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1.
J Nat Prod ; 87(5): 1479-1486, 2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38728656

RESUMO

Bioinspired skeleton transformation of a tricyclic lathyrane-type Euphorbia diterpene was conducted to efficiently construct a tetracyclic tigliane diterpene on a gram scale via a key aldol condensation. The tigliane diterpene was then respectively converted into naturally rare ingenane and rhamnofolane diterpenes through a semipinacol rearrangement and a visible-light-promoted regioselective cyclopropane ring-opening reaction. This work provides a concise strategy for high-efficiency access to diverse polycyclic Euphorbia diterpene skeletons from abundant lathyrane-type natural products and paves the way for biological activity investigation of naturally rare molecules.


Assuntos
Diterpenos , Euphorbia , Diterpenos/química , Diterpenos/isolamento & purificação , Euphorbia/química , Estrutura Molecular , Biomimética , Produtos Biológicos/química
2.
J Nat Prod ; 87(1): 113-120, 2024 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-38095929

RESUMO

The question of whether rare 10,11-seco-lathyranes are natural products or artifacts is thoughtfully considered after a Brønsted acid-mediated chemical conversion of naturally abundant 5/11/3 lathyrane type diterpenes into 10,11-seco-lathyranes was developed. Benefiting from this concise route, a series of 10,11-seco-lathyrane products (1-14) were smoothly synthesized. The conversion may involve an acid promoted cyclopropane ring opening accompanied by a double bond shift with final trapping of carbocation. The ease of this chemical conversion under mildly acidic conditions may imply that the 10,11-seco-lathyranes isolated to date are artifacts. This work not only develops a new modular synthetic strategy for efficient constructing rare 10,11-seco-lathyranes, but also provides a promising bioactive diterpene with excellent effect against the NO production on LPS-induced BV-2 cells.


Assuntos
Artefatos , Diterpenos , Diterpenos/farmacologia , Diterpenos/química , Estrutura Molecular
3.
Bioorg Chem ; 147: 107377, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38653150

RESUMO

The first systematic acylated diversification of naturally scarce premyrsinane diterpenes, together with their biosynthetic precursors lathyrane diterpene were carried out. Two new series of premyrsinane derivates (1a-32a) and lathyrane derivates (1-32) were synthesized from the naturally abundant lathyrane diterpene Euphorbia factor L3 through a bioinspired approach. The cholinesterase inhibitory and neuroprotective activities of these diterpenes were investigated to explore potential anti-Alzheimer's disease (AD) bioactive lead compounds. In general, the lathyrane diterpenes showed the better acetylcholinesterase (AChE) inhibitory activity than that of premyrsinanes. The lathyrane derivative 17 bearing a 3-dimethylaminobenzoyl moiety showed the best AChE inhibition effect with the IC50 value of 7.1 µM. Molecular docking demonstrated that 17 could bond with AChE well (-8 kal/mol). On the other hand, premyrsinanes showed a better neuroprotection profile against H2O2-induced injury in SH-SY5Y cells. Among them, the premyrsinane diterpene 16a had significant neuroprotective effect with the cell viability rate of 113.5 % at 12.5 µM (the model group with 51.2 %). The immunofluorescence, western blot and reactive oxygen species (ROS) analysis were conducted to demonstrate the mechanism of 16a. Furthermore, a preliminary SAR analysis of the two categories of diterpenes was performed to provide the insights for anti-AD drug development.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Inibidores da Colinesterase , Diterpenos , Euphorbia , Fármacos Neuroprotetores , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/síntese química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/síntese química , Euphorbia/química , Humanos , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Simulação de Acoplamento Molecular , Relação Dose-Resposta a Droga , Sobrevivência Celular/efeitos dos fármacos
4.
Chem Biodivers ; : e202402055, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39410822

RESUMO

Seven new aconitine-type C19-diterpenoid alkaloids, apetaldines K-Q (1-7), were isolated from the roots of Aconitum apetalum (Huth) B. Fedtsch. Their structures were established on the basis of extensive spectroscopic analyses (HRESIMS, 1D and 2D NMR). Among them, compounds 1 and 2 possess a unique 2-(E)-(2-methylbut-2-enamido)benzoate moiety at the C-18 position. Furthermore, cytotoxic activities of these diterpenoid alkaloids were also evaluated.

5.
J Org Chem ; 88(7): 4765-4769, 2023 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-36989387

RESUMO

Using Eosin Y as a metal-free photocatalyst and O2 as an oxidant, the present study reports a new photochemical protocol that enables efficient aerobic oxidation of various benzyl alcohols to the corresponding aldehydes or ketones in excellent yields under mild reaction conditions. The catalyst system presents good functional-group tolerance and exquisite chemoselectivity, which also can easily be scaled-up to gram scale. Moreover, the methodological applications in practical synthesis of several organic molecules and the primary reaction mechanism were also discussed.

