RESUMO
A series of novel stilbene derivatives has been synthesized and studied with the main goal to investigate SAR of the amino compound 1a, as well as to improve its water solubility, a potentially negative aspect of the molecule that could be a serious obstacle for a pre-clinical development. We have obtained derivatives with good cytotoxic activity, in particular, the derivatives 5c and 6b could represent two novel leads for further investigation. Compound 8b, a morpholino-carbamate derivative, prodrug of 1a, has a very good solubility in water, and is active in suppressing growth of tumor cells at a concentration of 5000 nM, which is a concentration 100 times higher than the parent stilbene 1a.
Assuntos
Antineoplásicos/síntese química , Estilbenos/síntese química , Aminas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Pró-Fármacos/química , Solubilidade , Estilbenos/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismoRESUMO
Colchicine site tubulin inhibitors are currently developed as vascular disrupting agents (VDAs). However, they were found to have cardiotoxicity in clinical trials. To overcome the problem, we developed a stilbene derivative, cis-3, 4', 5-trimethoxy-3'-aminostilbene (stilbene 5c), which is highly potent and has no bone marrow and cardiac toxicity in mice. Here we attempt to optimize stilbene 5c using computer-based drug design and synthesize derivatives with benzimidazole or indole group. Biological evaluation showed that they are weaker than stilbene 5c without better water solubility. Alternative approach was thus adopted to make prodrugs of stilbene 5c. A water-soluble prodrug PD7 was synthesized by addition of a morpholino group with carbamate linkage to the amino group of stilbene 5c. In vitro studies show that PD7 induces mitotic arrest and disrupts microtubule similar to stilbene 5c. The cell signaling events in Cdc2, p53, Akt, and aurora kinase are similar in cells treated with stilbene 5c, CA4 or PD7, suggesting that they share the same mechanism. Although PD7 is less effective than stilbene 5c in vitro, the biological activity of PD7 as a single agent is similar to that of stilbene 5c. Combination of PD7 with VEGF inhibitor bevacizumab significantly enhances the therapeutic efficacy of PD7 in mouse xenograft model. These data suggest that PD7 could be a good candidate for further pre-clinical and clinical development as a new VDA for cancer therapy.
Assuntos
Inibidores da Angiogênese/farmacologia , Morfolinas/síntese química , Morfolinas/farmacologia , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Pró-Fármacos/síntese química , Estilbenos/química , Animais , Antimitóticos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho Assistido por Computador , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Camundongos Nus , Microtúbulos/efeitos dos fármacos , Soluções Farmacêuticas/farmacologia , Pró-Fármacos/farmacologia , Estilbenos/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel class of combretastatins, modified at A-ring or both A- and B-rings, mainly by replacement with benzofuran or benzo[b]thiophene, were synthesized. The new heterocombretastatins showed good cytotoxic activity on BMEC and H-460 cell lines. The aminocombretastatin 9f potently inhibits cell growth of BMEC and combretastatin-resistant HT-29 cell lines, with potential interest to treat colon carcinoma. Heterocombretastatins 9a,b inhibit tubulin polymerization similarly to CA-4 by having a binding to colchicine site five times stronger.
Assuntos
Estilbenos/farmacologia , Animais , Sítios de Ligação , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais/efeitos dos fármacos , Humanos , Estrutura Molecular , Estereoisomerismo , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismoRESUMO
A new study on terphenyl and diaryl-isoxazole and -isoxazoline derivatives, maintaining a common 3-adamantyl-4-hydroxyphenyl moiety, has been conducted to find compounds with growth supporting and antiapoptotic properties. Unexpectedly, diphenyisoxazole derivatives bearing a nitro group replacing the carboxylic function have been found with the highest cell protective activity within the series, in complete and in serum-free conditions. Inhibition of apoptosis induced by daunorubicin has also been observed for the most active compound.
Assuntos
Apoptose/efeitos dos fármacos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Compostos de Terfenil/síntese química , Compostos de Terfenil/farmacologia , Linhagem Celular Tumoral , Humanos , Isoxazóis/química , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Terfenil/químicaRESUMO
A small series of aminobisphosphonates (N-BPs) structurally related to zoledronic acid was synthesized with the aim of improving activity toward activation of human gammadelta T cells and in turn their in vivo antitumor activity. The absence of the 1-OH moiety, together with the position and the different basicity of the nitrogen, appears crucial for antitumor activity. In comparison to zoledronic acid, compound 6a shows a greater ability to activate gammadelta T cells expression (100 times more) and a proapoptotic effect that is better than zoledronic acid. The potent activation of gammadelta T cells, in addition to evidence of the in vivo antitumor activity of 6a, suggests it may be a new potential drug candidate for cancer treatment.
Assuntos
Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Difosfonatos/síntese química , Difosfonatos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Difosfonatos/química , Desenho de Fármacos , Humanos , Ativação Linfocitária/imunologia , Camundongos , Camundongos SCID , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Several stilbenes, related to known resveratrol, have been synthesized and tested for their anticancer effect on HL60 leukemia cell line, taking particular care of the cell cycle analysis. The most potent compound was the known (Z)-3,4',5-trimethoxystilbene (6b) which was active as apoptotic agent at 0.24 microM. Differently from other stilbenes (including resveratrol) that induced a prevalent recruitment of cells in S phase of cell cycle, we found a peculiar behavior of 6b that caused a decrease of cells in all phases of cell cycle (G0-G1, S, and G2-M) and a proportional increase of apoptotic cells. The potent pro-apoptotic activity shown by compound 6b and its effects on cell cycle make this compound of great interest for further investigations.