RESUMO
We have recently shown that the combination of chemical motifs of vorinostat () and ferrocifen () in the single hybrid produced beneficial effects in terms of antiproliferative activity of both agents against cancer cells. Since hydroxylation of to form hydroxyferrocifen () improves the biological response, we explore in this work the anticancer effects of a new family of hybrid phenolic compounds bearing some molecular features of , and . Results concerning their cytotoxicity on both triple-negative MDA-MB-231 and hormone-dependent MCF-7 breast cancer cells are reported here. Organometallic compounds showed better antiproliferative activities than organic analogs. For instance, (IC50 = 1.5 µM) was around seven times more active than (IC50 = 10.9 µM) against MCF-7 cells. In the case of triple-negative MDA-MB-231 cells, the IC50 values for ferrocene compounds are in the range of 1.3-4.5 µM and those for organic derivatives are 5.2-34.5 µM. Studies concerning the isomerization and redox behaviors of these compounds are also presented. Despite the potential of to exhibit ex cellulo redox activation, it seems that this feature is not completely expressed in cellulo. This surprising behavior is related to the driving effect of the side chain to direct the new constructs to different targets.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Ferrosos/síntese química , Compostos Ferrosos/farmacologia , Neoplasias de Mama Triplo Negativas/patologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Estabilidade de Medicamentos , Eletroquímica , Compostos Ferrosos/química , Humanos , Isomerismo , Cinética , Células MCF-7 , OxirreduçãoRESUMO
Chemotherapeutic agents combining several active groups within a single molecule can modulate multiple cellular pathways and, thus, exhibit higher efficacy than single-target drugs. In this study, six new hybrid compounds combining tamoxifen (TAM) or ferrocifen (FcTAM) structural motifs with suberoylanilide hydroxamic acid (SAHA) were synthesised and evaluated. Antiproliferative activity was first explored in cancer cell lines. Combining FcTAM and SAHA structural motifs to form the unprecedented FcTAMSAHA hybrid molecule led to an increased cytotoxicity (IC50 = 0.7 µM) in triple-negative MDA-MB-231 breast cancer cells when compared to FcTAM or SAHA alone (IC50 = 2.6 µM and 3.6 µM, respectively), while the organic hybrid analogue TAMSAHA was far less cytotoxic (IC50 = 8.6 µM). In hormone-dependent MCF-7 breast cancer cells, FcTAMSAHA was more active (IC50 = 2.0 µM) than FcTAM (IC50 = 4.4 µM) and TAMSAHA (IC50 > 10 µM), but less toxic than SAHA (IC50 = 1.0 µM). Surprisingly, FcTAMPSA, an N1-phenylsuberamide derivative, also possessed strong antiproliferative activity (IC50 = 0.5 µM and 1.8 µM in MDA-MB-231 and MCF-7 cells, respectively). Subsequent biochemical studies indicate that estrogen receptor alpha (ERα) and histone deacetylases (HDAC) are not the main targets of the hybrid compounds for their antiproliferative effect. Interestingly, both organometallic compounds were able to induce p21waf1/cip1 gene expression in MCF-7 breast cancer cells in accordance with their antiproliferative activity.
Assuntos
Antineoplásicos/síntese química , Compostos Ferrosos/química , Ácidos Hidroxâmicos/química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/metabolismo , Feminino , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Células MCF-7 , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Tamoxifeno/química , Tamoxifeno/toxicidade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , VorinostatRESUMO
A new series of ferrocenyl selenoamides 7-11 (FcSeNH(CH(2))(n)CH(2)(R)OH, n = 1, 2, 3, R = H, Me, Ph) were prepared in good yields by selenative demetalation of Fischer aminocarbene complexes. The crystal structures of 7 [FcSeNH(CH(2))(2)OH] and 19 [PhSeNH(CH(2))(2)OH] reveal their capability to form intermolecular hydrogen bonding in solid state. Results of SRB assays show that these new selenium compounds have a good anticancer potency superior to tamoxifen and cisplatin, with IC(50) values ranging from 4.5 to 13.32 µM against human breast cancer cell lines. A preliminary model to explain the structure-cytotoxic activity relation is proposed where different structural parameters such as the alkyl chain length, the presence of bulky groups in the same chain, the effect of hydroxyl group, and also the role of ferrocene moiety are included as being responsible for the cytotoxic response.