Steroidal ferrocenes as potential enzyme inhibitors of the estrogen biosynthesis.

The potential inhibitory effect of diverse triazolyl-ferrocene steroids on key enzymes of the estrogen biosynthesis was investigated. Test compounds were synthesized via copper-catalyzed cycloaddition of steroidal azides and ferrocenyl-alkynes using our efficient methodology published previously. Inhibition of human aromatase, steroid sulfatase (STS) and 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) activities was investigated with in vitro radiosubstrate incubations. Some of the test compounds were found to be potent inhibitors of the STS. A compound bearing ferrocenyl side chain on the C-2 displayed a reversible inhibition, whereas C-16 and C-17 derivatives displayed competitive irreversible binding mechanism toward the enzyme. 17α-Triazolyl-ferrocene derivatives of 17ß-estradiol exerted outstanding inhibitory effect and experiments demonstrated a key role of the ferrocenyl moiety in the enhanced binding affinity. Submicromolar IC50 and Ki parameters enroll these compounds to the group of the most effective STS inhibitors published so far. STS inhibitory potential of the steroidal ferrocenes may lead to the development of novel compounds able to suppress in situ biosynthesis of 17ß-estradiol in target tissues.

Synthesis of methoxycarbonylpyrazolylandrostene derivatives, and their potential inhibitory effect on androgen biosynthesis and cell proliferation.

The Claisen condensations of 3ß-acetoxypregn-5-en-20-one (1) and 3ß-acetoxypregna-5,16-diene (7) with dimethyl oxalate are known to lead to 3ß-hydroxy-21-methoxalylpregn-5-en-20-one (2) and 3ß-hydroxy-21-methoxalylpregna-5,16-dien-20-one (8), respectively. The reactions of 2 with p-substituted phenylhydrazines afford pyrazol-5-yl derivatives (5) as main, and 3-yl regioisomers (4) as minor products. The corresponding reactions of 16-ene analogue 8 afford only pyrazol-5-yl regioisomer 9. Oppenauer oxidation of the pyrazolyl compounds yields the corresponding Δ(4)-3-ketosteroids. We investigated the antiandrogenic effects of new methoxycarbonylpyrazolyl compounds through determination of their in vitro inhibition of the activities of rat testicular C17,20-lyase, Δ(5)-3ß-hydroxysteroid dehydrogenase (Δ(5)-3ß-HSD) and 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3). A Δ(5)-3ß-hydroxy compound in the D-ring-saturated androst-5-ene series bearing an unsubstituted phenyl group on the pyrazolyl heterocycle (5a) proved to be a potent inhibitor of Δ(5)-3ß-HSD. The 4-methoxyphenyl derivative (5e) and the 3-oxo counterpart (6a) of 5a also displayed substantial inhibition. The other tested compounds exerted only weak inhibitory action against the enzymes investigated. The newly synthetized compounds were evaluated in vitro by means of MTT assays for antiproliferative activity against Hela (cervical carcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast adenocarcinoma) cells. In all four groups (3ß-hydroxy- and 3-ketosteroids with saturated or unsaturated ring D), the most potent analogs contain a 4-tolyl or 4-methoxyphenyl group. Compound 5d exhibited substantial antiproliferative action against the three cell lines investigated, whereas 9d inhibited the growth of Hela cells markedly. The most noteworthy inhibition was exerted by 6a against A431 cells.

[In the labyrinth of calcium metabolism]. / A kalcium-anyagcsere útvesztoi.

The authors present the case of a 27-year-old male patient. In 2010, he suffered from a bone fracture of the pelvis. As imaging techniques showed multiple osseal lytic lesions, diagnostic investigations were performed for multiple myeloma. Later, a mass lesion measuring 37 mm in size was removed from the left side of his mandible. Histology revealed a giant-cell tumour of the bone and oncologic therapy was considered. However, before this planned treatment a PET-CT was performed, which showed numerous distinct lesions with enhanced glucose metabolism in the skeleton as well as in soft tissue behind the right lobe of the thyroid. Hence, the patient was referred to endocrinologists. On the basis of severe hypercalcemia (serum calcium 3.66 mmol/l) and high serum parathyroid hormone level (162.5 pmol/l) the diagnosis of a right sided parathyroid tumour was established. After surgical excision of the parathyroid tumour, high levels of serum calcium and parathyroid hormone returned to normal. Histology failed to show malignancy and the patient recovered soon. This case report may shed some light on the importance of serum calcium measurements and the differential diagnostic significance of primary hyperparathyroidism.

Novel series of 17ß-pyrazolylandrosta-5,16-diene derivatives and their inhibitory effect on 17α-hydroxylase/C(17,20)-lyase.

The Claisen condensation of 3ß-acetoxypregna-5,16-dien-20-one (1) with ethyl formate in the presence of sodium methylate in pyridine is known to lead to 3ß-hydroxy-21-hydroxymethylidenepregna-5,16-dien-20-one (2) in good yield. With the methods described for the preparation of the saturated D-ring pyrazolyl series, the reactions of 2 with phenylhydrazine and its p-substituted derivatives in acetic acid resulted in mixtures of two steroidal regioisomers, the 1'-aryl-3'-pyrazolyl-(4a-e) and 1'-aryl-5'-pyrazolyl (5a-e) steroids. Compounds 4a-e are unknown in the literature. The arylpyrazoles produced were tested against 17α-hydroxylase/C(17,20)-lyase (P450(17α)) in vitro and neither of the regioisomers exerted efficient inhibition.

