Recent syntheses of steroidal derivatives containing heterocycles

It was found that the introduction of a heterocycle or replacement by a heteroatom of one or more carbon atoms in the steroidal moiety could have a significant biological impact


Introduction
2][3] Even after decades of research, the total synthesis of steroid nuclei by improved strategies continues to receive considerable attention.Numerous methods have been exploited for the total synthesis of steroids which are widely distributed in nature and which possess practical medical importance.Research into steroid total synthesis continues to this day. 4,5eterocycles are widespread in drug molecules because they possess hydrogen bond donors and acceptors in a rigid framework, and they can therefore effectively interact with target enzymes and receptors via hydrogen bond interactions.They can enhance binding affinity and improve in vitro potency.Heterocycles can modulate the lipophilicity of the drug molecules or improve aqueous solubility of the compounds, thus providing desired pharmacokinetic and pharmacodynamic properties. 6Heterocyclic compounds are therefore widely applied in pharmaceutical and agrochemical research.
4][15][16][17] Steroids containing heteroatoms have been widely researched and reported. 18][21][22] This article provides an overview of the various synthetic strategies which have been employed to synthesize steroidal derivatives containing heterocycles along with interesting biological activities, from the years 2013-2019.

Synthesis of Steroidal Heterocycles 2.1 A-Ring fused steroidal heterocycles
In 2013, Dutta et al. 23 developed a solventless one-pot reaction of a steroidal 1,5-diketo compound with urea employing BF 3 .OEt 2 as the catalyst, for the synthesis of steroidal A-and D-ring fused 4,6-diarylpyridines under microwave irradiation.The intermediate steroidal 1,5-diketo compounds were synthesized by Michael addition reaction of steroidal ketones with enones in situ-generated from aromatic ketones and aldehydes (Scheme 1).The reaction of steroidal ketone 1 with a variety of aromatic aldehydes and aryl ketones including both electron-deficient and electron-rich groups was investigated.The 1,5-dicarbonyl compounds were obtained in excellent yields in all cases and no undesired side reactions were observed.In the next step, the cyclization reaction of the diketones 4 afforded steroidal pyridines 5 in excellent yields.In 2013, the same authors developed a solvent-free multi-component reaction condition for the synthesis of steroidal A-ring fused 5,6-disubstituted pyridines using Pd(OAc) 2 as the catalyst under microwave irradiation. 24A wide variety of alkyl-, aryl-and ester-substituted alkynes undergo this highly regioselective -bromovinyl aldehyde 6, -cholestan-3-one by reaction with Vilsmeier reagent in refluxing chloroform. 25bromovinyl aldehyde 6, benzylamine, alkyne 7, palladium acetate (5 mol%), triphenylphosphine, Na 2 CO 3 and neutral alumina was then irradiated in a closed vessel in a Synthos 3000 microwave reactor at 600 Watts for 10 min, affording A-ring fused 5,6-disubstituted pyridines 8 (Scheme 2) in good yields.Instead of benzylamine, other amines such as tert-butylamine were tried, but a decreased yield of compound 8 was obtained, which could be due to the lower boiling point of tertbutylamine.They also observed that reducing the quantity of Pd(OAc) 2 decreased the yield of 8 while increase of catalyst loading to 10 mol% did not affect the yield of 8 at all.Scheme 2. Synthesis of steroidal A-ring fused substituted pyridines.

B-Ring fused steroidal heterocycles
In 2017, Ali et al. 26 prepared a series of novel steroidal pyrimidine derivatives via a multicomponent domino process.For the synthesis of steroidal pyrimidines 12-14 -acetoxycholestan-6-one 9c -chlorocholestan-6one 10c -cholestan-6-one 11c were synthesized by literature methods, 27 and these were treated with urea and benzaldehyde in DMF/CH 3 CN in the presence of TMSCl (used as promoter) under air; the reaction mixture was initially maintained at room temperature, and then warmed to 90 °C under reflux conditions (Scheme 3).The compounds 12-14 showed different cytotoxicity against three cancer cell lines.Scheme 3. Synthetic pathway for the formation of B-ring-fused steroidal pyrimidines 12-14.

