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1.
Brief Bioinform ; 25(3)2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38581415

RESUMO

Discovering hit molecules with desired biological activity in a directed manner is a promising but profound task in computer-aided drug discovery. Inspired by recent generative AI approaches, particularly Diffusion Models (DM), we propose Graph Latent Diffusion Model (GLDM)-a latent DM that preserves both the effectiveness of autoencoders of compressing complex chemical data and the DM's capabilities of generating novel molecules. Specifically, we first develop an autoencoder to encode the molecular data into low-dimensional latent representations and then train the DM on the latent space to generate molecules inducing targeted biological activity defined by gene expression profiles. Manipulating DM in the latent space rather than the input space avoids complicated operations to map molecule decomposition and reconstruction to diffusion processes, and thus improves training efficiency. Experiments show that GLDM not only achieves outstanding performances on molecular generation benchmarks, but also generates samples with optimal chemical properties and potentials to induce desired biological activity.


Assuntos
Benchmarking , Descoberta de Drogas , Difusão
2.
Proc Natl Acad Sci U S A ; 119(11): e2113237119, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35259015

RESUMO

SignificanceWe first observed a transient chirality inversion on a simple unimolecular platform during the racemization of a chiral helical complex [LCo3A6]3+, i.e., the helicity changed from P-rich (right-handed) to M-rich (left-handed), which then racemized to a P/M equimolar mixture in spite of the absence of a reagent that could induce the M helix. This transient chirality inversion was observed only in the forward reaction, whereas the reverse reaction showed a simple monotonic change with an induction time. Consequently, the M helicity appeared only in the forward reaction. These forward and reverse reactions constitute a hysteretic cycle. Compounds showing such unique time responses would be useful for developing time-programmable switchable materials that can control the physical/chemical properties in a time-dependent manner.

3.
Chem Soc Rev ; 53(1): 263-316, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38059728

RESUMO

The employment of light and/or electricity - alternatively to conventional thermal energy - unlocks new reactivity paradigms as tools for chemical substrate activations. This leads to the development of new synthetic reactions and a vast expansion of chemical spaces. This review summarizes recent developments in photo- and/or electrochemical activation strategies for the functionalization of strong bonds - particularly carbon-heteroatom (C-X) bonds - via: (1) direct photoexcitation by high energy UV light; (2) activation via photoredox catalysis under irradiation with relatively lower energy UVA or blue light; (3) electrochemical reduction; (4) combination of photocatalysis and electrochemistry. Based on the types of the targeted C-X bonds, various transformations ranging from hydrodefunctionalization to cross-coupling are covered with detailed discussions of their reaction mechanisms.

4.
Angew Chem Int Ed Engl ; 63(19): e202402050, 2024 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-38488804

RESUMO

Germacranolides, secondary metabolites produced by plants, have garnered academic and industrial interest due to their diverse and complex topology as well as a wide array of pharmacological activities. Molephantin, a highly oxygenated germacranolide isolated from medicinal plants, Elephantopus mollis and Elephantopus tomentosus, has exhibited antitumor, inflammatory, and leishmanicidal activities. Its chemical structure is based on a highly strained ten-membered macrocyclic backbone with an (E,Z)-dienone moiety, which is fused with an α-methylene-γ-butyrolactone and adorned with four successive stereogenic centers. Herein, we report the first synthesis of molephantin in 12 steps starting from readily available building blocks. The synthesis features the highly diastereoselective intermolecular Barbier allylation of the ß,γ-unsaturated aldehyde with optically active 3-bromomethyl-5H-furan-2-one intermediate and ensuing Nozaki-Hiyama-Kishi (NHK) macrocyclization for the construction of the highly oxygenated ten-membered macrocyclic framework. This synthetic route enabled access to another germacranolide congener, tomenphantopin F. Furthermore, cycloisomerization of molephantin into 2-deethoxy-2ß-hydroxyphantomolin could be facilitated by irradiation with ultraviolet A light (λmax=370 nm), which opened a versatile and concise access to the related furanogermacranolides such as EM-2, phantomolin, 2-O-demethyltomenphantopin C, and tomenphantopin C.


Assuntos
Oxigênio , Oxigênio/química , Asteraceae/química , Estereoisomerismo , Sesquiterpenos de Germacrano/química , Sesquiterpenos de Germacrano/síntese química , Furanos/química , Furanos/síntese química , Estrutura Molecular
5.
Angew Chem Int Ed Engl ; 62(10): e202217735, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36637448

RESUMO

A protocol for the generation of allylmagnesium reagents from 2-aryl-1,3-dienes was developed using magnesium hydride (MgH2 ) that is generated in situ by solvothermal treatment of sodium hydride (NaH) and magnesium iodide (MgI2 ) in tetrahydrofuran (THF). Downstream functionalization of the resulting allylmagnesium reagents with carbonyl compounds or alkyl (pseudo)halides delivers branched products having an allylic quaternary carbon center, whereas that with chlorosilanes resulted in formation of linear allylsilanes in regio and stereoselective manners. Further derivatizations of the homoallylic alcohols and allylsilanes were also demonstrated.

