D-homo Derivatives Research Articles

Structural analysis and biomedical potential of novel salicyloyloxy estrane derivatives synthesized by microwave irradiation

New estrane salicyloyloxy or D-homo derivatives were synthesized under microwave (MW) or conventional heating from estrane precursors and methyl salicylate. The MW technique provides advantages regarding product yield and reaction time, and represents a more environmentally friendly approach than conventional heating. Considering the biomedical potential of estrane compounds, we evaluated the antioxidant activity and cytotoxicity of synthesized estrane derivatives in a series of in vitro tests, as well as their 3β-hydroxysteroid dehydrogenase/Δ5 → Δ4 isomerase (3βHSD) and 17β-hydroxysteroid dehydrogenase types 1, 2 and 3 (17βHSD1, 17βHSD2 and 17βHSD3) inhibition potentials. In DPPH tests, 3-methoxyestra-1,3,5(10)-trien-17β-yl salicylate displayed antioxidant potential, while all compounds exhibited OH radical neutralization activity. 3-Oxoestr-4-en-17β-yl salicylate showed strong cytotoxicity against MDA-MB-231 breast cancer cells, while 17-oxoestra-1,3,5(10)-trien-3-yl salicylate, estra-1,3,5(10)-triene-3,17β-diyl 3-benzoate 17-salicylate and 3-benzyloxy-17-salicyloyloxy-16,17-secoestra-1,3,5(10)-triene-16-nitrile showed the strongest inhibition of PC-3 prostate cancer cell growth. 3-Hydroxyestra-1,3,5(10)-trien-17β-yl salicylate was the best inhibitor of 17βHSD2, suggesting potential use in treating pathological conditions associated with estrogen depletion. For 3-methoxyestra-1,3,5(10)-trien-17β-yl salicylate and 3-oxoestr-4-en-17β-yl salicylate, X-ray crystal structure analysis and molecular energy optimization were performed to define their conformations and energy minima. Very good overlap in the region of the steroidal nucleus was observed for the molecular structures of each analyzed molecule in the crystalline state and after energy optimization, while conformer analysis indicates conformational flexibility in the form of rotation around the C17···O2 bond. Structural geometry analysis for these compounds shows that the region of ring A in steroids, and especially the C3 atom functional group, is important structural features concerning antiproliferative activity against MDA-MB-231 cells.

Synthesis and antitumor activity of new d-seco and d-homo androstane derivatives

Starting from 3β-hydroxy-17-oxo-16,17-secoandrost-5-ene-16-nitrile ( 1), the new 16,17-secoandrostane derivatives 4– 9 were synthesized. On the other hand, 3β-hydroxy-17-oxa- d-homoandrost-5-ene-16-one ( 10) yielded the new d-homo derivatives 12, 13 and 15. In vitro antiproliferative activity of selected compounds against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER−, MDA-MB-231, prostate cancer AR−, PC-3, and normal fetal lung fibroblasts, MRC-5) was evaluated. Compounds 3 and 12 showed strong antiproliferative activity against PC-3 cells, the IC 50 values being 2 μM and 0.55 μM, respectively. Compounds 6 (10 μM) and 14 (9 μM) showed moderate activity against MDA-MB-231 cells. The synthesized compounds 1– 3, 5– 8, 10 and 12– 15 were not toxic to normal fetal lung fibroblasts cells, MRC-5.

Synthesis and stereochemical investigations of novel nitrogen-containing 13α-estrone derivatives

Novel tetrahydroquinoline 11 and N-aryl d-homo derivatives 12 in the 13α-estrone series were synthesized effectively, starting from the secoaldehyde 8 and mono- or disubstituted anilines 9. The chemoselectivity of the cyclization reactions depended upon the nature of the substituents in the anilines. All transformations proceeded in a highly stereoselective manner, yielding only one diastereomer. Condensed 11 and d-homo derivatives 12 both have the usual ring C chair conformation in the solid state.

Synthesis, X-ray crystal structures and biological activity of 16-amino-17-substituted-D-homo steroid derivatives

D-Homo derivatives in the androstane and estrane series, 12– 19, were synthesized by a fragmentation-cyclization reaction of 16-oximino-17-hydroxy-17-substituted derivatives 3– 9, or by cyclization of the corresponding D-seco derivatives 20– 26. The structures were confirmed by X-ray analysis of compounds 12 and 16. Preliminary assessment of inhibitory effects of D-homo derivatives from androstane series towards aromatase, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase/C17-20 lyase (P450c17) and 17β-HSD indicated much lower inhibitory potential compared to previously tested activity of another type of D-modified steroids, namely D-seco derivatives. Also, assessment of potential antiestrogenic activity of derivatives from estrane series showed absence of such an activity.