6.
J Nat Prod ; 86(4): 939-946, 2023 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-36808969

RESUMO

A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC50 = 0.19 µM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Neuroblastoma , Fármacos Neuroprotetores , Humanos , Galantamina/farmacologia , Galantamina/uso terapêutico , Acetilcolinesterase/metabolismo , Paládio , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Simulação de Acoplamento Molecular , Peróxido de Hidrogênio , Doença de Alzheimer/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Catálise , Relação Estrutura-Atividade , Estrutura Molecular
7.
Bioorg Chem ; 131: 106329, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36565674

RESUMO

A series of lathyrane-type Euphorbia diterpene derivatives featured 3R configuration (H-3ß) were synthesized from natural rich Euphorbia factor L3via modified Mitsunobu reaction based on configuration inversion strategy. The antiproliferation activity and MDR reversal ability of the lathyrane derivatives were evaluated, and the most synthesized compounds showed moderate or strong potencies. Among them, diterpenes 21 (IC50 values of 2.6, 5.2 and 13.1 µM, respectively) and 25 (IC50 values of 5.5, 8.6 and 1.3 µM, respectively) presented the strong cytotoxicity against MCF-7, 4 T1 and HepG2 cells. Meanwhile, derivative 25 exhibited excellent MDR reversal ability with the reversal fold of 16.1 higher than that of verapamil. The cellular thermal shift assay and molecular docking proved direct engagement of diterpene 25 to ABCB1, suggesting 25 could be a promising MDR modulator. Furthermore, the preliminary SARs of these diterpenes were also discussed.


Assuntos
Antineoplásicos , Diterpenos , Euphorbia , Humanos , Linhagem Celular Tumoral , Diterpenos/síntese química , Diterpenos/farmacologia , Euphorbia/química , Células Hep G2 , Simulação de Acoplamento Molecular , Estrutura Molecular , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia
8.
Chem Pharm Bull (Tokyo) ; 71(5): 349-353, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36858603

RESUMO

The direct modification of structurally complex natural product dehydroepiandrosterone (DHEA) through iron-catalyzed direct hydroamination of DHEA with various nitro(hetero)arenes was carried out to afford 5α-arylamino-DHEAs (1-25) in good yields (53-72%). Though as a radical reaction, it features high stereoselectivity, and only the 5α-substituted derivatives were produced. The in vitro antiproliferative activity of these synthesized compounds against the human breast cancer MCF-7 cell was evaluated, showing that most of DHEA analogues possessed the moderate cytotoxic activity. The preliminary structure-activity relationship analysis revealed that the electron-withdrawing groups installed at the para-position of arylamine ring had a great contribution to the improvement of the DHEA's cytotoxic potency. Among them, (4-trifluoromethylaniline)-DHEA (4) displayed the most potent cytotoxicity, with an IC50 value of 19.3 µM, which was 2.3-fold more active than DHEA.


Assuntos
Antineoplásicos , Desidroepiandrosterona , Humanos , Desidroepiandrosterona/farmacologia , Sulfato de Desidroepiandrosterona , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Catálise
9.
J Asian Nat Prod Res ; 25(11): 1097-1109, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37098899

RESUMO

A series of arylated huperzine A (HPA) derivatives (1-24) were efficiently synthesized in good yields (45-88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer's disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity. The present study demonstrably verifies pyridone carbonyl group could be the necessary and unchangeable pharmacophore for maintaining HPA's anti-AChE potency, and provides the helpful information on the further research for developing anti-AD HPA analogues.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase , Paládio , Catálise
10.
Angew Chem Int Ed Engl ; 62(31): e202306326, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37278098

RESUMO

(-)-Adenophorone (1), a caged polycyclic sesquiterpene featuring an unprecedented tricyclo[4.3.1.05,9 ]decane skeleton, was isolated from Eupatorium adenopharum Spreng. The structure of 1 was unambiguously established by a combination of spectroscopic analysis, X-ray crystallography, and bioinspired total synthesis. Key synthetic features include a sequential Reformatsky/oxidation/regio- and stereoselective hydrogenation, and subsequent merged MBH-Tsuji-Trost cyclization. The concise synthetic sequence efficiently constructs the bicyclic skeleton of cadinene sesquiterpene (+)-euptox A (2) in 8 steps from commercially available monoterpene (-)-carvone (6), with outstanding performance on diastereocontrol. The bioinspired synthesis of 1 was achieved from 2, a plausible biogenetic precursor, via transannular Michael addition. This work provides experimental evidence of our proposed biosynthetic hypothesis of 1. Additionally, compound 1 showed potent neuroprotective activity in H2 O2 -treated SH-SY5Y and PC12 cells.