D-Ring fused steroidal heterocycles
As described in Section 2.1, Dutta et al. 24 developed a solvent free multi-component reaction process for the synthesis of steroidal A-ring fused 5,6-disubstituted pyridines.The same method was used for the synthesis of steroidal D-ring fused 5,6-disubstituted pyridines using Pd(OAc) 2 as the catalyst under microwave irradiation.
-bromovinyl aldehyde 15 was synthesized starting commercially available 3-acetoxyandrost-5-en-17-one by treatment with Vilsmeier reagent prepared from PBr 3 and DMF. 25 Similarly, microwave reactions of -bromovinyl aldehyde 15 with alkynes 7 afforded steroidal D-ring fused substituted pyridines 16 in high yield -bromovinyl aldehydes with substituted alkynes and benzylamine under the reaction conditions described above (see 2.1), only one regioisomer of the pyridine derivative was obtained.

Scheme 4. Synthesis of steroidal D-ring fused pyridines.
In the same year, Zhang et al. 28 developed a convenient synthesis of pure, air-stable steroidal D-ring fused pyridine compound 22, D-ring fused thiazole imines and reductive products 25a-e and 26a-e, and D-ring fused imidazo[2,1-b]thiazole product 27 from readily available starting material dehydroepiandrosterone (DHEA) 17 (Schemes 5-7).This provided a simple strategy to synthesize steroids combined at the D-ring with heterocycles, extending the categories of heterosteroids.The strategy can be applied to diverse 3-or 17-ketosteroids and the steroidal thiazole-imines may allow further modification on the steroidal skeleton.They synthesized a series of D-ring fused pyridines with 17 as the starting material by the means of a Friedländer reaction (Scheme 5).Compound 18 was prepared by a standard procedure, by treating 17 with acetic anhydride catalyzed by DMAP with a good yield.Compound 19 was synthesized by a Vilsmeier reaction 29 and compound 21 was also synthesized according to Staudinger's procedure by treating 20 with Ph 3 P in THF/H 2 O (9:1).The yield was not very good (under 50%).Compound 20 was synthesized by treating 19 with NaN 3 in DMF/H 2 O.In the synthesis process of 22, when the base was replaced by NaOH, only the deacetylation product was detected.When they tried to expand the series of 22 with various reactive methylene species, such as acetophenone, 4-methoxyacetophenone, ethyl cyanoacetate, ethyl chloroacetate, ethyl acetoacetate, or ethyl 4-chloroacetoacetate, no product was obtained with any of them.In 2011, Elmegeed 30 -acetoxy--androstan-17-one, which is similar to 18, as the starting material without losing the acetyl group under the same condition, followed by the next cyclization step in THF, and catalyzed by piperidine with a yield of 50%.Their procedure here was carrying out this step in EtOH by using triethylamine as a catalyst with a yield over 50%.With 24 in hand, they selected a benzaldehyde without an electron-withdrawing or electron-donating group as the first aldehyde, to carry out the next step to generate thiazolyl imines.Compounds 25a-e were purified by column chromatography and then treated with NaBH 4 in MeOH to generate 26a-e (Scheme 6).
Scheme 7 outlines the synthetic procedures of compound 27; 28 the measures to prepare 24 were identical to the ways of synthesizing D-ring fused thiazole imine and reductive products.27 was synthesized by treating compound 24 with ethyl chloroacetate in DMF; it was characterized by 1D-and 2D-NMR spectroscopy.
The authors applied their protocol to the preparation of several new substituted aryl derivatives 29 and 30 (Scheme 9).These compounds were evaluated for their antiproliferation activity in vitro against EC109 (human esophageal carcinoma), EC9706 (human esophageal carcinoma) and MGC803 (human gastric carcinoma) cell lines.Bioactivity test results showed that compound 30 series have a relatively good activity against the three cell lines, especially the EC109 line.Both the synthesized compounds 28b-d, 29a-j and 30a-j are reported to have a good activity against the MGC803 cell line.Scheme 9. Synthesis of steroidal thiazole imines and corresponding reduction products.Anhydrous 1,4 dioxane and anhydrous methanol were found to be the most suitable solvents for the synthesis of pyrazolo-steroids.The compounds were purified by automated flash chromatography as they decompose while crystallizing in most solvents.Treatment with the pyrazoline substituted steroids considerably improved the LPS-induced learning, memory and movement deficits in animal models.Suppression of biochemical parameters of oxidative and nitrosative stress, acetylcholine esterase activity, and TNF-α levels was also observed.16,17-Pyrazolo-steroids 32-34c substituted with a 4-pyridyl moiety at the 5position of the heterocyclic ring were found to be the most potent agents and produced neuroprotective effects better than standard drugs celecoxib and dexamethasone.Of these pyrazoline-substituted steroids, the N-acetyl analogue 33c displayed better neuroprotective effects than N-phenyl 34c, which in turn showed a higher potency than the N-unsubstituted analogue 32.

