounds. believe transformation enables robust, efficient, economical access provides viable alternative current benchmark methods.

Language: Английский

Citations

20
Catalytic difluorocarbene insertion enables access to fluorinated oxetane isosteres DOI
Tong‐De Tan, Fang Zhou, Kevin P. Quirion

et al.

Nature Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Language: Английский

Citations

2
Biocatalytic enantioselective formation and ring-opening of oxetanes DOI Creative Commons
Xia Hua, Yuanfei Wang, Xiao Jin

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 30, 2025

Although biocatalysis offers complementary or alternative approaches to traditional synthetic methods, the limited range of available enzymatic reactions currently poses challenges in synthesizing a diverse array desired compounds. Consequently, there is significant demand for developing novel biocatalytic processes enable that were previously unattainable. Herein, we report discovery and subsequent protein engineering unique halohydrin dehalogenase develop platform enantioselective formation ring-opening oxetanes. This platform, exhibiting high efficiency, excellent enantioselectivity, broad scopes, facilitates preparative-scale synthesis chiral oxetanes variety γ-substituted alcohols. Additionally, both oxetane are proven scalable large-scale transformations at substrate concentrations, can be integrated efficiently one-pot, one-catalyst cascade system. work expands toolbox non-natural will promote further exploration catalytic repertoire dehalogenases pharmaceutical chemistry. Oxetane four-membered, oxygen-containing heterocyclic compound importance medicinal chemistry drug development. Here, authors dehalogenase,

Language: Английский

Citations

1
Taming 3-Oxetanyllithium Using Continuous Flow Technology DOI Creative Commons
Philipp Natho, Marco Colella, Michael Andresini

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(15), P. 3032 - 3036

Published: March 28, 2024

The oxetane ring has evolved as a useful bioisostere for dimethyl and carbonyl groups the improvement of physiochemical properties drug candidates. Herein, we report generation utilization highly unstable 3-oxetanyllithium hitherto unexplored nucleophile leveraging flash technology. A range different electrophiles are suitable reaction partners in this protocol, demonstrate utility protocol late-stage pharmaceutical analogue synthesis.

Language: Английский

Citations

7
Photoinduced arylative formal 4-endo-dig cyclization of propargyl alcohols/amines to access strained heterocycles DOI
Pammi Venka Reddy, Attunuri Nagireddy, Jagadeesh Babu Nanubolu

et al.

Green Chemistry, Journal Year: 2024, Volume and Issue: 26(5), P. 2705 - 2711

Published: Jan. 1, 2024

A novel synthetic strategy to access strained heterocycles is revealed through photocatalysed annulative formal 4- endo-dig cyclization of propargyl alcohols/amines with benzoquinones under catalyst/reagent-free conditions using non-hazardous solvent.

Language: Английский

Citations

6
Modular Access to Functionalized Oxetanes as Benzoyl Bioisosteres DOI

Dayu Tian,

Guang Chen, Xiaocheng Wang

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(26), P. 18011 - 18018

Published: June 21, 2024

Bioisosterism is a valuable principle exploited in drug discovery to fine-tune physicochemical properties of bioactive compounds. Functionalized 3-aryl oxetanes, as an important class bioisosteres for benzoyl groups (highly prevalent structures approved drugs), have been rarely utilized agrochemicals and pharmaceuticals due significant synthetic challenges. Here, we present modular strategy based on the unexplored yet readily available reagents, oxetanyl trichloroacetimidates, inspired by Schmidt glycosylation, enabling easy access library functionalized oxetanes. This operationally simple protocol leverages vast existing libraries aryl halides various nucleophiles. The power generality this approach demonstrated late-stage functionalization complex molecules, well rapid synthesis oxetane analogues molecules marketed drugs. Preliminary mechanistic study suggests that oxygen atom ring plays crucial role stabilizing carbocation intermediates.

Language: Английский

Citations

5
Occurrence of “Natural Selection” in Successful Small Molecule Drug Discovery DOI Creative Commons
Anna Lina Heinzke, Axel Pahl, Barbara Zdrazil

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(13), P. 11226 - 11241

Published: July 1, 2024

Published compounds from ChEMBL version 32 are used to seek evidence for the occurrence of "natural selection" in drug discovery. Three measures natural product (NP) character were applied, compare time- and target-matched reaching clinic (clinical phase 1-3 development approved drugs) with background (reference compounds). Pseudo-NPs (PNPs), containing NP fragments combined ways inaccessible by nature, increasing over time, 67% clinical first disclosed since 2010. PNPs 54% more likely be found post-2008 versus reference compounds. The majority target classes show increased compound their Only 176 appear >1000 published 2008, yet these make up on average 63% compound's core scaffolds. There is untapped potential awaiting exploitation, applying nature's building blocks─"natural intelligence"─to design.

Language: Английский

Citations

5
The Discovery and Preclinical Profile of ALG-000184, a Prodrug of the Potent Hepatitis B Virus Capsid Assembly Modulator ALG-001075 DOI

Sandrine Vendeville,

Franck Amblard,

Leda Bassit

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Chronic hepatitis B (CHB) represents a significant unmet medical need with few options beyond lifelong treatment nucleoside analogues, which rarely leads to functional cure. Novel agents that reduce levels of HBV DNA, RNA and other viral antigens could lead better outcomes. The capsid assembly modulator (CAM) class compounds an important modality for chronic suppression improve cure rates, either alone or in combination.

Language: Английский

Citations

5
Selective Synthesis of Tetrahydro Oxepines by Cu‐Catalyzed Condensations of Diazomalonates and gem‐Dialkyl Vinyl Oxetanes DOI Creative Commons
Claire Montagnon, Romain Pertschi, Céline Besnard

et al.

Advanced Synthesis & Catalysis, Journal Year: 2024, Volume and Issue: 366(5), P. 1070 - 1077

Published: Jan. 15, 2024

Abstract Thanks to an unprecedented gem ‐dialkyl substituent effect, efficient synthesis of tetrahydro oxepine derivatives is achieved by ring expansion vinyl oxetanes using acceptor(−acceptor) diazo reagents under Cu(II)‐catalysis. A large scope 2‐vinyl and either mono or diester give access a series functionalized oxepines.

Language: Английский

Citations

4