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1.
Molecules ; 28(22)2023 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-38005375

RESUMO

A facile and efficient visible-light-mediated method for directly converting 1,4-naphthoquinones into dihydrocyclo-buta[b]naphthalene-3,8-diones (DHCBNDOs) under mild and clean conditions without using any photocatalysts is reported. This approach exhibited favorable compatibility with functional groups and afforded a series of DHCBNDOs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

2.
J Org Chem ; 87(17): 11888-11898, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-35976796

RESUMO

An efficient one-pot reaction of propargylamides, isocyanides, and water catalyzed by zinc was developed for the rapid construction of 2-oxazolines with a wide functional group tolerance. The methylene-3-oxazoline was proven to play a vitally important role to start the tandem cascade transformation through unfunctionalized alkynes with sequential nucleophilic addition approaches of isocyanide and water. Notably, with a slight alteration of the reaction temperature and the addition of one molecule of water, various ß-amino amide derivatives were synthesized in good to excellent yields.


Assuntos
Amidas , Cianetos , Estrutura Molecular , Água , Zinco
3.
J Org Chem ; 87(1): 823-834, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34918940

RESUMO

Structurally unique 2,2-disubstituted indolin-3-ones with a quaternary carbon center have been constructed through a novel C-C bond formation at the C3 position of Ugi N-acylamino amide adducts employing an organic base-mediated Dieckmann condensation. This facile, flexible protocol can be fine-tuned to construct drug-like pyrazino[1,2-a]indole fragments with the same quaternary carbon center only through the variation of the acid part in Ugi input. This novel and expeditious methodology has a broad scope and can rapidly generate the drug-like indolin-3-one core.


Assuntos
Amidas , Indóis , Carbono , Estrutura Molecular
4.
Biol Res ; 54(1): 27, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488902

RESUMO

BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.


Assuntos
Autofagia , Neoplasias da Próstata , Apoptose , Linhagem Celular Tumoral , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Espécies Reativas de Oxigênio , Triterpenos
5.
J Org Chem ; 85(19): 12785-12796, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32847359

RESUMO

Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated gem-diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2 succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.

6.
Beilstein J Org Chem ; 16: 663-669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32318123

RESUMO

A facile microwave-assisted method for the synthesis of tetramic acid derivatives has been developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction has the potential to produce a large number of tetramic acid analogues, which cannot be easily accessed by the classic synthetic methods.

7.
J Org Chem ; 84(19): 12632-12638, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31357859

RESUMO

A facile and metal-free one-pot protocol for the synthesis of fused imidazopyridine scaffolds has been developed. This novel protocol combines the Groebke-Blackburn-Bienaymé reaction (GBBR) with a sequential TBAB-mediated cyclization cascade. Biological evaluation demonstrated that compound 6a inhibits human prostate cancer cell DU-145 proliferation with an IC50 of 1.6 µM. The molecular mechanism study indicates that 6a significantly suppresses the oncogenic Erk kinase phosphorylation at 3 µM.


Assuntos
Antineoplásicos/farmacologia , Imidazóis/farmacologia , Piridinas/farmacologia , Compostos de Amônio Quaternário/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ciclização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/química , Micro-Ondas , Modelos Moleculares , Estrutura Molecular , Piridinas/química , Compostos de Amônio Quaternário/química
8.
Chemistry ; 24(26): 6732-6736, 2018 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-29676029

RESUMO

A post-Ugi diastereoselective one-pot cascade reaction requiring no metal catalyst was developed. The reaction scope was wide with mild conditions and good yields. A collection of spiroindolines was prepared by the protocol and screening tests in several difficult-to-inhibit cancer cell lines were conducted. The relationship of structure and anticancer activities was promising and in the Huh7 cell lines compound 16 j is more potent than Vinbalstine. The cyclization design strategy could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like heterocycles.


Assuntos
Antineoplásicos/química , Indóis/química , Compostos de Espiro/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ciclização , Humanos , Indóis/síntese química , Indóis/farmacologia , Metais/química , Conformação Molecular , Estereoisomerismo
9.
Mol Divers ; 22(2): 503-516, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29340996

RESUMO

Isocyanide-based multicomponent reactions are among the most powerful synthetic tools available. Particularly, the isocyanide-based Ugi reaction can allow rapid preparation of [Formula: see text]-aminoacyl amide derivatives and polyazaheterocycles with extensive pharmaceutical applications. Moreover, bridged polyazaheterocycles, including one or more quaternary carbon centers, can be constructed via the Ugi cascade reaction in a few steps. This review will emphasize synthesis and bioactivities of bridged compounds with quaternary centers constructed through Ugi cascade reactions.