Synthesis of Steroidal Derivatives Containing Heterocyclic Side-chains
In 2014, a series of D-ring substituted pyrazolinyl pregnenolone (54) and pyrazolyl pregnenolone (56)  derivatives were synthesized and screened for their 5 -reductase inhibitory activity by Banday et al. 38 To a solution of pregnenolone 51 in ethanol was added a solution of KOH.Then aldehyde 52 was added to the reaction mixture to get the corresponding benzylidene derivative 53.The condensation product 53 was refluxed in acetic acid in the presence of hydrazine to yield the desired N-acetylpyrazolines (Scheme 14).Scheme 14. Synthesis of D-ring substituted pyrazolinyl-pregnenolones.

Scheme 15. Synthesis of D-ring substituted pyrazolyl-pregnenolones.
Cui et al. 41 synthesized a series of dehydroepiandrosterone-17-hydrazone and estrone-17-hydrazone derivatives possessing various aromatic heterocyclic structures at C-17 of their steroidal nucleus.Scheme 16 outlines the synthetic procedures of compounds 58-66.First, the dehydroepiandrosterone was converted into the corresponding dehydroepiandrosterone-17-hydrazone 57 via reaction with hydrazine hydrate in anhydrous ethanol.After crystallization, reaction of the pure steroidal hydrazone with aromatic aldehydes gave steroidal hydrazone derivatives 58-66.
To determine the effect of the A-ring structure in the steroidal nucleus on the cytotoxicity, they also synthesized compounds 69-73 (Scheme 17).Compounds 69-73 were prepared similarly as the procedures for the synthesis of compounds 58-66.In 2015, a series of new steroidal heterocyclic compounds with significant anti-tumor and antioxidant activities was successfully synthesized by Abad et al. 42 All the compounds (Scheme 18) were prepared by refluxing compounds 74e-76e with o-aminothiophenol/ o-aminophenol/ o-phenylenediamine in DMSO.Their anti-tumor activity in vitro was evaluated against Hep3B (human hepatocellular carcinoma), MCF7 (human breast adenocarcinoma), HeLa (human cervical carcinoma) cancer cell lines and on normal PBMCs (peripheral blood mononuclear cells).The results demonstrated that most of the synthesized derivatives showed significant anti-tumor activity; however compounds 78, 79, 81, 82 and 85 exhibited excellent activity with IC50 83-85 were found to be good antioxidants.Nonenzymatic degradation of DNA has also been investigated.The application of compounds 79 as DNA gene transporter was evaluated by DNA condensation and ascertained by employing TEM and AFM, which illustrated that the compound 79 induces the condensation of CT-DNA.Lipinski's 'Rule of Five' analysis predicted good oral absorption of the synthesized compounds.Moreover, the acetylcholinesterase (AChE) inhibitor activities of the steroidal derivatives were also evaluated using Ellman's method.From the results obtained they deduced that compound 77, 80 and 83 exhibited significant inhibition on AChE among all the synthesized compounds.
