Steroid Skeleton Research Articles

Synthesis of C–C bonded dimeric steroids by olefin metathesis

Five new C–C bonded steroidal homodimers derived from deoxycholic acid, pregnenolone, and progesterone were synthesized by an olefin metathesis reaction assisted by microwave heating. Microwave improved the yield and accelerated the reaction allowing the use of less catalyst with good results (2.5 mol %). Due to the bulky nature of the steroidal skeleton the more favorable E-dimers were formed as the sole or major products depending on the linker length.

Synthesis and Structure Activity Relationship of Organometallic Steroidal Androgen Derivatives

We present here the synthesis and the structure activity relationship of a series of organometallic complexes of the steroidal androgens testosterone and dihydrotestosterone (DHT) substituted at the C-17 position of the steroid skeleton with an ethynyl substituent grafted with various sandwich or semisandwich organometallic units [ferrocenyl, (η5-C5H4)-Re(CO)3, (η5-C5H4)-Mn(CO)3, (η6-C6H5)-Cr(CO)3] and of 3β-androstanediol substituted at C-16 and C-17 respectively by a ferrocenyl vinyl and a ferrocenyl ethynyl unit. In contrast to the estradiol series, there are currently very few examples of organometallic steroidal androgens in the literature. The ethynyltestosterone derivatives were obtained via a Stille coupling reaction between the appropriate iodo-organometallics and 17β-ethynyltestosterone stannyl derivatives. The ethynyl-DHT derivatives were synthesized by addition of the corresponding acetylide to the C-17 carbonyl of the steroid. The crystal structures of two ferrocenyl and one rhenium complexes...

Synthesis of C3, C5, and C7 pregnane derivatives and their effect on NMDA receptor responses in cultured rat hippocampal neurons

The synthesis of several novel 5α- and 5β-20-oxo-pregnane derivatives substituted in the position 3 and 7 of the steroid skeleton is described. Activity of synthesized compounds was studied in voltage-clamped cultured rat hippocampal neurons. Substituted derivatives inhibited NMDA-elicited neuronal activity. The relationship between biological activity and structure is discussed.

Chemical aromatization of 19-hydroxyandrosta-1,4-diene-3,17-dione with acid or alkaline: Elimination of the 19-hydroxymethyl group as formaldehyde

In order to determine whether or not a 19-hydroxymethyl group of 19-hydroxyandrosta-1,4-diene-3,17-dione ( 2, 19-hydroxy ADD), an intermediate of aromatase-catalyzed estrone formation from ADD, a suicide substrate of aromatase, is eliminated as formaldehyde, we examine chemical nature of removal of the 19-hydroxymethyl group. 19-Acetate 3 and 19-tert-butyldimethylsiloxy compound 4 are known to convert rapidly to estrone with treatment of NaOH or n-Bu 4NF. Since compound 2 was unstable and unobtainable under these conditions, compounds 3 and 4 as equivalents to compound 2 were used in this study. The acetate 3 with 5 mol/l HCl in acetone and 10% KOH in MeOH along with the silyl ether 4 with 5 mol/l HCl in acetone and 1 mol/l n-Bu 4NF in THF gave formaldehyde and estrone in which a ratio of the aldehyde to estrone was near 1. This result indicates that the 19-hydroxymethyl groups of compound 3 and 4 are eliminated as formaldehyde along with estrone derived from the steroid skeleton under the acid or base treatment. The findings suggest that a single hydroxylation at the 19 carbon of ADD ( 1) would be, chemically, all that was required for estrone formation.