[The importance of early diagnosis in acromegaly]. / Az acromegalia korai felismerésének jelentosége.

The authors review the historical and epidemiological aspects, clinical features and complications of acromegaly while emphasizing the importance of the early diagnosis and treatment. Acromegaly is a rare and mostly sporadic disorder due to excessive production of growth hormone. It is characterized by progressive somatic disfigurement (mainly involving the face and extremities) and systemic manifestations. The prevalence is estimated between 40 and 125 cases/million. Generally, it is diagnosed in middle-aged adults (mean age 40 years, men and women equally affected). Due to its insidious onset and slow progression, acromegaly is often diagnosed 7 to more than 10 years after its onset. The disease has cardiovascular, rheumatological, respiratory and metabolic consequences which highly determine its prognosis. Acromegaly is associated with a number of complications resulting in a two- or four-fold increase of mortality and a decrease of life expectancy by about 10 years. The major causes of death include cardiovascular and cerebrovascular events, respiratory diseases and malignancies. The duration of the disease before the introduction of effective therapy may be a major predictor of increased mortality mainly due to complications . The early diagnosis is important for timely commencement of treatment and for prevention of serious complications of the disease.

Steroselective synthesis of some steroidal oxazolines, as novel potential inhibitors of 17alpha-hydroxylase-C17,20-lyase.

17beta-Oxazolinyl steroids 7a-g and 8a-g were synthesized. The Lewis acid-catalysed reactions of (20R)-3beta-acetoxy-21-azidomethyl-20-hydroxypregn-5-ene with substituted aromatic aldehydes led to the formation of 3beta-acetoxyandrost-5-enes substituted in position 17beta with oxazolinyl residues (7a-g). Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids yielded the corresponding Delta(4)-3-ketosteroids. The inhibitory effects (IC(50)) of both 3-hydroxy compounds 7a-g and their Delta(4)-3-keto counterparts 8a-g on rat testicular C(17,20)-lyase were investigated with an in vitro radioligand incubation technique. The 3-chlorophenyl- (8d), and the 4-bromophenyl-17beta-(2-oxazolin-5-yl)androst-4-en-3-one derivatives (8f) were found to be modest inhibitors (IC(50)=4.8 and 5.0 microM, respectively).

Neighboring group participation Part 17 Stereoselective synthesis of some steroidal 2-oxazolidones, as novel potential inhibitors of 17alpha-hydroxylase-C(17,20)-lyase.

During the alkaline methanolysis of 3beta-acetoxy-21-chloropregn-5-ene-20beta-N-phenylurethane (4a), and its 4-monosubstituted (4b-e) and 3,5-disubstituted (4f) phenyl derivatives, cyclization occurs, in the course of which 17beta-[3-(N-phenyl)-2-oxazolidon-5-yl]androst-5-en-3beta-ol (5a) and its substituted phenyl derivatives (5b-f) are formed. The cyclization takes place with (N(-)-5) neighboring group participation. The reaction of 3beta-acetoxy-21-azidopregn-5-en-20beta-ol (3d) with triphenylphosphine gave 3beta-acetoxy-21-phosphiniminopregn-5-en-20beta-ol, which reacted in situ with carbon dioxide with the participation of the sterically favored 20beta-OH to give the unsubstituted steroidal cyclic carbamate (8). Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids (5a-f, 9) yielded the corresponding Delta(4)-3-ketosteroids (7a-f, 10). The inhibitory effects (IC(50)) of these compounds on rat testicular C(17,20)-lyase were investigated with an in vitro radioligand incubation technique. The N-unsubstituted 17beta-(2-oxazolidon-5-yl)-androst-4-en-3-one derivative (10) was found to be a potent inhibitor (IC(50)=3.0 microM).

Aortic stiffness is increased in acromegaly--a transthoracic echocardiographic study.

BACKGROUND: Acromegaly is associated with increased cardiovascular risk. Recent studies suggested a direct effect of growth hormone and insuline-like growth factor 1 excess on the vasculature over the conventional risk factors. The aim of the present study was to evaluate the stiffness of ascending aorta by means of transthoracic echocardiography (TTE) in patients with acromegaly. PATIENTS AND METHODS: The following patient populations were compared: 20 subjects with negative coronary angiograms, 16 acromegalics and 21 patients with significant coronary artery disease (CAD). Aortic stiffness index (beta) was evaluated by means of TTE by use of the formula: beta=ln (SBP/DBP)/(DeltaD/DD), where SBP and DBP are the systolic and diastolic blood pressures, DD is the diastolic aortic diameter, DeltaD is the pulsatile change in aortic diameter (systolic diameter minus diastolic diameter) and 'ln' is the natural logarithm. RESULTS: The average time from diagnosis was 162+/-127 days in acromegalic patients. Transsphenoidal hypophysectomy was performed in 12 patients, while the mean growth hormone level was 10.8+/-11.7 mIU/ml. beta was similarly increased in acromegalics and in CAD patients as compared to controls (6.23+/-3.29 vs 16.47+/-14.53 and 16.66+/-15.49, p<0.05, respectively). CONCLUSIONS: Stiffness of ascending aorta evaluated by a routine TTE examination is increased in acromegalics without overt cardiovascular disease as compared to controls and similar to CAD patients.