Elmegeed et al. 43   In 2016, Vitellozzi et al. 44 prepared a range of novel steroid analogues bearing a C-17 side-chain containing a 20R-hydroxyl group and a variety of heterocyclic substituents by organometallic additions to 3-methoxypregnenolone.This methodology was extended, by use of the Achmatowicz rearrangement and ring-closing metathesis approaches, to prepare pyrandione and δ-lactone steroidal analogues reminiscent of the withanolide natural products.The addition of simple lithiated heterocycles to the C-20 ketone of steroid 95 were studied first.Thus, 3β-methoxypregnenolone 95 was added to a solution of 2-lithiothiazole, and a chromatographically inseparable mixture of adducts 96R and 96S (84%, 9:1) was obtained; however, recrystallisation of the mixture from methanol gave the required R-diastereomeric adduct 96R in 48% isolated yield.The addition of other lithiated five-membered heterocycles onto ketone 95 was also investigated.Using thiophene, furan and TBS-protected furfurol, lithiation was aided by the addition of TMEDA, although the isolated yields of adducts 97-99 were depressed by the ease with which the products, particularly 97, underwent dehydration.Nevertheless, the reactions proceeded with complete diastereoselectivity, giving 97R-99R with no sign of the corresponding S-isomers.They next examined the addition of lithiated benzothiophene, benzofuran and N-methylindole (Scheme 21); organometallic addition of such reagents to 20-ketosteroids was not previously reported.All additions proceeded diastereoselectively, although the yields of the adducts were modest (101R, 47%; 102R, 56%) or low (103R, 12%).In each of these examples, nbutyllithium was used for the metallation reactions.

Scheme 21. Organometallic additions to ketone 95.
The authors then explored routes to systems containing a pyrandione or lactone ring in the side-chain to mimic the withanolide (and bufadienolide) natural products.The pyrandione analogue 105 was readily obtained from furan 98R using the Achmatowicz rearrangement 45 in the key step (Scheme 22).This sequence, originally developed by Kametani et al. 46 on a closely related system, proceeded efficiently using Nbromosuccinimide for the furan ring elaboration, and tetrapropylammonium perruthenate (TPAP)/ Nmethylmorpholine N-oxide for the oxidation of the lactol 104 to lactone 105.

Scheme 25. Synthesis of 16-(heteroarylmethylene)androstane-17-ones 120-122.
Motyan et al. 49 developed a microwave-assisted one-pot method for the facile and efficient synthesis of novel steroidal 17-exo-pyrazol-5'-ones from a β-ketoester precursor with arylhydrazine hydrochlorides.The steroidal β-ketoester precursor 126, suitable for the attempted heterocyclization reaction with hydrazines, was synthesized from commercially available pregnenolone acetate 123 via a multistep sequence (Scheme 26).First compound 123 was converted to the 17β-carboxylic acid 124b by the bromoform reaction and subsequent acetylation according to well-known literature procedures. 50After the activation of 124b with 1,1′-carbonyldiimidazole (CDI) as coupling reagent in THF, the magnesium enolate of malonic acid half ester prepared in situ was added.The acylation of magnesium methyl malonate by the preformed imidazole 125 led to the desired bifunctional starting material 126 in good yield (79%).Analogously, β-ketoester 126' could be obtained from pregnadienolone acetate 123' through a Δ 5,16 -carboxylic acid intermediate under identical conditions albeit in disappointing low yield (33%) which is presumably caused by the decreased propensity of the conjugated carbonyl compound to react with the magnesium enolate.