3D QSAR/CoMFA and CoMSIA Studies on Antileukemic Steroidal Esters Coupled with Conformationally Flexible Nitrogen Mustards

Thirty-eight antileukemic steroidal esters possessing conformationally flexible nitrogen mustards were studied, and the 3D QSAR/CoMFA and CoMSIA methodologies were applied in order to derive the correlation between their structure and the in vivo antileukemic activity. These compounds show significantly reduced toxicity and possibly increased bioavailability compared to free nitrogen mustards and therefore constitute potent antileukemic drugs. Both the CoMFA and CoMSIA studies gave similar results indicating that the steric effect and the hydrophobic/hydrophilic balance especially in the steroidal part of the molecules probably determined their bioactivity. Of paramount interest is the observation that the orientation of the alkylating part of the SMEs toward the surface of ring B of the steroidal skeleton was related with increased activity. Concerning the steroidal part, the presence of hydrophobic groups in rings B and D was found to be important for enhanced activity. Enhancement of antileukemic potency is further observed if hydrophilic/H-bond acceptor groups are present at the positions 7 and 17 of the steroidal skeleton. Leapfrog simulations provided novel compounds which lead our future synthetic endeavor for obtaining SMEs with optimum bioactivity.

Synthesis of ponasterone A derivatives with various steroid skeleton moieties and evaluation of their binding to the ecdysone receptor of Kc cells

A series of ponasterone A (PNA) derivatives with various steroid moieties were synthesized to measure their binding activity to the ecdysone receptors of Drosophila Kc cells. The activity of compounds was evaluated by determining the concentration required to give the 50% inhibition (IC 50 in M) of the incorporation of [ 3H]PNA to Drosophila Kc cells. Compounds with no functional groups such as OH and C O group in the steroid skeleton moiety were inactive. By the introduction of functional groups such as the OH and the C O group in the steroidal structure, these compounds became active. Some compounds containing the A/B- trans ring fusion, which is different from that (A/B- cis) of ecdysteroids were also active. The oxidation of CH 2 at 6-position to C O, enhanced the activity 19 times, but the activity was erased by the reduction of oxo to OH group at 6-position. The activity was enhanced about 250 times by the conversion of A/B ring configuration from trans [(20 R,22 R)-2β,3β,20,22-tetrahydroxy-5α-cholestan-6-one: pIC 50 = 4.84] to cis [(20 R,22 R)-2β,3β,20,22-tetrahydroxy-5β-cholestan-6-one: pIC 50 = 7.23]. The latter cis-type compound which is the most potent among compounds synthesized in this study was equipotent to the natural molting hormone, 20-hydroxyecdysone, even though it is 1/50 of PNA.

Novel ecdysteroid analogs with oxygen-containing heterocycles in the steroid skeleton

The reaction of ecdysteroids (20-hydroxyecdysone and its acetonides) with lithium in liquid ammonia gave novel analogs with an oxetane 9α,14α-oxacycle in the steroid skeleton. In aqueous alcohol solution the 9,14-oxa analogs rearrange to the more stable 9α,13α-oxa analogs through a 1,2-migration of the 18-Me group from the C-13 to the C-14 atom.

Stereochemical assignments of 22-isoxazolinylsteroids using circular dichroism

Circular dichroism (CD) spectra of 22-hydroxy- and 22-acetoxy-22-isoxazolinylsteroids were studied. The configuration of the C-5′ center of the heterocycle was established from the sign of the n-π*-transition band of the azomethine chromophore. The band molecular ellipticity was shown to depend on the mutual placement of the isoxazoline ring and the steroid skeleton of the studied compounds.

Conformation of 17-chloro-16-formylandrosta-5,16-dien-3β-yl acetate and 17-chloroandrosta-5,16-dien-3β-yl acetate

In the title compounds, C(22)H(29)ClO(3), (I), and C(21)H(29)ClO(2), (II), respectively, the B rings adopt a half-chair conformation and the D rings adopt an envelope conformation. A twist of the steroid skeleton of both compounds is observed. There is a positional disorder of the acetoxy group of (II), with the terminal atoms disordered over two positions with near equal occupancy. Quantum-mechanical ab initio calculations using a molecular orbital Hartree-Fock method were performed for the isolated molecules, thus allowing the distinction within the structural features of these two androstane derivatives of which characteristics are intrinsic to the molecules and which are due to packing effects. The skeletal twisting was found to be innate to the molecules, while the acetoxy disorder is due to packing effects.

