RESUMO
HER3 (human epidermal growth factor receptor 3) acts through heterodimerization with EGFR (epidermal growth factor receptor) or HER2 to play an essential role in activating phosphoinositide 3-kinase (PI3K) and AKT signaling-a crucial pathway that promotes tumor cell survival. HER3 is a promising target for cancer therapy, and several HER3-directed antibodies have already entered into clinical trials. In this study we characterized a novel anti-HER3 monoclonal antibody, SIBP-03. SIBP-03 (0.01-10 µg/mL) specifically and concentration-dependently blocked both neuregulin (NRG)-dependent and -independent HER3 activation, attenuated HER3-mediated downstream signaling and inhibited cell proliferation. This antitumor activity was dependent, at least in part, on SIBP-03-induced, cell-mediated cytotoxicity and cellular phagocytosis. Importantly, SIBP-03 enhanced the antitumor activity of EGFR- or HER2-targeted drugs (cetuximab or trastuzumab) in vitro and in vivo. The mechanisms underlying this synergy involve increased inhibition of HER3-mediated downstream signaling. Collectively, these results demonstrated that SIBP-03, which is currently undergoing a Phase I clinical trial in China, may offer a new treatment option for patients with cancers harboring activated HER3, particularly as part of a combinational therapeutic strategy.
Assuntos
Anticorpos Monoclonais , Antineoplásicos , Neoplasias , Receptor ErbB-3 , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/metabolismo , Transdução de Sinais , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias/terapiaRESUMO
Hsp90 is a potential therapeutic target for tumor, as it maintains the stability of a variety of proteins related to tumor development and progression. Autophagy is a self-degradation process to maintain cellular homeostasis and autophagy inhibitors can suppress tumor growth. In this study, we identified DCZ5248, a triazine derivative, was a dual inhibitor of both Hsp90 and late-autophagy with potent antitumor activity against colon cancer cells in vitro and in vivo. We showed that DCZ5248 (0.1-10 µM) induced dose-dependent degradation of Hsp90 client proteins (AKT, CDK4, CDK6 and RAF-1) in HCT 116 colon cancer cells through a proteasome-dependent pathway. Meanwhile, DCZ5248 (0.3 µM) induced cytoplasmic vacuole formation, LC3 II conversion, p62 protein upregulation, and inhibited autophagy at the late stage in the colon cancer cell lines tested. We further revealed that the inhibition of autophagy was achieved by impairing lysosomal functions through induction of lysosomal acidification and attenuation of lysosomal cathepsin activity. The modulation of autophagy by DCZ5248 was independent of Hsp90 inhibition as the autophagy inhibition was not blocked by Hsp90 knockdown. Importantly, inhibition of both Hsp90 function and autophagy by DCZ5248 induced G1-phase cell cycle arrest, apoptosis, and exerted potent antitumor activity against colon cancer cells both in vitro and in vivo. These findings demonstrate that DCZ5248 is a novel dual inhibitor of Hsp90 and autophagy with potential for colon cancer therapy.