Assuntos
Compostos Heterocíclicos/química , Compostos Aza/química
10.
Mol Divers ; 20(2): 575-80, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26577113

RESUMO

Two series of fused benzimidazoles were synthesized via a facile, one-pot procedure under microwave irradiation. This procedure generated the desired products in high yields and could provide a useful synthetic platform with potential applications in medicinal chemistry.


Assuntos
Benzimidazóis/química , Benzimidazóis/síntese química , Micro-Ondas , Técnicas de Química Sintética , Cianetos/química , Piridinas/química
11.
Org Lett ; 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39440848

RESUMO

Site-selective hydrogen atom transfer (HAT) from the N═Csp2-H bonds of quinoxaline-2(1H)-ones is a highly attractive but underdeveloped domain. Reported herein is a highly selective, practical, and economically efficient approach for facile assembly of pyrroloquinoxalinones by synergistic photocatalysis and HAT catalysis. The reaction proceeds through bromine radical-mediated HAT of quinoxalinones and imine radical addition to α-cyano-α,ß-unsaturated ketones that establishes a cross-coupling/annulation cascade process, resulting in the synthesis of a series of functionalized pyrroloquinoxalinones. This protocol does not require transition metals or excess oxidants and uses easy-to-synthesize starting materials with excellent scalability and broad substrate scope. The establishment of N═Csp2 radical chemistry illustrates great potential for the synthesis of imine-containing molecules that are not possible with some traditional methods.

12.
Org Lett ; 26(15): 3304-3309, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38587334

RESUMO

A facile and efficient radical tandem vinylogous aldol and intramolecular [2 + 2] cycloaddition reaction for direct synthesis of cyclobutane-containing benzocyclobutenes (BCBs) under extremely mild conditions without using any photocatalysts is reported. This approach exhibited definite compatibility with functional groups and afforded new BCBs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost, and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

13.
ACS Omega ; 8(1): 1577-1587, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36643431

RESUMO

Described herein is a concise and practical direct amidation at the C-3 position of quinoxalin-2(1H)-ones through an acid-promoted carbamoylation with isocyanide in water. In this conversion, environmentally friendly water and commercial inexpensive isocyanide were used as a solvent and carbamoylation reagent, respectively. This study not only provides a green and efficient strategy for the construction of 3-carbamoylquinoxalin-2(1H)-one derivatives that can be applied to the synthesis of druglike structures but also expands the application of isocyanide in organic chemistry.

14.
Eur J Med Chem ; 240: 114565, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35797901

RESUMO

Triple-negative breast cancer (TNBC) with the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 ptotein, is the highly aggressive subtype of breast cancer that exhibits poor prognosis and high tumor recurrence. It is vital to develop effective agents regulating the core molecular pathway of TNBC. Through a medium throughput screening and iterative medicinal chemistry optimization, we identified compound 7h as an autophagic flux inhibitor, which showed potent activities against human TNBC (MDA-MB-231 and MDA-MB-468) cell lines with IC50 values of 8.3 µM, and 6.0 µM, respectively, which are comparable to the potency of 5-FU and Cisplatin, the first line therapies for TNBC. Extensive investigation of mechanisms of action indicated that 7h inhibits autophagic flux and sequential accumulation of p62, leading to DNA damage and disrepair in TNBC cells. Importantly, nuclear p62 accumulation induced by compound 7h results in the inhibition of RNF168-mediated chromatin ubiquitination and the degradation of HR-related proteins in regulating the DNA damage response (DDR) process. In in vivo studies, compound 7h completely suppressed tumor growth in the MDA-MB-231 xenograft model at a dose of 15 mg/kg/q.d. Our findings indicate that compound 7h is an autophagic flux inhibitor and induced the degradation of HR-related proteins. Compound 7h could be potentially developed as an anti-cancer therapeutics for TNBC.


Assuntos
Neoplasias de Mama Triplo Negativas , Autofagia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Imidazóis/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases
15.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 9): o2286, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22058929

RESUMO

In the title compound, C(20)H(14)N(4), the dihedral angles between the central benzene ring and the pendant benzimidazole ring systems are 46.60 (15) and 47.89 (16)°. The dihedral angle between the benzimidazole ring systems is 85.62 (12)° and the N atoms lie to the same side of the mol-ecule. In the crystal, mol-ecules are linked by C-H⋯N inter-actions and weak aromatic π-π stacking [shortest centroid-centroid separation = 3.770 (2) Å] is observed.

