Synthesis and cytotoxic effect on cancer cell lines and macrophages of novel progesterone derivatives having an ester or a carbamate function at C-3 and C-17.

In this study we report the cytotoxic effect on human cancer cells of two series of novel progesterone derivatives; the first containing an aromatic ester (8a-e) or a carbamate functions both linked to C-3 (9a-e) on the pregn-4,16-diene-6,20-dione skeleton. In the second series, both functional groups (ester and carbamate) are bound to C-17 on the pregn-4,6-diene-3,20-dione scaffold (13a-e and 14a-e). The panel cancer cell lines used in this study were the following: PC-3 (human prostate cancer cell line), MCF-7 (human breast cancer cell line), HCT-15 (human colon cancer cell line) and J774 (noncancerous murine macrophages) for comparison. The results from this study showed that steroid 14a, having a carbamate function at C-17, was the most potent against PC-3 cell line (96.6%) while 8c and 8e showed much higher cytotoxic activity (100%) for MCF-7 cell line. Finally, compounds 8c and 14a displayed selective properties towards tumor cell lines than noncancerous murine macrophages.

Diagnóstico citológico de lesiones focales intra-abdominales en pacientes que acuden al Servicio de Gastroenterología del Hospital Central Universitario “Antonio María Pineda”: Barquisimeto-Estado Lara / Cytological diagnosis of intra-abdominal focal lesions in patients attending the Hospital Central Universitario

Las lesiones focales de los órganos intra - abdominales comprenden un amplio espectro, produciendo desde pocas o inaparentes consecuencias, hasta un deterioro significativo de la calidad de vida pudiendo representar una condición severa asociada con mal pronóstico y alta mortalidad. Determinar el diagnóstico citológico de lesiones focales intra-abdominales mediante punción aspiración con aguja fina en pacientes que acuden al Servicio de Gastroenterología del Hospital Central Universitario “Antonio María Pineda”. Barquisimeto. Estado Lara. Se realizó una investigación de tipo descriptiva transversal, practicándose punción aspiración con aguja fina a todos los pacientes con lesiones focales intra-abdominales que acudierón al Servicio de Gastroenterología del HCUAMP durante el periodo Julio 2008 - Diciembre 2008 excluyéndose aquellos con ausencia de un trayecto seguro para la aguja, poca abordabilidad de la lesión, trastornos de coagulación o trombocitopenia severa, infecciones de la piel en el área de la punción, enfermedades neurológicas agudas, estado crítico o terminal y pacientes poco colaboradores. 62% de los pacientes con lesiones focales intra-abdominales pertenecían al sexo femenino y 38% al sexo masculino. 54% de los pacientes tenían entre 40 y 69 años. La localización intra-abdominal más frecuente de las lesiones fue Hígado en 84%, Páncreas en 10% Retroperitoneo en 4% y Bazo en 2%. La categoría citológica fue benigna en 30% seguido de 23% maligna y 7% sospechosa para malignidad mientras que en 37% no se reportaron hallazgos citológicos patológicos. El diagnóstico citológico más frecuente de las lesiones benignas fue Absceso en 65%. De los pacientes con lesiones categorizadas como malignas, 62% presentó diagnóstico citológico de Adenocarcinoma, 15% Carcinoma, 15% neoplasia epitelial neuroendocrina y 8% Linfoma. No se presentaron complicaciones. La principal limitación fue la no disponibilidad de patólogo en el momento de la toma de las muestra...

Focal lesions in intra-abdominal organs comprehend a wide spectrum, resulting into a few or non-apparent consequences up to a significant damage of living standards, which might represent a severe condition associated with a bad patient outlook and high morbidity. Determining the cytological diagnosis of intraabdominal focal lesions by puncture/aspiration with fine needle in patients attending the Hospital Central Universitario Antonio Maria Pineda’s (HCUAMP) Gastroenterology Service, at Barquisimeto, State of Lara. A cross-sectioned descriptive research was developed; fine-needle puncture/aspiration was practiced on all patients with intra-abdominal focal lesions who attended the HCUAMP’s Gastroenterology Service between July-September 2008, excluding those who did not show a safe routing for the needle, scarce approachability to the lesion, coagulation disturbances, severe thrombocytopenia, skin infection on the puncture area, acute neurologic diseases, critical or terminal stage, and uncooperative patients. 62% of patients with intra-abdominal focal lesions were female, and 38% were male. 54% of patients were between 40 and 69 years old. The most frequent intra-abdominal lesions were: Liver, 84%; Pancreas, 10%; retroperitoneum, 4%; and Spleen, 2%. Cytological category was 30% benign, followed by 23% malignant; and 7% probably malignant, while 37% did not report pathologic cytological findings. The most frequent cytological diagnosis in benign lesions was 65% of abscess. From the patients with lesions categorized as malignant, 62% presented a cytological diagnosis of adenocarcinoma; 15%, Carcinoma; 15%, neuroendocrinal epithelial neoplasm; and 8% Lymphoma. No complications were present. The non availability of pathologist at the time of sample collection was the main limitation. The puncture/aspiration by ultrasound-guided fine needle in intraabdominal focal lesions is a rapid and efficient diagnosis alternative, rendering high specificity...

