Benzyl Analogues Research Articles

Derivatives of D(−) glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-I: Synthesis, biological screening and in silico binding interaction analysis

Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML. In this article, some D(−)glutamine derivatives were synthesized and evaluated through cell-based antileukemic assays and tested against gelatinases. The lead compounds, i.e., benzyl analogs exerted the most promising antileukemic potential showing nontoxicity in normal cell line including efficacious gelatinase inhibition. Both these lead molecules yielded effective apoptosis and displayed marked reductions in MMP-2 expression in the K562 cell line. Not only that, but both of them also revealed effective antiangiogenic efficacy. Importantly, the most potent MMP-2 inhibitor, i.e., benzyl derivative of p-tosyl D(−)glutamine disclosed stable binding interaction at the MMP-2 active site correlating with the highly effective MMP-2 inhibitory activity. Therefore, such D(−)glutamine derivatives might be explored further as promising MMP-2 inhibitors with efficacious antileukemic profiles for the treatment of CML in the future.

Variable Ca-Caryl Hapticity and its Consequences in Arylcalcium Dimers.

The dimeric β-diketiminato calcium hydride, [(Dipp BDI)CaH]2 (Dipp BDI = HC{(Me)CN-2,6-i-Pr2 C6 H3 }2 ), reacts with ortho-, meta- or para-tolyl mercuric compounds to afford hydridoarylcalcium compounds, [(Dipp BDI)2 Ca2 (μ-H)(μ-o-,m-,p-tolyl)], in which dimer propagation occurs either via μ2 -η1 -η1 or μ2 -η1 -η6 bridging between the calcium centers. In each case, the orientation and hapticity of the aryl units is dependent upon the position of the methyl substituent. While wholly organometallic meta- and para-tolyl dimers, [(Dipp BDI)Ca(m-tolyl)]2 and [(Dipp BDI)Ca(p-tolyl)]2 , can be prepared and are stable, the ortho-tolyl isomer is prone to isomerization to a calcium benzyl analog. Computational analysis of this latter process with density functional theory (DFT) highlights an unusual mechanism invoking the generation of an intermediate dicalcium species in which the group 2 centers are bridged by a toluene dianion formed by the formal attachment of the original hydride anion to the initially generated ortho-tolyl substituent. Use of a more sterically encumbered aryl substituent, {3,5-t-Bu2 C6 H3 }, facilitates the selective formation of [(Dipp BDI)Ca(μ-H)(μ-3,5-t-Bu2 C6 H3 )Ca(Dipp BDI)], which can be converted into the unsymmetrically-substituted σ-aryl calcium complexes, [(Dipp BDI)Ca(μ-Ph)(μ-3,5-t-Bu2 C6 H3 )Ca(Dipp BDI)] and [(Dipp BDI)Ca(μ-p-tolyl)(μ-3,5-t-Bu2 C6 H3 )Ca(Dipp BDI)] by reaction with the appropriate mercuric diaryl. Conversion of [(Dipp BDI)Ca(H)(Ph)Ca(Dipp BDI)] to afford [{{(Dipp BDI)Ca}2 (μ2 -Cl)}2 (C6 H5 -C6 H5 )], comprising a biphenyl dianion, is also reported. Although this latter transformation is serendipitous, AIM analysis highlights that, in a related manner to the ortho-tolyl to benzyl isomerization, the requisite C-C coupling may be facilitated in an "across dimer" fashion by the experimentally-observed polyhapto engagement of the aryl substituents with each calcium.

Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against Mycobacterium abscessus and Malaria Parasites.