6.
Angew Chem Int Ed Engl ; 62(40): e202309764, 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37582050

RESUMO

The facile construction of C(sp3 )-rich carbo- and heterocyclic compounds is a pivotal synthetic strategy to foster contemporary drug discovery programs. The downstream dearomatization of readily accessible two-dimensional (2D) planar arenes represents a direct pathway towards accessing three-dimensional (3D) aliphatic scaffolds. Here, we demonstrate that polysulfide anions are capable of catalyzing a dearomatization process of substituted naphthalenes, indoles, and other related heteroaromatic compounds in the presence of potassium formate and methanol under visible light irradiation. The developed protocol exhibits broad functional group tolerance, operational simplicity, scalability, and cost-effectiveness, representing a practical and sustainable synthetic tool for the arene dearomatization.

7.
J Am Chem Soc ; 143(1): 481-487, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33356206

RESUMO

Polysulfide anions are endowed with unique redox properties, attracting considerable attentions for their applications in alkali metals-sulfur batteries. However, the employment of these anionic species in redox catalysis for small molecule synthesis remains underdeveloped due to their moderate-poor electrochemical potential in the ground state, whereas some of them are characterized by photoabsorptions in visible spectral regions. Herein, we disclose the use of polysulfide anions as visible light photoredox catalysts for aryl cross-coupling reactions. The reaction design enables single-electron reduction of aryl halides upon the photoexcitation of tetrasulfide dianions (S42-). The resulting aryl radicals are engaged in (hetero)biaryl cross-coupling, borylation, and hydrogenation in a redox catalytic regime involving S4• -/S42- and S3• -/S32- redox couples.

8.
Angew Chem Int Ed Engl ; 60(1): 217-221, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32936502

RESUMO

A protocol for regio-controlled hydromagnesiation of 1,3-enynes was developed using magnesium hydride that is generated in situ by solvothermal treatment of sodium hydride (NaH) and magnesium iodide (MgI2 ) in THF. The resulting allenylmagnesium species could be converted into tri- and tetra-substituted allenes by subsequent treatment with various carbon- and silicon-based electrophiles with the aid of CuCN as a catalyst.

9.
Chemistry ; 26(37): 8230-8234, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32428360

RESUMO

A catalytic enantioselective synthesis of ß-amino secondary amides was achieved using vinyl azides as the enamine-type nucleophile and chiral N-Tf phosphoramide as the chiral Brønsted acid catalyst through a five-step sequential transformation in one pot. The established sequential transformation involves an enantioselective [4+2] cycloaddition reaction of vinyl azides with N-acyl imines as the key stereo-determining step that is efficiently accelerated by a chiral N-Tf phosphoramide catalyst in a highly enantioselective manner in most cases. Further generation of the iminodiazonium ion intermediate through ring opening of the cycloaddition product and subsequent skeletal rearrangement involving Schmidt-type 1,2-aryl group migration followed by recyclization of the resulting nitrilium ion were also initiated by the same acid catalyst. Final acid hydrolysis of the recyclized products in the same pot gave rise to enantioenriched ß-amino amides through C-C bond formation at the α-position of the secondary amides.

10.
Angew Chem Int Ed Engl ; 59(29): 11903-11907, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-32329555

RESUMO

A new method for the synthesis of α-branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional-group compatibility, operates under transition-metal-free reaction conditions, and is suitable for various synthetic applications on both sub-millimole and on multigram scales.

11.
Chemistry ; 25(12): 2962-2966, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30600562

RESUMO

We developed a new strategy, ligand exchange strategy, for tuning the response speeds of helicity inversion of a metal-containing helical structure. This is based on the exchange of the two axial amine ligands of the octahedral Co3+ centers in the metallocryptands [LCo3 X6 ] (X=axial amine ligand). The response speeds of the helicity induction were controlled by using different combinations of achiral and chiral amines as the starting and entering ligands, respectively. The response speeds of the helicity inversion from P to M were also tuned by using different combinations of chiral amines.