Synthesis and biological activity of progesterone derivatives as 5alpha-reductase inhibitors, and their effect on hamster prostate weight.

In this study, we report the synthesis and biological evaluation of four 6- and 17-substituted progesterone derivatives (7-10). These compounds were prepared from the commercially available 17alpha-acetoxyprogesterone. The biological effect of these steroids was demonstrated in in vivo as well as in vitro experiments. In the in vivo experiments, we measured the activity of 6-10 on the weight of the prostate glands of gonadectomized hamsters treated with testosterone (T). For the studies in vitro, we determined the IC(50) value by measuring the concentration of steroidal derivative that inhibited 50% of the activity of 5alpha-reductase present in the human prostate. The results from this work indicated that compounds 6-9 significantly decreased the weight of the prostate as compared to testosterone-treated animals and this reduction of prostate weight was comparable to that produced by finasteride. Steroid 8 was the most effective of the tested compounds. However, compound 10 did not exhibit this capacity. On the other hand, 6-9 exhibited a high inhibitory activity for the human 5alpha-reductase enzyme with IC(50) values of 10, 70, 22, and 19 nM, respectively. However, 10 was not effective for the inhibition of 5alpha-reductase activity. In conclusion, the compounds that contained the acetate ester moiety in the molecule (6, 7, 8, and 9) inhibited the activity of 5alpha-reductase and decreased the weight of the prostate. Nevertheless, the double bond in ring B seems to diminish the inhibitory potency (7 and 9), since 6, which does not possess a double bond at C-6, had the highest inhibitory activity (the lowest IC(50) value).

Novel C-6 substituted and unsubstituted pregnane derivatives as 5alpha-reductase inhibitors and their effect on hamster flank organs diameter size.

The present study is addressed to ascertain the inhibitory effect of several progesterone derivatives having a chlorine substituent at C-6 (12a-12d), 15 with a bromine substituent at C-6 and 14a-14d, without any halogen atom at C-6 all having an ester side chain at C-17 (benzoate ester bearing a Cl, F and a Br atom at C-4 position of the phenyl ring) on the 5alpha-reductase enzyme activity present in human prostate. In addition, it was also of interest to investigate the pharmacological effect on hamster flank organs diameter size. In order to study the structure-activity relationships of steroids 12a-12d, 14a-14d and 15 we determined the concentration of these steroids that inhibited 50% of the activity of human prostate 5alpha-reductase enzyme (IC(50)), as well as the in vivo effect of these compounds in the hamster flank organs diameter size. We also ascertained, the capacity of these steroids to bind to the androgen receptors present in the rat prostate cytosol using labeled mibolerone (MIB) for monitoring the binding to the androgen receptor. The results from this study indicated that compounds 12a-12d (having a chlorine substituent at C-6), 14a-14d (lacking a halogen atom at C-6), 13 and 15 (having a bromine atom at C-6) showed an increased antiandrogenic effect (lower value for the diameter of the flank organs) as compared to the flank organs from testosterone-treated hamsters. On the other hand, the series of compounds containing a chlorine substituent at C-6 compounds (12a-12d) showed a higher antiandrogenic activity as compared to the compounds lacking a halogen atom at C-6 (14a, 14b and 14d). Although compounds 13 and 15 decreased the flank organs diameter size, however, this increase was not statistically significant as compared to that of the commercially available product finasteride. The steroidal derivatives 13, 14a-14d (lacking the chlorine substituent at C-6) and 15 (having a bromine atom at C-6) exhibited a higher 5alpha-reductase inhibitory activity (lower IC(50) values) as compared to the series of compounds 12a-12d having the halogen substituent at C-6. Finasteride reduced the diameter size of the flank organs. The effect of this steroid and compounds 12a-12d, 13, 14a-14d and 15 on hamster flank organs can be explained by the fact that these steroids did not bind to the androgens receptor, which indicates that its mechanism of action is an inhibiting for the 5alpha-reductase activity. This enzyme is present in the hamster flank organs and was inhibited by the novel steroids in the human prostate homogenates.