SQ109 is a tuberculosis drug candidate that has high potency against Mycobacterium tuberculosis and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca2+ homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against M. smegmatis, M. tuberculosis, M. abscessus, Bacillus subtilis, and Escherichia coli, as well as against the protozoan parasites Trypanosoma brucei, T. cruzi, Leishmania donovani, L. mexicana, and Plasmodium falciparum. Activity against the mycobacteria was generally less than with SQ109 and was reduced by increasing the size of the alkyl adduct, but two analogs were ∼4-8-fold more active than SQ109 against M. abscessus, including a highly drug-resistant strain harboring an A309P mutation in MmpL3. There was also better activity than found with SQ109 with other bacteria and protozoa. Of particular interest, we found that the adamantyl C-2 ethyl, butyl, phenyl, and benzyl analogs had 4-10× increased activity against P. falciparum asexual blood stages, together with low toxicity to a human HepG2 cell line, making them of interest as new antimalarial drug leads. We also used surface plasmon resonance to investigate the binding of inhibitors to MmpL3 and differential scanning calorimetry to investigate binding to lipid membranes. There was no correlation between MmpL3 binding and M. tuberculosis or M. smegmatis cell activity, suggesting that MmpL3 is not a major target in mycobacteria. However, some of the more active species decreased lipid phase transition temperatures, indicating increased accumulation in membranes, which is expected to lead to enhanced uncoupler activity.

Discovery of Putative Dual Inhibitor of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs.

Combretastatin A-4 (CA-4, 1) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (2). A series of branched and unbranched homologs of the lead-compound 2, and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and 2 on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC50 values ranging from 0.030 μM to 7.53 μM (MTT at 72 h) and 0.096 μM to 8.768 μM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog 10 (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound 2 (LASSBio-1586) and the methylated homolog 3 (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog 10 was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 (10) as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives.

Probing O-substituted nifuroxazide analogues against Leishmania: Synthesis, in vitro efficacy, and hit/lead identification

Leishmaniasis is a neglected tropical disease affecting millions of people worldwide, with 650 000 to 1.1 million new infections reported annually by the World Health Organization. Current antileishmanial treatments are unsatisfactory due to the development of parasitic resistance and the toxicity associated with the drugs used, and this highlights the need for the development of new antileishmanial drugs. In this study, a series of nifuroxazide analogues were synthesized in a single step reaction and investigated for their antileishmanial potential. The sulfonate 1l, bearing pyridine ring, was deemed an antileishmanial hit, targeting the amastigotes of Leishmania (L.) donovani and L. major, the pathogens of visceral and cutaneous leishmaniasis, respectively, with micromolar potencies. The benzyl analogues 2c and 2d were also confirmed as submicromolar active leads against amastigotes of L. major. These analogues stand as promising candidates for further investigation involving the evaluation of their in vivo activities and molecular targets.

Synthesis and in vitro antileishmanial efficacy of benzyl analogues of nifuroxazide.

Leishmaniasis is a vector-borne parasitic disease that mostly affects populations in tropical and subtropical countries. There is currently no vaccine to protect against and only a handful of drugs are available to treat this disease. Leishmaniasis is curable, but its eradication and elimination are hindered by the emergence of multidrug resistant strains of the causative pathogens, accentuating the need for new and effective antileishmanial drugs. In search for such agents, nifuroxazide, a clinical antibiotic, was evaluated through investigation of its benzyl analogues for in vitro antileishmanial efficacy against promastigotes of various Leishmania (L.) strains. The monobenzylated analogues 1 and 2 were the most potent of all, possessing nanomolar activities up to 10-fold higher than the parent drug nifuroxazide against all three tested Leishmania strains. Both analogues stand as antipromastigote hits for further lead investigation into their potential to act as new antileishmanial agents.

Exploring Stereochemical and Conformational Requirements at Cannabinoid Receptors for Synthetic Cannabinoids Related to SDB-006, 5F-SDB-006, CUMYL-PICA, and 5F-CUMYL-PICA.

Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly expanding class of new psychoactive substances (NPSs). Despite the prevalence and potency of recent chiral indole-3-carboxamide SCRAs, few pharmacological data are available regarding the enantiomeric bias of these NPSs toward human CB1 and CB2 receptors. A series of homochiral indole-3-carboxamides derived from (S)- and (R)-α-methylbenzylamine and featuring variation of the 1-alkyl substituent were prepared, pharmacologically evaluated, and compared to related achiral congeners derived from cumyl- and benzylamine. Competitive binding assays demonstrated that all analogues derived from either enantiomer of α-methylbenzylamine (14-17) showed affinities for CB1 (Ki = 47.9-813 nM) and CB2 (Ki = 47.9-347 nM) that were intermediate to that of the corresponding benzylic (10-13, CB1 Ki = 550 nM to >10 μM; CB2 Ki = 61.7 nM to >10 μM) and cumyl derivatives (6-9, CB1 Ki = 12.6-21.4 nM; CB2 Ki = 2.95-24.5 nM). In a fluorometric membrane potential assay, all α-methylbenzyl analogues (excluding 17) were potent, efficacious agonists of CB1 (EC50 = 32-464 nM; Emax = 89-104%) and low efficacy agonists of CB2 (EC50 = 54-500 nM; Emax = 52-77%), with comparable or greater potency than the benzyl analogues and much lower potency than the cumyl derivatives, consistent with binding trends. The relatively greater affinity and potency of (S)-14-17 compared to (R)-14-17 analogues at CB1 highlighted an enantiomeric bias for this series of SCRAs. Molecular dynamics simulations provided a conformational basis for the observed differences in agonist potency at CB1 pending benzylic substitution.

O-Substituted N(3)-benzyl analogs of vitamin B1 as inhibitors of acetylcholinesterase or butyrylcholinesterase

O-Substituted N(3)-benzyl analogs of vitamin B1 as inhibitors of acetylcholinesterase or butyrylcholinesterase

Statistical and Continuous Manufacturing approach by Design of Experiment (DoE) for a Robust Synthetic Process of a Sorafenib Analogue

Graphical-Statistical Design of experiment (DoE) is a new approach to reaction chemist over the age old technique of Quality by Testing. Modern era of ‘Continuous Manufacturing’, as a newly proposed ICH guideline Q13 introduces new concept of robust reaction designing bypassing the myriad of reactions involved in traditional approach as One Variable at a Time (OVAT). Present study demonstrates the amalgamation of complete reaction process with stat-software analysis of a novel multikinase inhibitor Sorafenib's analogue using Design Expert ® Software. The Benzyl Analogue of Sorafenib is designed using Sorafenib as lead molecule. Each step of synthesis process involves the selection of solvents and bases scientifically and through Principal Component Analysis (PCA). Further, the key factors were established with low and high range as a preliminary study. The key factors like substrate molar concentration, temperature and time of reaction, were considered for DoE study wherein influence of factors and their interactions were studied over yield and quality of the product in a statistically relevant manner. For each step of reaction ‘Response Surface Methodology’ (RSM) was adopted with either Central Composite or Box-Behnken randomized matrix model design type. Synopsis for each DoE study was elaborated through analysis of variance (ANOVA) of defined model type. Data from non-linear studies have been shown through Contour plots, 3-D di-interaction plots and Coded Factor Interaction Reaction Equations. A cost effective and an unambiguous robust design space for each step of reaction was achieved with practical confirmation. The cost reduction of about 81.8% with exceptionally reduced number of experiments is obtained.

Synthesis and Inhibition Evaluation of New Benzyltetrahydroprotoberberine Alkaloids Designed as Acetylcholinesterase Inhibitors.

Secondary metabolites from natural products are a potential source of acetylcholinesterase inhibitors (AChEIs), which is a key enzyme in the treatment of many neurodegenerative diseases. Inspired by the reported activities of isoquinoline-derivative alkaloids herein we report the design, one step synthesis and evaluation by capillary enzyme reactor (ICER) of benzyl analogs (1a–1e) of the tetrahydroprotoberberine alkaloid stepholidine, which is abundant in Onychopetalum amazonicum. Docking analysis based on the crystal structure of Torpedo californica AChE (TcAChE) indicated that π-π interactions were dominant in all planned derivatives and that the residues from esteratic, anionic and peripheral subsites of the enzyme played key interaction roles. Due to the similarities observed when compared with galantamine in the AChE complex, the results suggest that ligand-target interactions would increase, especially for the N-benzyl derivatives. From a series of synthesized compounds, the alkaloids (7R,13aS)-7-benzylstepholidine (1a), (7S,13aS)-7-benzylstepholidine (1b), and (S)-10-O-benzylstepholidine (1d) are reported here for the first time. The on flow bioaffinity chromatography inhibition assay, based on the quantification of choline, revealed the N-benzylated compound 1a and its epimer 1b to be the most active, with IC50 of 40.6 ± 1 and 51.9 ± 1 μM, respectively, and a non-competitive mechanism. The proposed approach, which is based on molecular docking and bioaffinity chromatography, demonstrated the usefulness of stepholidine as a template for the design of rational AChEIs and showed how the target-alkaloid derivatives interact with AChE.

