Ferrozoles: Ferrocenyl derivatives of letrozole with dual effects as potent aromatase inhibitors and cytostatic agents.

In the treatment of hormone-dependent cancers, aromatase inhibitors (AI) are receiving increased attention due to some undesirable effects such as the risk of endometrial cancer and thromboembolism of SERMs (selective estrogen receptor modulators). Letrozole is the most active AI with 99% aromatase inhibition. Unfortunately, this compound also exhibits some adverse effects such as hot flashes and fibromyalgias. Therefore, there is an urgent need to explore new types of AIs that retain the same-or even increased-antitumor ability. Inspired by the letrozole structure, a set of new derivatives has been synthesized that include a ferrocenyl moiety and different heterocycles. The derivative that contains a benzimidazole ring, namely compound 6, exhibits a higher aromatase inhibitory activity than letrozole and it also shows potent cytostatic behavior when compared to other well-established aromatase inhibitors, as demonstrated by dose-response, cell cycle, apoptosis and time course experiments. Furthermore, 6 promotes the inhibition of cell growth in both an aromatase-dependent and -independent fashion, as indicated by the study of A549 and MCF7 cell lines. Molecular docking and molecular dynamics calculations on the interaction of 6 or letrozole with the aromatase binding site revealed that the ferrocene moiety increases the van der Waals and hydrophobic interactions, thus resulting in an increase in binding affinity. Furthermore, the iron atom of the ferrocene fragment can form a metal-acceptor interaction with a propionate fragment, and this results in a stronger coupling with the heme group-a possibility that is consistent with the strong aromatase inhibition of 6.

Effect of the aniline fragment in Pt(II) and Pt(IV) complexes as anti-proliferative agents. Standard reduction potential as a more reliable parameter for Pt(IV) compounds than peak reduction potential.

The problems of resistance and side effects associated with cisplatin and other chemotherapeutic drugs have boosted research aimed at finding new compounds with improved properties. The use of platinum(IV) prodrugs is one alternative, although there is some controversy regarding the predictive ability of the peak reduction potentials. In the work described here a series of fourteen chloride Pt(II) and Pt(IV) compounds was synthesised and fully characterised. The compounds contain different bidentate arylazole heterocyclic ligands. Their cytotoxic properties against human lung carcinoma (A549), human breast carcinoma (MCF7) and human colon carcinoma (HCT116 and HT29) cell lines were studied. A clear relationship between the type of ligand and the anti-proliferative properties was found, with the best results obtained for the Pt(II) compound that contains an aniline fragment, (13), thus evidencing a positive effect of the NH2 group. Stability and aquation studies in DMSO, DMF and DMSO/water mixtures were carried out on the active complexes and an in-depth analysis of the two aquation processes, including DFT analysis, of 13 was undertaken. It was verified that DNA was the target and that cell death occurred by apoptosis in the case of 13. Furthermore, the cytotoxic derivatives did not exhibit haemolytic activity. The reduction of the Pt(IV) compounds whose Pt(II) congeners were active was studied by several techniques. It was concluded that the peak reduction potential was not useful to predict the ability for reduction. However, a correlation between the cytotoxic activity and the standard reduction potential was found.

[Streptococcus gallolyticus (ex S. bovis) bacteremia and its relationship with colonic or hepatobiliary disease and endocarditis]. / Bacteriemias por Streptococcus gallolyticus (ex S. bovis) y su relación con patología colónica o hepatobiliar y endocarditis.

BACKGROUND: Bacteremia due to Streptococcus bovis (now S. gallolyticus) has been traditionally associated to colon or hepatobiliar disease and endocarditis but there is no information on this matter in Chile. AIMS: To describe clinical features of adult patients suffering bacteremia by S. bovis/S. gallolyticus, identify the source of the bacteremia and the frequency of endocarditis. METHODS: Retrospective-descriptive study using laboratory records. RESULTS: Between January 2003 and August 2014, 23 S. bovis/S. gallolyticus bacteremic events were identified among 22 patients. Mean age was 72.7 years (range 46-96). Co-morbidities were frequent (9.1 to 47.6%). The primary source of bacteremia was intestinal in 52.2%; hepatobiliar in 17.4% and in 34.8% it was not elucidated. Six patients had infective endocarditis (26.1%) and one patient had espondylodiscitis (4.3%). S. bovis represented 39.1% of isolates (all until 2008), S. gallolyticus subsp pasteurianus 39.1% and, S. gallolyticus subsp infantarius and S. gallolyticus subsp gallolyticus 8.7% each one, respectively. Association studies between the bacteremic source or endocarditis with specific S. gallolyticus subspecies were limited by the small number of isolates. Seven patients (30.4%) underwent surgical interventions. In-hospital mortality reached 21.7% (n=5). CONCLUSIONS: Although infrequent, bacteremic events by S. gallolyticus/S. bovis have increased in-hospital mortality, require surgical intervention and affect older patients with co-morbidities. Near two-thirds suffer from colonic or hepatobiliary disease that act as the primary source of bacteremia. In addition, near one fourth is affected by infective endocarditis. Detection of S. gallolyticus/S. bovis in blood cultures prompts a thorough clinical evaluation in order to clarify the source of the bloodstream infection and the presence of complications.