Solid state molecular assemblies of five bile acid derivatives

Abstract The crystal structures of five bile acid derivatives are reported: 1: 6α,7α-Dihydroxy-5β-cholan-24-oic acid; 2: 3α,6α-Dihydroxy-5β-cholan-24-oic acid (Hyodeoxycholic acid); 3: 3α,7α,12α-Trihydroxy-5β-cholan-24-hydrazide hemihydrate; 4: 3-Dimethyl ketal,7,12-dioxo-5β-cholan-24-oic acid and 5: 3α,7α-Di-O-acetyl-12-oxo-5β-cholan-24-oic acid methyl ester. In all the structures the four saturated cycles, forming the common alicyclic steroidal skeleton, have the same conformation, while the flexible side chain adopts different conformations. Whereas all the crystal structures of Cholic Acid inclusion compounds are characterized by the formation of a bilayer-type structure with channels within the lipophilic layers, the chemical variations of the substituents on the cholanic framework induce remarkable changes in the H-bond scheme and in the crystal packing arrangements. For instance, the structures 1, 2, having a different number and position of the hydroxyl groups on the rigid skeleton, display a variety of supramolecular architectures dominated by networks of cooperative …O—H…O… H-bonds which do not produce typical molecular layers and channels of Cholic Acid inclusion compounds. Cholic hydrazide hemihydrate, 3, where both the hydrazide group and water molecule are strongly involved in the H-bond system, forms an overall structural motif similar to that observed in CA inclusion compounds containing hydrophilic and lipophilic layers and small channels. Compound 4, containing only the carboxylic OH group as H-bond donor, makes simple antiparallel chains of molecules, while compound 5, lacking of H-bond donors, forms a crystal aggregation dominated by weak C—H…O contacts and van der Waals interactions leading to a crystal packing where neither molecular layers nor channels are recognizable.

Study of the Interaction between Progesterone and β-Cyclodextrin by Electrochemical Techniques and Steered Molecular Dynamics

The interaction of progesterone with beta-cyclodextrin (beta-CD) was studied by differential pulse polarography. The aim of the present work was to study the effect of beta-CD on the electrochemical behavior of progesterone in aqueous solution and also to analyze the molecular interactions involved in formation of the inclusion complex. The complex with stoichiometry of 1:1 was thermodynamically characterized. In addition, steered molecular dynamics (SMD) was used to investigate the energetic properties of formation of the inclusion complex along four different pathways (reaction coordinates), considering two possible orientations. From multiple trajectories along these pathways, the potentials of mean force for formation of the beta-CD progesterone inclusion complex were calculated. The energy analysis was in good agreement with the experimental results. In the beta-CD progesterone inclusion complex, a large portion of the steroid skeleton is included in the beta-CD cavity. The lowest energy was found when the D-ring of the guest molecule is located near the secondary hydroxyls of the beta-CD cavity. In the most probable orientation, one intermolecular hydrogen bond is formed between the O of the C-20 keto group of the progesterone and a secondary hydroxyl of the beta-CD.

Synthesis of 16 E-[3-methoxy-4-(2-aminoethoxy)benzylidene]androstene derivatives as potent cytotoxic agents

The synthesis and cytotoxic studies of a new series of 16 E-arylidene androstene derivatives are reported herein. The impact of incorporating bis-tertiary amino functionalities in the steroid skeleton on cytotoxicity has also been observed. The compounds have been evaluated at National cancer Institute, Bethesda, Maryland, USA for their antineoplastic activity against various tumor cell lines. The synthesized 16 E-arylidenosteroids exhibited significant cytotoxicity. Bis-tertiary amino steroid 29 possessing a diethylaminoalkoxy functionality was the most promising compound of the series with a total IP and SC score of 20 in in vivo hollow fiber assay and was selected for further detailed in vivo xenograft testing.