Assuntos
Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Triazinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Lisossomos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A 17-membered macrocyclolipopeptide, named dysoxylactam A (1) comprising an unprecedented branched C19 fatty acid and an l-valine, was isolated from the plants of Dysoxylum hongkongense. The challenging relative configuration of 1 was established by means of residual dipolar coupling-based NMR analysis. The absolute configuration of 1 was determined by single-crystal X-ray diffraction on its p-bromobenzoate derivative (2). Compound 1 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 28.4 to 1039.7 at the noncytotoxic concentration of 10 µM. The mode-of-action study of 1 revealed that it inhibited the function of P-glycoprotein (P-gp), a key mediator in multidrug resistance.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lipopeptídeos/farmacologia , Peptídeos Cíclicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lipopeptídeos/síntese química , Lipopeptídeos/química , Lipopeptídeos/isolamento & purificação , Meliaceae/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/isolamento & purificaçãoRESUMO
Emerging evidence demonstrates that a c-Met antibody-drug conjugate (ADC) has superior efficacy and safety profiles compared with those of currently available small molecules or antibody inhibitors for the treatment of c-Met-overexpressing cancers. Here we described both the in vitro and in vivo efficacies of SHR-A1403, a novel c-Met ADC composed of a humanized IgG2 monoclonal antibody against c-Met conjugated to a novel cytotoxic microtubule inhibitor. SHR-A1403 showed high affinity to c-Met proteins derived from human or monkey and potent inhibitory effects in cancer cell lines with high c-Met protein expression. In mice bearing tumors derived from cancer cell lines or patient HCC tissues with confirmed c-Met overexpression, SHR-A1403 showed excellent anti-tumor efficacy. Antibody binding with c-Met contributed to SHR-A1403 endocytosis; the subsequent translocation to lysosomes and cytotoxicity of the released toxin are speculated to be predominant mechanisms underlying the anti-tumor activity of SHR-A1403. In conclusion, SHR-A1403 showed significant anti-tumor activity in cancer cell lines, xenograft mouse models and an HCC PDX model, which all have high c-Met levels. These data provide references for SHR-A1403 as a potential therapy for the treatment of cancers with c-Met overexpression.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Imunoconjugados/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Moduladores de Tubulina/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/toxicidade , Antineoplásicos/imunologia , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Imunoconjugados/imunologia , Imunoconjugados/toxicidade , Macaca fascicularis , Masculino , Camundongos Endogâmicos BALB C , Microtúbulos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/imunologia , Moduladores de Tubulina/imunologia , Moduladores de Tubulina/toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BRAF and MEK inhibitors have shown remarkable clinical efficacy in BRAF-mutant melanoma; however, most patients develop resistance, which limits the clinical benefit of these agents. In this study, we found that the human melanoma cell clones, A375-DR and A375-TR, with acquired resistance to BRAF inhibitor dabrafenib and MEK inhibitor trametinib, were cross resistant to other MAPK pathway inhibitors. In these resistant cells, phosphorylation of ribosomal protein S6 (rpS6) but not phosphorylation of ERK or p90 ribosomal S6 kinase (RSK) were unable to be inhibited by MAPK pathway inhibitors. Notably, knockdown of rpS6 in these cells effectively downregulated G1 phase-related proteins, including RB, cyclin D1, and CDK6, induced cell cycle arrest, and inhibited proliferation, suggesting that aberrant modulation of rpS6 phosphorylation contributed to the acquired resistance. Interestingly, RSK inhibitor had little effect on rpS6 phosphorylation and cell proliferation in resistant cells, whereas P70S6K inhibitor showed stronger inhibitory effects on rpS6 phosphorylation and cell proliferation in resistant cells than in parental cells. Thus regulation of rpS6 phosphorylation, which is predominantly mediated by BRAF/MEK/ERK/RSK signaling in parental cells, was switched to mTOR/P70S6K signaling in resistant cells. Furthermore, mTOR inhibitors alone overcame acquired resistance and rescued the sensitivity of the resistant cells when combined with BRAF/MEK inhibitors. Taken together, our findings indicate that RSK-independent phosphorylation of rpS6 confers resistance to MAPK pathway inhibitors in BRAF-mutant melanoma, and that mTOR inhibitor-based regimens may provide alternative strategies to overcome this acquired resistance.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteína S6 Ribossômica/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Imidazóis/farmacologia , Melanoma/tratamento farmacológico , Melanoma/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Oximas/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/farmacologia , Pirimidinonas/farmacologiaRESUMO
A series of E-ring lactone-opened camptothecin (CPT) derivatives bearing with terminal aza-heterocyclic groups were synthesized, and their antitumor activity was evaluated both in vitro and in vivo. Hydroxyl-amide analogues with morpholin-4-yl displayed excellent antitumor activity in vitro and efficient inhibition on tumor xenograph model in nude mice. Ester-amide compounds acted less active in vitro cytotoxicity and lower inhibition activity in vivo. Substitutions at 7- and 10- positions favored the antitumor activity.