Scheme 26.
-ketoesters 126 and 126' from pregnenolone acetate 123 and pregnadienolone acetate 123' The ring-closure reactions of 126 with unsubstituted and monosubstituted hydrazines as binucleophilic reagents were investigated next.First, compound 126 was reacted with hydrazine hydrate 127a in refluxing ethanol containing a catalytic amount of AcOH (Scheme 27).Full conversion of 126 within 4 h reaction time afforded a fairly polar product insoluble or only slightly soluble in all commonly used NMR solvents.However, a subsequent derivatization with acetic anhydride in pyridine to afford 130, allowed its structure verification indirectly.This derivatization did not only improve the solubility of the compound, but also eliminated the possibility of prototropic tautomerism through acetylation of both the amino and hydroxy groups present in the heterocyclic ring in 128a.The reaction with phenylhydrazine 127b was completed within 7 h in refluxing EtOH in the presence of an acid catalyst.A reduction of the reaction time to 3 h could be achieved by changing the solvent to AcOH affording the desired product 128b in high yield (86%, Scheme 27).On the other hand, the reaction of 126 with methylhydrazine 127c required a longer reaction time in refluxing AcOH to furnish the purified product 128c in a diminished yield (61%).This may be attributed to the weaker nucleophilic character of the external N compared to the internal one in 127c, 51 in contrast to phenylhydrazine 127b, making the first condensation step more difficult.The regioselectivity of the reactions with monosubstituted hydrazines is controlled by the higher reactivity of the ketone moiety over the ester towards nucleophiles, and the least hindered terminal nitrogen atom of the binucleophiles.Both reactions were repeated in AcOH under microwave conditions at 120 °C furnishing products 128b and 128c within a shorter time (20 min and 40 min), however, without substantial improvement in the yields.Scheme 27.Cyclization of compound 126 with hydrazine hydrate 127a, phenylhydrazine 127b and methylhydrazine 127c.
After optimizing the conditions for the MW-assisted synthesis of 128b from 126 with 127•HCl, analogous heterocyclization reactions were carried out with different substituted phenylhydrazine hydrochlorides 127dj.All reactions furnished the corresponding 17-exo-heterocycles 129d-j in good to excellent yields (83-92%, Scheme 28).Some of these compounds (128h, 129f, 129i and 129j) exerted considerable antiproliferative activity with promising cancer selectivity on a panel of human breast cancer cell lines.This indicates that the pyrazolone heterocyclic ring at the 17β position is a promising scaffold for the design of anticancer agents of the Δ 5 -androstene series.Scheme 28.Synthesis of steroidal N(1')-aryl-substituted pyrazol-5'-ones.Kotovshchikov et al. 52 developed a regioselective approach to 5-carboxy-1,2,3-triazoles based on the Cucatalyzed synthesis of 5-iodo-1,2,3-triazoles and subsequent Pd-catalyzed carbonylation.To demonstrate the applicability of their protocol for the derivatization of complex natural products, they introduced an azido group to cortexolone 130, an important steroidal hormone (Scheme 29).Azide 131 was subsequently transformed into iodotriazole 132 and the corresponding methyl ester 133, in high yields for both steps (91 and 84%, respectively).Scheme 29.Modification of cortexolone.
Initially, they investigated the one-pot sequential four-component reaction involving ninhydrin 141, 1,2phenylenediamine 142, sarcosine 143 and estrone-derived dipolarophiles 140a-h which proceeded well in the ionic liquid 144 to give a series of novel steroidal dispiroindenoquinoxaline pyrrolidines 145a-h as the only products in good yield (76-85%).The formation of the hybrid steroidal heterocyclic scaffold 145 involved a multistep sequence.This method of sequential assembly of steroid grafted spiro-pyrrolidines in ionic liquid medium offers several advantages including its simplicity with a one-pot four-component approach, mild reaction conditions, easy workup, affording the desired products in good yield from readily and cheaply available starting materials in a single step.This method is general and is applicable for the synthesis of a variety of unusual complex highly substituted pyrrolidines containing steroidal and spiro-indenoquinoxaline moiety of biological significance.