Synthesis and receptor-binding examinations of the normal and 13- epi-D-homoestrones and their 3-methyl ethers

An effective epimerization of the normal estrone 3-methyl and 3-benzyl ethers by using o-phenylenediamine and AcOH made the possibility for facile entry into the 13α-estrone series. Combination of this synthetic methodology with an isolation step carried out by means of the Girard-P reagent, the corresponding ethers of 13- epi-estrone were obtained in excellent yields. The 3-hydroxy and 3-methoxy D-homoestrone derivatives in both the normal and the 13α-estrone series were then synthesized and tested in vitro in a radioligand-binding assay. The estrogen receptor recognizes these compounds, but their relative binding affinities (RBAs) are lower than that of the reference compound 3,17β-estradiol. The progesterone receptor-binding affinities of the four D-homo derivatives were also tested showing low values for 13α-D-homoestrone and its 3-methyl ether. Pharmacologically, these 13α-D-homoestrone derivatives are estrogen receptor-selective molecules.

Synthesis and stereochemistry of 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and d-homo derivatives

From the condensation reaction of O-methylbutyrolactim ( 2), O-methylvalerolactim ( 3), O-methylcaprolactim ( 4) and O-methyl-4- t-butylcaprolactim ( 5) with ethyl 6,7-dimethoxy-α-[1-(1,2,3,4-tetrahydro-isoquinolyl)]acetate ( 1), 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one ( 6) d-homo-derivatives ( 7–9), and medium-sized ring cyclic diamides ( 10,11) were obtained. The stereoselective reduction of compounds 6–9 by Adam’s platinum catalyst afforded 8,13-diaza-2,3-dimethoxygona-1,3,5(10)-trien-12-one ( 12) and its d-homo derivatives ( 13–15). The structures of the compounds obtained were established by NMR and X-ray crystallographic analyses.

Digitalis-like compounds: Synthesis and biological evaluation of seco-D and D-homo derivatives

The synthesis of seco-D and D-homo digitalis derivatives, from the carda-14,20(22)-dienolide 1, is described. Selective ozonolysis gave the seco-D 14-ketoaldehyde 2a. Modification of the two carbonyl groups and of the α, β-unsaturated lactone ring of the seco-D 14-ketoaldehyde 2a allowed preparation of derivatives with a broad range of binding affinity to the Na +, K +-ATPase receptor. Some of the seco-D derivatives ( 10, 11b, and 13b) showed a binding affinity similar to that of digitoxigenin, demonstrating that the D-ring is not essential for recognition by the digitalis receptor. In the class of D-homo derivatives the highest binding value, about 15 times lower than that of digitoxigenin, was that of the C >D cis compound 29b; the C D trans analog 28b showed a 7-fold decrease in binding affinity, indicating that the C D configuration plays an important role in D-homo derivatives as in the classical digitalis compounds.

Pharmacokinetics and metabolism of moxestrol in humans

Moxestrol, the 11β-methoxy derivative of ethynyl estradiol and a highly potent estrogen, is rapidly distributed in the body (AIVD = 148.6 ± 19.71, MCR = 79.9 ± 10.51/h) after i.v. administration because it is not bound by SBP and has low affinity for albumin. Its oral bioavailability is about 33% after administration of 30 or 100μg to healthy volunteers and slightly lower than that of ethynyl estradiol (50%) due to a “first-pass effect”. Moxestrol is rapidly metabolized by the liver as shown by the much increased bioavailability (60.5%) in patients with impaired liver function. The radioimmunoassay for moxestrol measures plasma moxestrol levels ranging from 100 pg/ml (maximum) to 10 pg//ml (24 h value) after treatment with a 100 μg commercial formulation (Surestryl ®). Moxestrol metabolism was studied on urine which contained 28% of administered radioactivity after i.v. or oral administration. Hydroxylation was the main transformation pathway as for ethynyl estradiol. Moxestrol yielded metabolites hydroxylated (or methoxylated) at C-2, C-15 and C-16, but not at C-6, and also gave rise to D-homo derivatives. The main difference between moxestrol and ethynyl estradiol lies in the relative importance of these pathways. The presence of the ethynyl group of ethynyl estradiol impedes attack at C-16 and hydroxylation at C-2 to form catechol estrogens becomes a major pathway, whereas the 11β-methoxy group of moxestrol impedes hydroxylation at C-2 and ring D hydroxylated products of moxestrol are formed. The low amount of catechol estrogens obtained with moxestrol compared to ethynyl estradiol could have important physiological implications in the human.

D-Homo Rearrangement of Cortical Steroids. Interrelationship of D-Homo Derivatives in the 11-Oxygenated Pregnane Series1

D-Homo Rearrangement of Cortical Steroids. Interrelationship of D-Homo Derivatives in the 11-Oxygenated Pregnane Series¹