Syntheses and structural study of bile acid amidoalcohols

Preparation, structural and thermoanalytical characterization of fourteen N-hydroxyalkyl 5β-cholan-24-amides have been performed in this study. The utilized techniques include liquid state and CP-MAS 13C NMR spectroscopy, thermogravimetry, differential scanning calorimetry, and also powder and single crystal X-ray crystallography. The results were discussed and compared to each other and also to previous findings on similar compounds. One pure hydrate form was obtained. Six new single crystal structures were determined, including one hydrated chloroform solvate. Decomposition temperatures were found to correlate with the side chain length, and the number of the hydroxyl groups. The spatial direction of the groups in the steroid skeleton was also found to be relevant in predicting the thermal properties of bile acid amidoalcohols studied.

Cocrystal Screening of Stanolone and Mestanolone Using Slurry Crystallization

A slurry crystallization technique was used in cocrystal screening of two nonionizable pharmaceutical host compounds, stanolone and mestanolone, with 11 pharmaceutically acceptable guest acids. Crystallization was performed simply by adding crystallization solvents to solid mixtures of a host and a guest, which had been prepared using lyophilization of their dimethyl sulfoxide solution. Powder X-ray diffraction and thermogravimetric/differential thermal analysis were used to identify new solid forms. Two resultant new forms, stanolone l-tartaric acid 1:1 cocrystal and mestanolone salicylic acid 1:1 cocrystal, were characterized using single-crystal X-ray diffraction. The hosts, despite having the same steroidal skeleton and the same functional groups that form strong hydrogen bonds, each formed a cocrystal with a different guest molecule. All functional groups of the host and guest molecules that form strong hydrogen bonds were engaged in hydrogen bonding, but, despite the highly analogous molecular structures of the hosts, the two cocrystals exhibited dissimilar crystal structures. The present study shows the slurry technique to be viable and practical for cocrystal screening and demonstrates the importance not only of hydrogen bonding but also of geometric fit in cocrystal formation.

Molecular association via halogen bonding and other weak interactions in the crystal structures of 11-bromo-12-oxo-5β-cholan derivatives

Methyl 3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 2, methyl 11α-bromo-3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 3, methyl 11β-bromo-3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 4 and methyl 11,11-dibromo-3α,7α-diacetoxy-12-oxo-5β-cholan-24-oate 5 were synthesized. The crystal structures of these molecules were resolved to study the effect of bulky bromine atom in the steroid skeleton of cholic acid with different stereo-chemical orientations at C-11 on the two-dimensional arrangement of molecules and solid-state properties. All the molecules associate only via weak intermolecular interactions in their crystal structures, notable one being the Halogen Bonded assembly (C–Br…O) in 5.

Studies of the effects of new progestins from the pentarane series on viability, epidermal growth factor receptor expression, and apoptosis of cultured HeLa and MCF-7 cells

The effects of six new steroids of the pregnane series, with substituents at the 16α, 17α, and-or 3 and 19 positions of the steroid skeleton, on the viability of cultured breast cancer MCF-7 and cervical cancer HeLa cells were studied. The results showed that 3-keto-4-dehydrosteroids with a 16α,17α-spiropentane substituent and 3-keto-4-dehydro-16α,17α-cyclohexanopregnanes with 3-or 19-oxyimino groups decreased the viability of both types of cell culture. These compounds had negative influences on the expression of the epidermal growth factor receptor (EGFR) and induced apoptosis.