Stereoselective synthesis of some 17beta-dihydrooxazinyl steroids, as novel presumed inhibitors of 17alpha-hydroxylase-C17,20-lyase.

17beta-Dihydrooxazinyl steroids 5a-l and 6a-l were synthetized. The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids with substituted aromatic aldehydes led to the formation of androst-5-en-3beta-ols substituted in position 17beta with dihydrooxazine residues. The inhibitory effects of these compounds on rat testicular C(17,20)-lyase were investigated with an in vitro radioincubation technique.

Neighboring group participation. Part 15. Stereoselective synthesis of some steroidal tetrahydrooxazin-2-ones, as novel presumed inhibitors of human 5alpha-reductase.

During the alkaline methanolysis of 3beta-acetoxy-21-chloromethyl-pregn-5-ene-20beta-N-phenylurethane, and its p-substituted phenyl derivatives, cyclization occurs, in the course of which 17beta-[3-(N-phenyl)tetrahydrooxazin-2-on-6-yl]androst-5-en-3beta-ol and its p-substituted phenyl derivatives are formed. The cyclization takes place with (N(-)-6) neighboring group participation. Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids yielded the corresponding delta4-3-ketosteroids. The structures of the new compounds were proved by IR, 1H and 13C NMR spectroscopy, using up-to-date measuring techniques such as 2D-COSY, HMQC, and HMBC. The inhibitory effects (CI50) of the delta4-3-ketosteroids on 5alpha-reductase were studied.

[Current alternative in the pharmacotherapy of acromegaly: the long-acting somatostatin analogue octreotide]. / Korszerú lehetóség az acromegalia gyógyszeres kezelésére: octreotid, a tartós hatású somatostatin-analóg.

Twelve active acromegalic patients (10 women, 2 men) were chronically treated with a long-acting microcapsulated preparation of octreotide (Sandostatin LAR, Novartis). In each case, a growth hormone-producing pituitary adenoma was responsible for the development of acromegaly (microadenomas in 3 and macroadenomas in the rest of the patients). Treatment with long-acting octreotide was indicated for those patients who had not reacted satisfactorily upon previous therapeutic procedures or proved to be unsuitable for irradiation therapy and/or surgery or refused both of these therapies. The preparation was given intramuscularly in every fourth week, generally in a dose of 20-30 mg. After a 6-month treatment, the daily mean of serum growth hormone became suppressed below 2.5 ng/ml in 58.3% of the patients, whereas the growth hormone nadir during oral glucose tolerance test was found at or below 2.5 ng/ml in an even higher proportion of patients (70%). During a 2-year period, the growth hormone-suppressive effect of long-acting octreotide remained stable in all but one patient. The size of the pituitary adenomas remarkably decreased in 50% of this patient cohort. The medication with this preparation was well tolerated. As adverse events, asymptomatic cholelithiasis was detected in 2 patients and biliary sludge-formation in 1 patient. The total number of patients with glucose metabolism disturbances increased only moderately, however, the occurrence of manifest diabetes mellitus became doubled. On the basis of relevant literature data, it can be stated that the mortality rate of successfully treated acromegalics significantly improves. The present retrospective study yields evidence for the microcapsulated octreotide to be an effective tool in the modern therapy of acromegaly.

[Octreotide therapy in multiple endocrine neoplasia type-1]. / Octreotid kezelés multiplex endokrin neoplasia 1. típusában.

In multiplex endocrine neoplasia type 1, hyperparathyroidism, pancreas tumor and pituitary tumor are generally combined. The authors report two patients with this syndrome, in whom overproduction of parathormone and gastrin was detected, and parathyroid adenomas were detected by parathyroid scintigraphy. Pancreatic adenomas were discovered with somatostatin receptor scintigraphy or magnetic resonance imaging. Hyperprolactinaemia without pituitary tumor in the first case, and prolactinoma in the second case, as well as nonfunctioning adrenal adenomas in both cases were also observed. After several unsuccessful surgical interventions a long-term octreotide (Sandostatin, Novartis) treatment was started; in the first patient subcutaneous injection was given for 6 months, then the treatment was continued with the long-acting intramuscular preparation (Sandostatin LAR, Novartis). The second patient received long-acting octreotide from the beginning of medical therapy. The authors intended to obtain data about the effects of this therapy on all overproduced hormones. In the first case, a 6-months treatment with subcutaneous octreotide surprisingly resulted not only in a decrease of serum gastrin, but also in that of parathormone level. In the second case, serum gastrin was normalized, but parathormone did not change. The levels of prolactin and adrenocortical hormones were not affected. At present, the two patients are without any symptoms of their disease.