Scheme 31. Synthesis of steroidal spiro-indenoquinoxaline-pyrrolidines 145a-h.
In 2018, Yamansarova et al. 56 reported the synthesis of 1,2,4-trioxolanes of deoxycholic acid by the Griesbaum co-ozonolysis and compared their antimalarial activity with 1,2,4,5-tetraoxanes obtained by acidcatalyzed peroxycondensation.They used deoxycholic acid as an available starting material to synthesize steroidal peroxides.The required ketone 147 was obtained according to the procedure previously described. 57he next step included high-yield selective preparation of O-methyl oxime 148 (90%) as a mixture of syn-/antiisomers in a ratio of 1:1 (Scheme 32).Thus, they introduced the unsaturated C=N double bond into the structure of the initial substrate.In the subsequent synthesis intermediate 148 was applied as a mixture of oximes.The Griesbaum co-ozonolysis 58 of 148 in the presence of fluorinated ketones CF 3 C(O)CH 3 or CF 3 C(O)Ph gave 1,2,4-trioxolanes 149 and 150 in yields of 50% and 38%, respectively.A byproduct of these reactions was the expected lactam 151 isolated in yields of 14% and 10%, respectively.Surprisingly, the ozonolysis of 148 without the presence of ketones gave the lactam 151 as the major reaction product (52%).It was noted that the Griesbaum co-ozonolysis of 148 in the presence of acetone gave no 1,2,4-trioxolanes, perhaps due to its low dipolarophilicity.The ozonolysis reactions were carried out in cyclohexane-CH 2 Cl 2 solvent mixture at 0 °C and the ozonides obtained were isolated as the mixtures of achiral diastereomers.For compound 149, the only major diastereomer 149a was separated from hexane by crystallization of a stereoisomeric mixture and individually characterized.A (3S,3′R)-configuration was assigned based on X-ray crystallographic analysis.Scheme 32.Preparation of the ozonide 149a.
In 2018, Romero-Hernandez al. 60 the straightforward preparation of novel conformationallyrestricted steroids from trans-androsterone and estrone with spirocyclic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents.The key step to synthesize these heterocycles on the steroidal backbone was access to an aminomethyl alcohol on C-17 and its transformation into transient isocyanates and thioureas.The synthesis of the aminoalcohol was accomplished in three steps from transandrosterone and four steps from estrone (Scheme 34).
Trans-androsterone was treated with trimethylsulfonium iodide under basic conditions to obtain epoxide 155 in a total stereoselective fashion via a Corey-Chaykovsky reaction. 61Nucleophilic opening of epoxide 155 was carried out using sodium azide in the presence of boric acid to form the azide 156 in quantitative yield; the absolute configuration of the new chiral carbon was assigned for compound 156 as the (S)-diastereomer.Azide 156 was reduced by catalytic hydrogenation to get the aminomethylalcohol 157, which in turn was treated with triphosgene, as a safe alternative to hazardous phosgene, in a MeOH-CH 2 Cl 2 mixture to obtain the transient isocyanate 158; this compound underwent a spontaneous cyclization involving the nucleophilic attack of the free OH to the heterocumulene, affording the spirooxazolidin-2-one (spirocarbamate) 159 (52%); the use of MeOH as solvent led also to carbamate 160 as a by-product (25%).The same reaction sequence was applied to form the estrone derived spirocarbamate 167; changing the nature of the A-ring (aromatic for estrone) might modify the biological properties and thus afford valuable structure-activity relationships.For this purpose, the free OH on C-3 was first protected as its benzyl ether, and then, the functionalization of the C-17 was accomplished.Epoxide 163 was obtained in a stereoselective fashion, using KOtBu to form the sulfur ylid.The nucleophilic opening of 163 was carried out using sodium azide in DMF.The structure of azide 164 obtained by single crystal X-ray diffraction showed the configuration of C-17 as (S).Reduction of azide 164 under catalytic hydrogenation conditions also eliminated the benzyl group at C-3, giving amine 165 in a 77% yield after four steps.Reaction between 165 and triphosgene gave isocyanate 166, which was not isolated and spontaneously gave the final compound 167 and the by-product 168 in a 3:1 ratio (Scheme 34).Scheme 34.Synthesis of oxazolidin-2-ones 159-167 from trans-androsterone and estrone.Aminoalcohols from trans-androsterone and estrone were also used to obtain 2-aminooxazolines.Derivatives 157 and 165 were treated with different isothiocyanates (butyl, cyclohexyl and phenyl) under basic conditions, giving thioureas 161 and 169.The cyclodesulfurization reaction of thioureas promoted by yellow HgO afforded 2-aminooxazolines 162 and 170 with good to excellent yields (Scheme 35).Compounds 156-162 and 164-170 were tested as potential antiproliferative agents, and the order of activity was found to be aminooxazoline > spirocarbamate > thiourea.The lead compounds, bearing a spiranic aminooxazoline motif on an estrone backbone, exhibited GI 50 values in the low micromolar to submicromolar range (0.34-with particular increase in activity against drug-resistant cell lines compared to other steroidal chemotherapeutic agents (Abiraterone and Galeterone).