Assuntos
Antineoplásicos Fitogênicos/síntese química , Camptotecina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/síntese química , Linhagem Celular Tumoral , Humanos , Camundongos , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h-1·kg-1; dogs, 0.40±0.06 L·h-1/kg-1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 µmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.
Assuntos
Indóis/administração & dosagem , Indóis/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Células CACO-2 , Cromatografia Líquida , Neoplasias do Colo/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Cães , Interações Medicamentosas , Feminino , Células HEK293 , Meia-Vida , Xenoenxertos , Humanos , Absorção Intestinal , Masculino , Espectrometria de Massas , Taxa de Depuração Metabólica , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Animais , Modelos Biológicos , Transplante de Neoplasias , Ligação Proteica , Ratos Sprague-Dawley , Especificidade da Espécie , Distribuição TecidualRESUMO
Three steroidal saponins, including astrogorgiosides A (1) and B (2) bearing acetamido-glucose moieties, and astrogorgioside C (3) with a 19-nor and bearing an aromatized B ring steroid aglycone, together with a known major saponin dimorphoside A (4), were obtained from the gorgonian Astrogorgia dumbea collected near Dongshan Island in East China Sea. Structures of these compounds were elucidated by in-depth spectral and chemical methods, including 2D-NMR, HR-ESI-MS spectra, and acidic hydrolysis. For the first time, acetamido-glucose moiety is being reported from a gorgonian. The B-ring aromatized steroid aglycone of compound 3 is also rare in marine natural products. Compounds 1-3 exhibited moderate cytotoxic activity with IC50 values of 26.8-45.6 µM against human tumor cells Bel-7402 and K562.
Assuntos
Besouros/química , Saponinas/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , China , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Saponinas/química , Saponinas/farmacologiaRESUMO
AIM: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. METHODS: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. RESULTS: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC50 at low micromole levels. C817 (0.5 or 1 µmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. CONCLUSION: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Benzamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Mutação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Apoptose/efeitos dos fármacos , Curcumina/análogos & derivados , Relação Dose-Resposta a Droga , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Predisposição Genética para Doença , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Fenótipo , FosforilaçãoRESUMO
Inspired by the structure of dysoxylactam A (DLA) that has been demonstrated to reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) effectively, 61 structurally simplified cyclolipopeptides were thus designed and synthesized via an effective method, and their reversing P-gp-mediated MDR potentials were evaluated, which provided a series of more potent analogues and allowed us to explore their structure-activity relationship (SAR). Among them, a well-simplified compound, 56, with only two chiral centers that all derived from amino acids dramatically reversed drug resistance in KBV200 cells at 10 µM in combination with vinorelbine (VNR), paclitaxel (PTX), and adriamycin (ADR), respectively, which is more promising than DLA. The mechanism study showed that 56 reversed the MDR of tumor cells by inhibiting the transport function of P-gp rather than reducing its expression. Notably, compound 56 effectively restored the sensitivity of MDR tumors to VNR in vivo at a dosage without obvious toxicity.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Resistencia a Medicamentos Antineoplásicos , Lipopeptídeos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Doxorrubicina/farmacologia , Linhagem Celular TumoralRESUMO
