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 , EstereoisomerismoRESUMO
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 , IndóisRESUMO
Achieving regioselective synthesis in complex molecules with multiple reactive sites remains a tremendous challenge in synthetic chemistry. Regiodivergent palladium-catalyzed CâH 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 , CatáliseRESUMO
(-)-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 (+)-euptoxâ 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 MolecularRESUMO
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 , CatáliseRESUMO
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 MolecularRESUMO
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/farmacologiaRESUMO
Microtubules are the fundamental part of the cell cytoskeleton intimately involving in cell proliferation and are superb targets in clinical cancer therapy today. Microtubule stabilizers have become one of the effectively main agents in the last decades for the treatment of diverse cancers. Taccalonolides, the highly oxygenated pentacyclic steroids isolated from the genus of Tacca, are considered a class of novel microtubule-stabilizing agents. Taccalonolides not only possess a similar microtubule-stabilizing activity as the famous drug paclitaxel but also reverse the multi-drug resistance of paclitaxel and epothilone in cellular and animal models. Taccalonolides have captured numerous attention in the field of medicinal chemistry due to their variety of structures, unique mechanism of action, and low toxicity. This review focuses on the structural diversity, semi-synthesis, modification, and pharmacological activities of taccalonolides, providing bright thoughts for the discovery of microtubule-stabilizing drugs.
RESUMO
A series of new paclitaxel-benzoxazoles hybrids were designed based on both the molecular docking mode of beta-tubulin with paclitaxel derivatives (7a and 7g), and the activity-structure relationship of C-13 side chain in paclitaxel. Palladium-catalyzed direct Csp2-H arylation of benzoxazoles with different aryl-bromides was used as the key synthetic strategy for the aryl-benzoxazoles moieties in the hybrids. Twenty-six newly synthesized hybrids were screened for their antiproliferative activity against human cancer cell lines such as human breast cancer cells (MDA-MB-231) and liver hepatocellular cells (HepG2) by the MTT assay and results were compared with paclitaxel. Interestingly, most hybrids (7a-7e, 7i, 7k, 7l, 7A, 7B, 7D and 7E) showed significantly active against both cell lines at concentration of 50 µM, which indicated that the hybrid strategy is effective to get structural simplified paclitaxel analogues with high anti-tumor activity.