The first mesomorphic benzimidazolium-based silver(I)-N-heterocyclic dicarbene complexes: Synthesis, characterization and phase properties

The first mesomorphic benzimidazolium based mononuclear silver (I) N-heterocyclic dicarbene complexes, Ag(I)-NHC were prepared via in situ deprotonation of 1-octadecyl-3-alkyl/arylbenzimidazolium salts with silver oxide (Ag2O). Both series of Ag (I)-NHC complexes contained a C18 alkyl chain on one N atom and differed in term of the substituent (alkyl and substituted benzyl moiety) on the other N atom in the benzimidazolium ring. All the synthesized compounds were characterized by elemental analysis, Fourier-transform infrared, 1H and 13C NMR spectroscopy. Cation geometry, anion and alkyl chain length were found to be essential parameters for mesophase formation in the salts and Ag(I)-NHC complexes in this study. All dialkylated salts except the one with the shortest chain, n = 10 were smectogenic. On the other hand, a large width-to-length ratio of the cationic core in the benzyl analogues had a negative effect on the formation and stability of mesophase. No mesophases were observed for these compounds. Wider mesophase range was seen with decrease in anion size and elongation of alkyl chains. A metastable SmA phase was observed in two Ag(I)-NHC complexes. The minimum chain length required for compounds with different anions to exhibit liquid crystal (LC) properties was addressed. Mesophase was observed for bromide salts with C12 onwards while C14 is the minimum chain length required for the hexaflurophosphate containing Ag(I)-NHC complexes to display LC properties. All Ag(I)-NHC complexes except the one bearing a cyano group could be considered ionic liquids with melting/clearing temperatures below 100 °C.

Click Chemistry Inspired Design, Synthesis and Molecular Docking Studies of Coumarin, Quinolinone Linked 1,2,3‐Triazoles as Promising Anti‐Microbial Agents

AbstractA series of new coumarin, quinolinone and benzyl linked 1,2,3‐triazole derivatives have been synthesized and screened for their anti‐bacterial and anti‐fungal activities. Results of bioassay indicate that, compounds containing chloro and methoxy substituents in coumarin (6 j), chloro substitution in quinolinone (7 g) and 3‐chloro benzyl analogue (8 f) exhibit excellent anti‐bacterial activities. The results of anti‐fungal activities also reveal that methoxy and chloro substituted coumarins (6 e and 6 j) were highly active against yeast strains. In addition, chloro and methyl substituted coumarins (6 h and 6 i) were also exhibited excellent activity. Further, methyl substituted quinolinone with chloro substituted coumarin (7 f) was found to highly active against yeast fungi and filamentous strain A.niger. It is evident from the results obtained and SAR studies that electron withdrawing or donating character of the substituents do not seem to be a major factor in increasing or decreasing anti‐microbial activity.

Design, Synthesis and Anti‐Cancer Activities of Benzyl Analogues of Garlic‐Derived Diallyl Disulfide (DADS) and the Corresponding Diselenides

AbstractThe anti‐cancer activity of garlic mainly arises due to the presence of various organosulfur compounds including diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS). Herewith, we report a number of 4‐substituted benzyl analogs of DADS and their selenium counterparts for a detailed structure‐activity relationship towards their anti‐proliferative activities in human breast cancer cell lines. Disulfide having 4‐cyano group exhibited highest activity among all disulfides. In contrast, all diselenides exhibited very good anti‐proliferative activities than DADS. Furthermore, unlike disulfides, diselenides were more selective towards cancer cells over normal cells. Some active compounds were further tested for their activities in some organ specific cell lines such as HepG2, PC‐3 and HCT‐116 to understand their efficacy. Elevated level of intracellular reactive oxygen species (ROS) by most of the benzyl diselenides reveals a possible mode of their action. Therefore, this study indicates that the anti‐proliferative activity of DADS can be significantly enhanced upon suitable structural modifications.