Assuntos
Ageratina , Neuroblastoma , Sesquiterpenos , Humanos , Ageratina/química , Ciclização , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Estrutura Molecular
11.
J Org Chem ; 87(19): 13411-13415, 2022 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-36126306

RESUMO

Naturally occurring 1(15 → 14)abeo-lathyrane rearrangement-type diterpene lathyranone A (1) was prepared from lathyrane-type Euphorbia factor L11 (1a) via an efficient Sc(OTf)3/Et2NH-catalyzed α-ketol rearrangement, which was also suitable for the synthesis of lathyranones 2 and 3. This skeletal conversion strategy had the characteristic of biogenetically patterned synthesis and provided a convenient method for accessing naturally rare functionalized lathyranones from lathyranes. Moreover, the absolute configuration of the lathyranone skeleton was confirmed for the first time by the X-ray diffraction of 2.


Assuntos
Diterpenos , Euphorbia , Catálise , Estrutura Molecular , Escândio , Esqueleto
12.
J Nat Prod ; 85(8): 2026-2034, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-35920623

RESUMO

Pd(OAc)2/NiXantphos efficiently catalyzed the direct arylation at the C-14 position of matrine, leading to 38 arylmatrine derivatives (1a-19a and 1b-19b) in good yields. Most of these matrine analogues showed enhanced insecticidal effects superior to the parent compound matrine. Among them, the 3,5-diphenylbenzene analogue (8b) exhibited the most potent in vivo antifeedant activity (EC50 = 0.19 mg/mL) against Spodoptera exigua (Hübner), with approximately 25-fold more activity than matrine, for which the preliminary mechanism of action was verified through enzyme inhibition activities and molecular docking. Compound 8b as well displayed in vitro antiproliferation activity on Sf9 insect cells (IC50 = 8.1 µM), and its apoptotic induction effect was illustrated by morphological observation and DNA fragment analysis. Overall, the above results provide further information on the potential of arylmatrine-type lead compounds for the prevention and control of insect pests.


Assuntos
Inseticidas , Animais , Catálise , Insetos , Inseticidas/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Paládio/farmacologia , Spodoptera , Relação Estrutura-Atividade
13.
Chem Biodivers ; 19(10): e202200483, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36094326

RESUMO

Two new lappaconitine-type C18 -diterpenoid alkaloids, named as leucostosines C (1) and D (2), together with six known compounds (3-8), were isolated from the roots of Aconitum leucostomum Worosch. Their structures were elucidated by various spectroscopic analyses, including IR, HR-ESI-MS, NMR spectra and X-ray experiments. Leucostosine C is the first diterpenoid alkaloid bearing the 7-amino group. The isolated compounds were tested for the acetylcholinesterase (AChE) inhibitory effect and neuroprotective activity, none of them showed significant activities.


Assuntos
Aconitum , Alcaloides , Diterpenos , Aconitum/química , Acetilcolinesterase , Estrutura Molecular , Alcaloides/química , Diterpenos/química , Raízes de Plantas/química
14.
Chem Pharm Bull (Tokyo) ; 69(8): 811-816, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334527

RESUMO

Three new aconitine-type C19-diterpenoid alkaloid namely novolunines A (1), B (2), and C (3), along with fifteen known diterpenoid alkaloids were isolated from the roots of Aconitum novoluridum, whose phytochemical investigations have never been reported before. The structures of three new alkaloids were established on the basis of spectra data (high-resolution electrospray ionization (HR-ESI)-MS, IR, one dimensional (1D)- and 2D-NMR). Noteworthily, novolunines A (1) and B (2) are two diterpenoid alkaloids bearing conformational isomerism. In addition, the diterpenoid alkaloids 1-3 did not show any anti-acetylcholinesterase (AChE) or anti-inflammatory activities.


Assuntos
Acetilcolinesterase/metabolismo , Aconitum/química , Anti-Inflamatórios/farmacologia , Inibidores da Colinesterase/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Electrophorus , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7
15.
Chem Biodivers ; 17(1): e1900600, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31793197

RESUMO

Four new hetisine-type C20 -diterpenoid alkaloids, named as coreanines A-D (1-4), were isolated from the roots of Aconitum coreanum, together with thirteen known alkaloids (5-17). Their structures were elucidated by extensive spectroscopic methods including IR, HR-ESI-MS and NMR techniques. All the isolated compounds were screened for the acetylcholinesterase (AChE) inhibitory effects, and none of them showed considerable inhibitory activity.