(20R,22R)-6α,7α-Epoxy-5α,27-dihydroxy-1-oxowitha-2,24-dienolide in Leaves of Withania somnifera: Isolation and its Crystal Structure

(20R,22R)-6α,7α-Epoxy-5α,27-dihydroxy-1-oxowitha-2,24-dienolide (27-hydroxy-withanolide B) was isolated from Withania somnifera. The structure of the withanolide was established by spectral analysis and X-ray diffraction studies. The compound crystallizes in the orthorhombic space group P212121 with unit cell parameters: a = 9.2163(3), b = 11.1828(4), c = 23.6146(9) A, Z = 4. The crystal structure was refined to R = 0.0495 for 3,284 observed reflections. All the rings of the steroid skeleton are trans connected. Rings A and B exist in a half-chair conformation, ring C a chair, and five membered ring D is intermediate between a half-chair and an envelope. The δ-lactone ring E adopts a distorted sofa conformation. The twist along the length of the steroid nucleus is −6.5°. The characteristic pattern observed in the packing diagram is the appearance of twisted chains of molecules packed together to form layers. Isolation and crystal structure analysis of (20R,22R)-6α,7α-epoxy-5α,27-dihydroxy-1-oxowitha-2,24-dienolide.

1H-Indazole and 2H-indazole derivatives of androsta-5,16-dien-3β-ol

The title compounds, 17-(1H-indazol-1-yl)androsta-5,16-dien-3beta-ol, (I), and 17-(2H-indazol-2-yl)androsta-5,16-dien-3beta-ol, (II), both C(26)H(32)N(2)O, have an indazole substituent at the C17 position. The six-membered B ring of each compound assumes a half-chair conformation. A twist of the steroid skeleton is observed and reproduced in quantum-mechanical ab initio calculations of the isolated molecule using a molecular orbital Hartree-Fock method. In the 1H-indazole derivative, (I), the molecules are joined in a head-to-head fashion via O-H...O hydrogen bonds, forming chains along the a axis. In the 2H-indazole derivative, (II), the molecules are joined in a head-to-tail fashion with one of the N atoms of the indazole ring system acting as the acceptor. The hydrogen-bond pattern consists of zigzag chains running along the b axis. Substituted steroids have proven to be effective in inhibiting androgen biosynthesis through coordination of the Fe atoms of some enzymes, and this study shows that indazole-substituted steroids adopt twisted conformations that restrict their intermolecular interactions.

Rational design, synthesis, and in vivo evaluation of the antileukemic activity of six new alkylating steroidal esters

The synthesis and the in vivo evaluation against leukemias P388 and L1210 of six new alkylating steroidal esters are described. The esteric derivatives incorporating the 17β-acetamido-B-lactamic steroidal skeleton exhibited increased antileukemic activity and lower toxicity, compared to the 17β-acetamido-7-keto analogs. Among the 17β-acetamido-B-lactamic steroidal esters, the most potent compound afforded four out of six cures in leukemia P388 and was measured to be almost non-toxic, producing significant low levels of toxicity.

Characterization of the complexation of tauro- and glyco-conjugated bile salts with γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin using affinity capillary electrophoresis

The complexation of seven bile salts, present in the small intestine of rat, dog and man, (taurocholate, tauro-β-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate) with γ-cyclodextrin and the chemically modified 2-hydroxypropyl-γ-cyclodextrin, was studied using affinity capillary electrophoresis (ACE). The cyclodextrins (CDs) were investigated due to their use in drug formulation as excipients for solubilisation of poorly soluble drugs and drug candidates. Using mobility shift ACE, the bile salt cyclodextrin interactions were characterized demonstrating 1:1 binding stoichiometry with stability constants ranging from 2 × 103 to 8 × 104 M−1. The binding constants showed a systematic dependence on the number and position of hydroxyl groups on the steroid skeleton and the stability constants were in general higher for complexation with the native cyclodextrin than with the modified cyclodextrin. Based upon the size of the complexation constants, it was suggested that the interaction between the CDs and the bile salts takes place at the C and D ring of the steroid skeleton. The complexation of bile salts with the γ-cyclodextrins may compete with drug-γ-cyclodextrin complex formation and, thus, potentially affect drug absorption and efficacy.