Synthesis, characterisation, and polymerisation studies of hexamethylindenyl zirconocenes and hafnocenes

A family of group 4 metallocene complexes based on the hexamethylindenyl ligand (C9Me6H; Ind#) have been prepared and fully characterised. The complexes rac-Ind2#ZrCl2 (rac-1), meso-Ind2#ZrCl2 (meso-1), rac-Ind2#HfCl2 (rac-2), meso-Ind2#HfCl2 (meso-2) were prepared by the reaction of Ind#Li with the corresponding MCl4 (where M = Zr, Hf); and rac-Ind2#Zr(CH2Ph)2 (rac-3) was derived from rac-1 using two equivalents of potassium benzyl (KCH2Ph). All five species were characterised by NMR spectroscopy, single crystal X-ray diffraction and studied using density functional theory. The zirconocenes were tested for their activity as solution-phase ethylene polymerisation catalysts and rac-1 was found to outperform the meso-1 at most temperatures. The benzyl analogue, rac-3, peaked at more than double the activity reported for the dihalide species.

Discovery of small molecular (d)-leucinamides as potent, Notch-sparing γ-secretase modulators

Structural optimization of the prior lead 3 led to the small molecular (d)-leucinamides with potent modulating activity and Notch-sparing selectivity on the proteolytic processing of amyloid-β precursor proteins. The N-(R)-epoxypropyl analog 10c exhibited potent γ-secretase modulation compared to DAPT and showed substantial substrate selection for APP cleavage over Notch cleavage, while N-(2-fluoro)benzyl analog 10e showed the most potent γ-secretase inhibition with dull selectivity. The exceptional suppression of ERK-mediated activation suggested that these potent γ-secretase modulators may adapt an alternative pathway to prominently induce the differential inhibition of C99 cleavage by γ-secretase.

Synthesis of porphyrin glycoconjugates bearing thiourea, thiocarbamate and carbamate connecting groups: Influence of the linker on chemical and photophysical properties

In the present work, we have synthesized new porphyrin conjugates bearing thiourea, thiocarbamate and carbamate linkers using conventional and ultrasound-assisted methods. These molecules were synthesized by addition reactions using isothiocyanate derivates and amino- or hydroxyl-functionalized meso-tetra(aryl)porphyrins to give porphyrin analogs linked to glycosyl or benzyl moieties. Glycoporphyrin derivates could be obtained with better yields than their respective benzyl analogs. Thiourea and carbamate glycoporphyrins were also successfully synthesized through an ultrasound protocol with a remarkable decreasing of the reaction time. By NMR experiments we were able to evaluated the linker conformations which showed a preferred Z,Z conformation for the thiourea and carbamate derivatives. In addition, porphyrins were evaluated in terms of their UV–Vis spectra, singlet oxygen production, photostability and aggregation properties. Correlations between the linker type and the corresponding photophysical properties were observed. Carbamate porphyrins seem to be the most promising photosensitizers among the studied molecules due to their high singlet oxygen production, photostability and absence of self-assembling behavior in aqueous media.

Solvent-Free Synthesis of a Secondary N-Benzhydrylamine as a Chiral Reagent for Asymmetric Deprotonation of Bicyclic N-Benzylamino Ketones

Several chiral secondary N -benzhydrylamines were synthesized in good yields (68–92%) without racemization by the direct alkylation of amines with benzhydryl chloride under solvent-free conditions. Using the solvent-free conditions ( R )- N -benzhydryl-1-phenylethylamine was obtained with the highest yield (92%), purified on ion-exchange resin, and converted to its hydrochloride salt. The resulting chiral amine hydrochloride was transformed into lithium amide/lithium chloride mixture used in asymmetric deprotonations of N -benzyl analogues of tropinone and granatanone followed by aldol reactions giving products in high ­diastereomeric purities (up to 96%) and enantiomeric excesses of 77 to 96%.