OBJECTIVE: Lobaplatin is used to treat patients with breast cancer, small-cell lung cancer, and chronic myelogenous leukemia in China. In this study, we assessed the in-vitro and in-vivo activities of lobaplatin alone or in combination with antitubulin agents against human non-small-cell lung cancer (NSCLC). METHODS: The cytotoxicities of lobaplatin against NSCLC cells were determined by the sulforhodamine B (SRB) assay. Cell cycle analysis and apoptosis were assessed using flow cytometry, and the in-vivo antitumor activities were evaluated in human NSCLC xenografts in nude mice. RESULTS: The cytotoxicity of lobaplatin was similar to or higher than that of cisplatin and carboplatin, with a mean IC(50) of 2.5 µmol/l in a variety of NSCLC cells. In addition, lobaplatin arrested cells in the S phase and triggered apoptosis. The combination of lobaplatin with antitubulin agents yielded synergistic cytotoxic activity in vitro. In NSCLC xenografts, lobaplatin alone showed significant antitumor activity. The combination of lobaplatin with antitubulin agents, especially with paclitaxel, led to significantly enhanced activity, which was superior to that of cisplatin combined with antitubulin agents. CONCLUSION: These data demonstrate that the use of lobaplatin alone or in combination with antitubulin agents might be a rational and novel therapeutic strategy for human NSCLC and warrants further clinical investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclobutanos/administração & dosagem , Ciclobutanos/farmacologia , Docetaxel , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacologia , Paclitaxel/administração & dosagem , Taxoides/administração & dosagem , Moduladores de Tubulina/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Vimblastina/administração & dosagem , Vimblastina/análogos & derivados , Vinorelbina , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A new ent-atisanoid, eriocatisin A (1), six new ent-abietanoids, eriocasins B-E (2-4, 7), 3-acetyleriocasin C (5), and 3ß-acetoxyeriocasin D (6), and seven new ent-kauranoids, maoesins A-F (8, 10-14) and 3α-acetoxy-maoesin A (9), together with 21 known compounds, were isolated from the aerial parts of Isodon eriocalyx. The structures of 1-14 were determined by spectroscopic data interpretation. All compounds isolated were evaluated for their in vitro growth inhibitory activity against the HT-29, BEL-7402, and SK-OV-3 human cancer cell lines. Compounds 17, 18, and 20 showed inhibitory effects for all three tumor cell lines used, with IC(50) values in the range 2.1-7.3 µM.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Isodon/química , Antineoplásicos Fitogênicos/química , Diterpenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
A series of 3-demethoxycarbonyl-3-amide methyl anhydrovinblastine derivatives (5b-24b) was designed, synthesized, and evaluated for their proliferation inhibition activities against two tumor cell lines (A549 and HeLa). Most of the amide anhydrovinblastine derivatives exhibited potent cytotoxicity, with the size of the introduced substituents being the foremost factor in determining the resultant cytotoxic activity. Test results in vivo against sarcoma 180 of three potent compounds (6b, 12b, and 24b) indicated that the introduction of an amide group at the 22-position of anhydrovinblastine (1e) improved both potency and toxicity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Vimblastina/análogos & derivados , Antineoplásicos/química , Técnicas de Química Combinatória , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Vimblastina/síntese química , Vimblastina/química , Vimblastina/farmacologia , VinorelbinaRESUMO
Twenty-one derivatives of taxchinin A (1) and brevifoliol (2) were synthesized and evaluated for cytotoxicity against human non-small lung cancer (A549) cell line. Nine derivatives showed potent activity with IC(50) values from 0.48 to 6.22microM. 5-Oxo-13-TBDMS-taxchinin A (11) and 5-oxo-13,15-epoxy-13-epi-taxchinin A (15) are the most potent derivatives, with IC(50) at 0.48 and 0.75microM, respectively. The structure-activity relationship (SAR) of these compounds established that exocyclic unsaturated ketone at ring C is the key structural element for the activity, while the alpha,beta-unsaturated ketone positioned at ring A has no effect for the activity. The significant cytotoxicity of derivatives 11 and 15 may be due to the conformational change in the taxane rings. The 3D-QSAR study was conducted on this series of compounds, which provided optimal predictive comparative molecular field (CoMFA) model with cross-validated r(2) (q(2)) value of 0.64.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Taxoides/química , Células Tumorais CultivadasRESUMO