Bacteriemias por Streptococcus gallolyticus (ex S. bovis) y su relación con patología colónica o hepatobiliar y endocarditis / Streptococcus gallolyticus (ex S. bovis) bacteremia and its relationship with colonic or hepatobiliary disease and endocarditis

Background: Bacteremia due to Streptococcus bovis (now S. gallolyticus) has been traditionally associated to colon or hepatobiliar disease and endocarditis but there is no information on this matter in Chile. Aims: To describe clinical features of adult patients suffering bacteremia by S. bovis/S. gallolyticus, identify the source of the bacteremia and the frequency of endocarditis. Methods: Retrospective-descriptive study using laboratory records. Results: Between January 2003 and August 2014, 23 S. bovis/S. gallolyticus bacteremic events were identified among 22 patients. Mean age was 72.7 years (range 46-96). Co-morbidities were frequent (9.1 to 47.6%). The primary source of bacteremia was intestinal in 52.2%; hepatobiliar in 17.4% and in 34.8% it was not elucidated. Six patients had infective endocarditis (26.1%) and one patient had espondylodiscitis (4.3%). S. bovis represented 39.1% of isolates (all until 2008), S. gallolyticus subsp pasteurianus 39.1% and, S. gallolyticus subsp infantarius and S. gallolyticus subsp gallolyticus 8.7% each one, respectively. Association studies between the bacteremic source or endocarditis with specific S. gallolyticus subspecies were limited by the small number of isolates. Seven patients (30.4%) underwent surgical interventions. In-hospital mortality reached 21.7% (n = 5). Conclusions: Although infrequent, bacteremic events by S. gallolyticus/S. bovis have increased in-hospital mortality, require surgical intervention and affect older patients with co-morbidities. Near two-thirds suffer from colonic or hepatobiliary disease that act as the primary source of bacteremia. In addition, near one fourth is affected by infective endocarditis. Detection of S. gallolyticus/S. bovis in blood cultures prompts a thorough clinical evaluation in order to clarify the source of the bloodstream infection and the presence of complications.

Antecedentes: Los cuadros de bacteriemia por Streptococcus bovis (actualmente S. gallolyticus) han sido tradicionalmente asociados a patología colónica o hepatobiliar y endocarditis pero no se conoce de estudios en Chile que hayan abordado este tema. Objetivos: Describir aspectos clínicos de pacientes adultos afectados por bacteriemias por S. bovis/S. gallolyticus, identificar la fuente de la bacteriemia y la frecuencia de endocarditis. Métodos: Diseño de tipo retrospectivo, descriptivo, con el registro de casos bacteriemia. Resultados: Entre enero de 2003 y agosto de 2014 se identificaron 23 eventos de bacteriemia por S. bovis/S. gallolyticus en 22 pacientes. La edad promedio fue de 72,7 años (rango 46-96). La prevalencia de diferentes co-morbilidades fue elevada (9,1 a 47,6%). El foco primario de la bacteriemia fue intestinal en 52,2%, hepatobiliar en 17,4% y, en 34,8% no se aclaró el foco. Seis pacientes presentaron endocarditis infecciosa (26,1%) y uno espondilodiscitis (4,3%). S. bovis representó 39,1% de los aislados (todos hasta el 2008), S. gallolyticus subsp pasteurianus 39,1%, S. gallolyticus subsp infantarius y S. gallolyticus subsp gallolyticus 8,7%, respectivamente. Los estudios de asociación estuvieron limitados por el bajo número de aislados. Siete pacientes (30,4%) debieron ser intervenidos quirúrgicamente. La mortalidad hospitalaria fue de 21,7% (n: 5). Conclusiones: Aunque infrecuentes, los eventos de bacteriemia por S. gallolyticus/S. bovis tienen una elevada mortalidad hospitalaria, requieren con frecuencia procedimientos quirúrgicos y afectan a pacientes mayores con co-morbilidades. Cerca de dos tercios padecen de una patología colónica o hepatobiliar que actúa como foco primario y cerca de un cuarto presenta endocarditis infecciosa. La detección de este grupo bacteriano en los hemocultivos requiere una evaluación para establecer el origen de la bacteriemia y la presencia de complicaciones.