N6-Isopentenyladenosine and its Analogue N6-Benzyladenosine Induce Cell Cycle Arrest and Apoptosis in Bladder Carcinoma T24 Cells

Cytokinins are phytohormones critically involved in the regulation of plant growth and development. They also affect the proliferation and differentiation of animal cells, thus representing new tools to treat diseases that involve dysfunctional cell growth and/or differentiation. Recently, by performing structure-function studies on human cells, we found that only N6-isopentenyladenosine and its benzyl analogue N6-benzyladenosine suppress the clonogenic activity and the growth of different neoplastic cells. We here broaden our studies on bladder carcinoma T24 cells, because, due to the high recurrence rate of bladder cancer, new active molecules are sought to contrast the growth of this tumor. Early events induced by N6-isopentenyladenosine and N6-benzyladenosine are the alteration of T24 cell morphology and the disorganization of the actin cytoskeleton. After 24 h N6-isopentenyladenosine and N6-benzyladenosine inhibit growth by arresting the cells in the G0/G1 phase of the cell cycle. We also show that the two compounds induce apoptosis, an event linked to the activation of caspase 3. Since DNA damage is a prime factor resulting in cell cycle arrest and apoptosis, it is noteworthy that we do not detect any genotoxic effect upon treatment of T24 cells with N6-isopentenyladenosine and N6- benzyladenosine. Because the disruption of actin filaments leads to G1 arrest and is also implicated in apoptosis, we hypothesize that cytoskeletal rearrangement might be responsible for triggering the antiproliferative and proapotpotic effects of N6-isopentenyladenosine and N6- benzyladenosine in T24 cells.

Farnesyl Diphosphate Analogues with Aryl Moieties Are Efficient Alternate Substrates for Protein Farnesyltransferase

Farnesylation is an important post-translational modification essential for the proper localization and function of many proteins. Transfer of the farnesyl group from farnesyl diphosphate (FPP) to proteins is catalyzed by protein farnesyltransferase (FTase). We employed a library of FPP analogues with a range of aryl groups substituting for individual isoprene moieties to examine some of the structural and electronic properties of the transfer of an analogue to the peptide catalyzed by FTase. Analysis of steady-state kinetics for modification of peptide substrates revealed that the multiple-turnover activity depends on the analogue structure. Analogues in which the first isoprene is replaced with a benzyl group and an analogue in which each isoprene is replaced with an aryl group are good substrates. In sharp contrast with the steady-state reaction, the single-turnover rate constant for dansyl-GCVLS alkylation was found to be the same for all analogues, despite the increased chemical reactivity of the benzyl analogues and the increased steric bulk of other analogues. However, the single-turnover rate constant for alkylation does depend on the Ca(1)a(2)X peptide sequence. These results suggest that the isoprenoid transition-state conformation is preferred over the inactive E·FPP·Ca(1)a(2)X ternary complex conformation. Furthermore, these data suggest that the farnesyl binding site in the exit groove may be significantly more selective for the farnesyl diphosphate substrate than the active site binding pocket and therefore might be a useful site for the design of novel inhibitors.

Design and Diastereoselective Synthesis of C‐2,C‐20‐Diaryl Steroidal Derivatives

AbstractA novel and efficient synthetic strategy to access unique C‐2 substituted steroid analogues 3 and 4 is described. The unusual C‐2 aryl ether analogues 3 were shown to act as virtual antagonists of LRH‐1 and were prepared as single diastereoisomers, employing a fifteen‐step sequence from pregnenolone (9). The key steps include the stereoconvergent nucleophilic displacement of an epimeric mixture of 3‐keto 2‐bromo steroids, chemoselective carbonylation of an enol triflate and conversion of a thiopyridyl ester into an aryl ketone. The related C‐2 benzyl analogues 4 were prepared in a similar manner.