Ten new highly oxygenated triterpenoids, kadcoccilactones A-J (1-10), and two known triterpenoids, kadsuphilactone A and micrandilactone B, were isolated from the stems of the evergreen climbing plant Kadsura coccinea. The structures of the new compounds were elucidated by spectroscopic evidence, with that of 1 confirmed by single-crystal X-ray diffraction analysis. This is the first report on nortriterpenoids (2, 4-6, 8-10) from the genus Kadsura.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Kadsura/química , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Conformação Molecular , Estrutura Molecular , Caules de Planta/química , Triterpenos/química , Triterpenos/farmacologiaRESUMO
Novel lipophilic platinum(II) complexes (LSPt-1-3), containing 3,5-diisopropylsalicylate (DIPS) as a leaving group and 2NH(3) or 1R,2R-diaminocyclohexane or (4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane as the carrier, have been synthesized, characterized and evaluated in vitro and in vivo. The octanol/water distribution coefficient of the complexes has also been measured. The results showed that the complexes achieved a typical square planar and the octanol/water distribution coefficient logP was 4.27, 4.37 and 4.31. The complexes were tested by SRB method to be more cytotoxic than Carboplatin, Oxaliplatin and Eptaplatin against 3AO, A549, NCI-H460 and SGC-7901 human cancer cell lines. Among complexes, LSPt-2 was much more effective than Carboplatin and Oxaliplatin in treating the NCI-H460 non-small-cell lung tumor-bearing mice. Its optimal activity was 38.8% (T/C) at a dose of 30 mg/kg following i.p. administration. LD(50) for the complex was found to be 230.9 mg/kg. LSPt-2 exhibited great anticancer activity, good lipophilic ability and low toxicity and therefore, it is a promising candidate for effective and stable pharmaceutical liposomal platinum anticancer drug.
Assuntos
Compostos de Platina/síntese química , Compostos de Platina/farmacologia , Salicilatos/química , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Camundongos , Compostos de Platina/química , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria UltravioletaRESUMO
ent-Abietane diterpenoids, hebeiabinins A-F (1-5), together with seven known diterpenoids were isolated from leaves of Isodon rubescens var. rubescens. The structures of 1-5 were established on the basis of spectroscopic analyses, including application of 2D NMR spectroscopic techniques. The diterpenoids isolated were evaluated for the cytotoxicity against A549, HT-29, and K562 tumor cells. Compound 5 was the most active with IC(50) value of 0.91 microM against A549 cells.
Assuntos
Abietanos/química , Sobrevivência Celular/efeitos dos fármacos , Isodon/química , Folhas de Planta/química , Abietanos/isolamento & purificação , Abietanos/toxicidade , Antineoplásicos/toxicidade , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Isodon/toxicidade , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologiaRESUMO
Four new withanolides, physagulins L-O (1-4), were isolated from the MeOH extract of the aerial parts of Physalis angulata L. (Solanaceae), together with seven known withanolides, compounds 5-11. Their structures were determined by spectroscopic techniques, including 1H-, 13C-NMR (DEPT), and 2D-NMR (HMBC, HMQC, 1H,1H-COSY, NOESY) experiments, as well as by HR-MS. All eleven compounds were tested for their antiproliferative activities towards human colorectal-carcinoma (HCT-116) and human non-small-cell lung-cancer (NCI-H460) cells. Compound 5 exhibited the highest anticancer activity against the HCT-116 cell line, with an IC50 value of 1.64+/-0.06 microM. Compound 9 exhibited the highest cytotoxicity towards the NCI-H460 cell line, with an IC50 value of 0.43+/-0.02 microM.
Assuntos
Citotoxinas/isolamento & purificação , Physalis , Componentes Aéreos da Planta , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Citotoxinas/química , Humanos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , WithaniaRESUMO
[reaction: see text] A phytochemical study of the secondary metabolites produced by the species of Isodon rubescens has led to the isolation of three new dimeric ent-kauranoids and two known ones. The most important of these compounds are bisrubescensin A (1), which contains an unprecedented C(23) ent-kaurane unit, and bisrubescensin C (3), which is the precursor of bisrubescensin B (2) from the viewpoint of biosynthesis. Their structures were determined on the basis of extensive spectroscopic analysis and chemical evidence.