12.
Angew Chem Int Ed Engl ; 58(15): 4992-4997, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30761712

RESUMO

New protocols for controlled reduction of carboxamides to either alcohols or amines were established using a combination of sodium hydride (NaH) and zinc halides (ZnX2 ). Use of a different halide on ZnX2 dictates the selectivity, wherein the NaH-ZnI2 system delivers alcohols and NaH-ZnCl2 gives amines. Extensive mechanistic studies by experimental and theoretical approaches imply that polymeric zinc hydride (ZnH2 )∞ is responsible for alcohol formation, whereas dimeric zinc chloride hydride (H-Zn-Cl)2 is the key species for the production of amines.

13.
Angew Chem Int Ed Engl ; 58(46): 16368-16388, 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30990931

RESUMO

Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cSN Ar) rather than classical, two-step, SN Ar mechanisms. Whereas traditional SN Ar reactions require substantial activation of the aromatic ring by electron-withdrawing substituents, such activating groups are not mandatory in the concerted pathways.

14.
Int J Mol Sci ; 19(10)2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30241392

RESUMO

BACKGROUND: Peroxisome proliferator⁻activated receptor (PPAR) ß/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARß/δ has been linked to carcinogenesis and was reported to inhibit melanoma cell proliferation, anchorage-dependent clonogenicity and ectopic xenograft tumorigenicity. However, PPARß/δ's role in tumour progression and metastasis remains controversial. METHODS: In the present studies, the consequence of PPARß/δ inhibition either by global genetic deletion or by a specific PPARß/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models. RESULTS: Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparß/δ-/- mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparß/δ-/- mice as demonstrated in the same animal model. CONCLUSION: These results indicated a protective role of PPARß/δ in melanoma progression and metastasis.


Assuntos
Melanoma/genética , Metástase Neoplásica/genética , PPAR delta/fisiologia , PPAR beta/fisiologia , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Melanoma/patologia , Camundongos , Invasividade Neoplásica/genética , Metástase Neoplásica/patologia , PPAR delta/genética , PPAR delta/metabolismo , PPAR beta/genética , PPAR beta/metabolismo
15.
Angew Chem Int Ed Engl ; 57(21): 6181-6185, 2018 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-29575429

RESUMO

A new protocol for the deoxygenation of alcohols and the hydrogenation of alkenes under Brønsted acid catalysis has been developed. The method is based on the use of either a benzyl or isopropyl ether as a traceless hydrogen-atom donor, and involves an intramolecular hydride transfer as a key step, which is achieved in a regio- and stereoselective manner.

16.
Beilstein J Org Chem ; 14: 3047-3058, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30591827

RESUMO

The degenerative transfer of xanthates to olefins is enabled by the iridium-based photocatalyst [Ir{dF(CF3)ppy}2(dtbbpy)](PF6) under blue LED light irradiation. Detailed mechanistic investigations through kinetics and photophysical studies revealed that the process operates under a radical chain mechanism, which is initiated through triplet-sensitization of xanthates by the long-lived triplet state of the iridium-based photocatalyst.

17.
Bioconjug Chem ; 28(4): 897-902, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-28212596

RESUMO

Herein, we report use of 2-azidoacrylates to perform site-specific dual functionalization of the cysteine residue of peptides and bovine serum albumin (BSA), a native protein containing one free cysteine residue. The sulfhydryl group of the cysteine residue could be conjugated with 2-azidoacrylates bearing various functionalities, such as fluorescent dyes under physiological aqueous buffer conditions, to afford peptide and protein conjugates anchoring an azide moiety. Successive azide-alkyne cycloaddition enables installation of the second functionality, thus affording dual-functionalized peptide- and protein-based materials.


Assuntos
Acrilatos/química , Azidas/química , Cisteína/química , Peptídeos/química , Soroalbumina Bovina/química , Alcinos/química , Animais , Bovinos , Química Click , Corantes Fluorescentes/química , Modelos Moleculares , Compostos de Sulfidrila/química
18.
J Org Chem ; 82(23): 11981-11989, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29091436

RESUMO

Among organic azides, vinyl azides have shown versatile chemical reactivities in the recent development of new synthetic methodologies mainly for nitrogen-containing molecules. This synopsis highlights and discusses recent advances on use of vinyl azides in chemical synthesis as a radical acceptor and an enamine-type nucleophile.

19.
Chem Soc Rev ; 45(16): 4504-23, 2016 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-26865058

RESUMO

This review updates recent advances in Cu-catalyzed (anaerobic) oxidative carbon-heteroatom bond formation on sp(3)- and sp(2)-C-H bonds as well as alkenes, classified according to the types of stoichiometric oxidants.

20.
Angew Chem Int Ed Engl ; 56(23): 6544-6547, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28449253

RESUMO

A new protocol for amide-directed ortho and lateral C-H sodiation is enabled by sodium hydride (NaH) in the presence of either sodium iodide (NaI) or lithium iodide (LiI). The transient organosodium intermediates could be transformed into functionalized aromatic compounds.

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