16.
Oncol Rep ; 45(3): 1261-1272, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33469671

RESUMO

Glioblastoma (GBM) is an aggressive malignancy with a high rate of tumor recurrence after treatment with conventional therapies. Parthenolide (PTL), a sesquiterpene lactone extracted from the herb Tanacetum parthenium or feverfew, possesses anticancer properties against a wide variety of solid tumors. In the present study, a series of PTL derivatives were synthesized and screened. An inhibitor, dimethylaminoparthenolide (DMAPT)­D6, a derivative of the PTL prodrug DMAPT in which the hydrogen of the dimethylamino group is substituted for the isotope deuterium, induced significant cytotoxicity in GBM cells in vitro and induced cell cycle arrest at the S­phase in a dose­dependent manner. Furthermore, mechanistic investigation indicated that through increasing the levels of intracellular accumulation of reactive oxygen species (ROS), DMAPT­D6 triggered DNA damage and finally death receptor­mediated extrinsic apoptosis in GBM cells, suggesting that DNA damage induced by DMAPT­D6 initiated caspase­dependent apoptosis to remove damaged GBM cells. Taken together, these data suggested that ROS accumulation following treatment with DMAPT­D6 results in DNA damage, and thus, death­receptor­mediated apoptosis, highlighting the potential of DMAPT­D6 as a novel therapeutic agent for the treatment of GBM.


Assuntos
Dano ao DNA/efeitos dos fármacos , Deutério/administração & dosagem , Glioblastoma/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Deutério/química , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Receptores de Morte Celular/metabolismo , Sesquiterpenos/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
17.
Onco Targets Ther ; 13: 10111-10121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116593

RESUMO

BACKGROUND: Breast cancer exhibits poor prognosis and high relapse rates following chemotherapy therapeutics. Thus, this study aims to develop effective novel agents regulating the core molecular pathway of breast cancer such as Wnt/ß-catenin signaling. METHODS: The present study screened a novel inhibitor, called "C188", using MTT assay. The molecular formula of C188 is C21H15FN4O3 and the molecular weight is 390. Flow cytometry and Western blotting were employed to assess cell cycle arrest after treatment with C188. Wound-healing and transwell assays were applied to measure the cell migration and invasion viability. The regulatory effects of C188 on Wnt/ß­catenin signaling and localization of ß­catenin in the nucleus were investigated by Western blotting and immunofluorescence. RESULTS: We found that C188 significantly suppressed proliferation and growth in a dose- and time-dependent manner in breast cancer cells, but not in normal breast cells. The inhibitory effect was caused by cell cycle arrest at the G1-phase which is induced by C188 treatment. Additionally, C188 dramatically inhibited cell migration of breast cancer cells in a dose-dependent manner. The migration inhibition was attributed to the suppression of Wnt/ß­catenin signaling and localization of ß­catenin in the nucleus mediated by regulating phosphorylation of ß­catenin and its subsequent stability. Furthermore, the target genes, including Axin 2, c-JUN, and c-Myc, were downregulated due to the decrease of ß­catenin in the nucleus after exposure to C188. CONCLUSION: C188 treatment resulted in the downregulation of cyclin D which led to cell cycle arrest at the G1 phase, and the inhibition of cell migration, indicating that C188 may be an effective novel therapeutic candidate as a potential treatment for human breast cancer.

18.
Sci Rep ; 10(1): 9281, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518332

RESUMO

The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel cascade reaction features an intramolecular N2-arylation of pyrazoles with allenes at the C-ß position of triple bond. Screening in the colorectal cancer cell lines HCT116 and SW620 validated the feasibility of the methodology for generating bioactive compounds. The lead compound 7h which is active against HCT116 and SW620 with IC50 of 1.3 and 1.8 µM, respectively, can be synthesized and purified in a gram process synthetic scale in 7 hours. The mechanical studies indicated that compound 7h can induce cell cycle arrest in the G2/M phase and inhibit proliferation and viability in human colon cancer cells. Overall, compound 7h is represented as a promising starting point for the development of new anti-colorectal cancer drugs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Pirazinas/síntese química , Pirazóis/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Humanos , Pirazinas/farmacologia , Pirazóis/farmacologia , Relação Estrutura-Atividade
19.
Chem Commun (Camb) ; 56(14): 2210, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32031562

RESUMO

Correction for 'One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction' by Jie Lei et al., Chem. Commun., 2020, DOI: .

20.
Chem Commun (Camb) ; 56(14): 2194-2197, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-31971170

RESUMO

An Ugi, novel pseudo-Knoevenagel, ring expansion cascade reaction was discovered and utilized for the synthesis of aziridinyl succinimides in one-pot. Subsequently, densely functionalized aziridines and maleimides have been designed and synthesized through similar cascade reactions. The target compounds were prepared by means of a mild reaction and a simple operation procedure, which could be applicable to a broad scope of starting materials. This series of novel cascade reactions generates opportunities for the tailored synthesis of a wide range of biologically active scaffolds through tuneable Ugi inputs. Discovery of compound 8i with comparable potency to sorafenib in liver cancer cell lines could provide a new avenue for liver cancer drug discovery.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Maleimidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Aziridinas/síntese química , Aziridinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Maleimidas/síntese química , Maleimidas/química , Estrutura Molecular
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