Assuntos
Acetilcolinesterase/metabolismo , Aconitum/química , Alcaloides/farmacologia , Inibidores da Colinesterase/farmacologia , Diterpenos/farmacologia , Raízes de Plantas/química , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Inibidores da Colinesterase/química , Inibidores da Colinesterase/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Electrophorus , Estrutura Molecular
16.
ACS Omega ; 9(36): 38169-38179, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39281889

RESUMO

Introducing a sulfur atom into active agricultural molecules is an important strategy for pesticide development. Matrine, an environmentally friendly botanical pesticide, has the advantage of being easily degraded and has drawn attention in the agricultural field. To explore the novel matrine-type pesticides, in this study, we designed and synthesized 13/14-arylthioether matrine derivatives by introducing various aryl sulfide motifs into bioactive matrine. Most of the synthesized arylthioether matrines exhibited good antifeedant activity against Spodoptera exigua. Among them, compound 2q showed the best antifeedant effect with an EC50 value of 0.038 mg/mL, which is approximately 125-fold more activity than matrine and reached the activity level of commercial standard azadirachtin A. Furthermore, compound 2q exhibited an inhibitory effect on antifeedant-related enzyme carboxylesterase (CarE) from S. exigua. In short, the high activity of arylthioether matrines offers new insights into developing new antifeedants.

17.
Fitoterapia ; 177: 106131, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39067489

RESUMO

The late-stage difunctionalization of diterpene oridonin by light-promoted direct oxyamination with various O-benzoylhydroxylamines was carried out to afford C16α-N-C17-OBz-oridonin derivatives (1-25) for the first time. Though as a radical reaction, it features high stereoselectivity to only produce C16α-N-C17-OBz-oridonins. The in vitro antiproliferative activity of these C16α-N-C17-OBz-oridonins against the human breast cancer cell lines (MCF-7) was evaluated by MTT assay, showing that most of the synthesized compounds possessed moderate anticancer activity against MCF-7 cell lines superior or similar to the parent compound oridonin. The derivative 25 with a N-methyl-N-(naphthalen-1-ylmethyl) substitution showed better cytotoxicity against MCF-7 cells (IC50 value of 11.75 µM) than oridonin (IC50 value of 17.95 µM).


Assuntos
Antineoplásicos Fitogênicos , Diterpenos do Tipo Caurano , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Humanos , Estrutura Molecular , Células MCF-7 , Antineoplásicos Fitogênicos/farmacologia , Luz , Estereoisomerismo
18.
Future Med Chem ; 16(10): 983-997, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38910574

RESUMO

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.


[Box: see text].


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Butirilcolinesterase , Inibidores da Colinesterase , Desenho de Fármacos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Relação Estrutura-Atividade , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/síntese química , Estrutura Molecular , Linhagem Celular Tumoral , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Indóis
19.
Sci Adv ; 10(10): eadl0026, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457511

RESUMO

Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed C─H arylation of complex antitumor drug osimertinib with various aryl bromides via the late-stage functionalization strategy was demonstrated here. This reaction displayed a switch in regioselectivity under complete base control. Potassium carbonate (K2CO3) promoted the arylation of acrylamide terminal C(sp2)-H, affording 34 derivatives. Conversely, sodium tert-butoxide (t-BuONa) mediated the aryl C(sp2)-H arylation of the indole C2 position, providing 27 derivatives. The derivative 3r containing a 3-fluorophenyl group at the indole C2 position demonstrated similar inhibition of EGFRT790M/L858R and superior antiproliferative activity in H1975 cells compared to osimertinib, as well as similar antiproliferative activity in A549 cells and antitumor efficacy in xenograft mouse model bearing H1975 cells. This approach provides a "one substrate-multi reactions-multiple products" strategy for the structural modification of complex drug molecules, creating more opportunities for the fast screening of pharmaceutical molecules.


Assuntos
Acrilamidas , Compostos de Anilina , Neoplasias Pulmonares , Paládio , Pirimidinas , Humanos , Animais , Camundongos , Paládio/química , Receptores ErbB , Mutação , Inibidores de Proteínas Quinases , Indóis/química , Catálise
20.
Front Chem ; 11: 1282978, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38144888

RESUMO

A series of novel N-aryl-debenzeyldonepezil derivatives (1-26) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. In vitro cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue 13 possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Furthermore, Compound 13 did not show significant cytotoxicity on SH-SY5Y. These results suggest that 13 is a potential multifunctional active molecule for treating Alzheimer's disease.

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