Conclusions
The present review offers an up-to-date literature on the latest syntheses of steroidal derivatives containing heterocycles reported during the last years.Several of these syntheses may be useful, and in most cases reporting the cytotoxicity of the tested compounds, there seems to be a link to the incorporation of heterocyclic ring into the steroid moiety.In addition, some reports verified the importance of the presence of heterocyclic moieties as pharmacophores for the activity against cancer cell lines.
Overall, the interest in steroids and related compounds continue to expand given the diversity of structure and emerging bioactivity inherent in this compound class.

Frédéric
Dumur received his PhD in chemistry in 2002 from the University of Angers (France) under the supervision of Professor Pietrick Hudhomme.After Post-Doctoral studies at the University of Groningen (The Netherlands), Reims Champagne-Ardennes (France) and Versailles Saint-Quentin-en-Yvelines (France), he joined the Faculty of Sciences at Aix-Marseille University in 2008, where he is currently working as an Associate Professor.His research interests include the synthesis of phosphorescent dopants for OLEDs and photoinitiators of polymerization.He co-authored about 225 publications and 5 book chapters.

Table of Contents
30nthesized new hetero-steroids with promising anticancer effects.The reaction of compound 86 with 4-amino-2-thiouracil 87 in ethanolic solution containing acetic acid afforded the corresponding thioxopyrimidinyl androstane derivative 88 in 75% yield.Compound 88 reacted with hydrazine hydrate in boiling ethanol to give the hydrazinyloxopyrimidinyl androstane derivative 89 in 58% yield.Treatment of compound 89 with glacial acetic acid gave the triazolopyrimidinyl androstane derivative 90 in 64% yield (Scheme 19).Reaction of compound 9130with compound 89 in ethanol gave the corresponding hydroxypyridazinylpyrimidinyl androstane derivative 92.The structure of compound 92 was confirmed based on the analytical and spectral data.The reaction of compound 89 with curcumin 93 in glacial acetic acid containing sodium acetate afforded pyrazolo-curcumin-pyrimidinyl androstane derivative 94 in 75% yield (Scheme 19).Compound 88, 90, 92, 94, showed significant cytotoxic effect on breast cancer cells.This study clarified that the compounds 88, 90, 92, 94 are the most promising as pro-apoptotic factors.Compounds 88, 94, act through the downregulation of CCND1, survivin, BCL-2 and CDC2 gene expression, while compounds 90 and 92 activate the P53/P21 pathway, resulting in tumor suppression and increased apoptosis.