Steroidal tetraoxanes: synthesis and biologycal activity

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Hemija - sintetička organska hemija i medicinska hemija / Chemistry - synthetic organic chemistry and medicinal chemistry

U toku izrade ove doktorske disertacije sintetisani su tetraoksani derivata holne kiseline i ispitana je njihova antimalarijska, citotoksična i antiproliferativna aktivnost. U toku rada dobijeni su sledeći rezultati: 1. Razvijena su dva postupka za sintezu bis-steroidnih tetraoksana: 1) direktna peroksiacetalizacija odgovarajućih 3-keto derivata holne kiseline, 2) derivatizacija prethodno dobijenih bis-steroidnih tetraoksana. Primenom oba postupka sintetisano je 14 bis-steroidnih tetraoksana derivata holne kiseline, 123- 136. Prema prvom postupku sintetisani su bis-steroidni tetraoksani 123 - 128. Proizvodi 123 i 124 dobijeni su reakcijom ketona 119 sa 30% H2O2 / 50% H2SO4, u prinosu od 25% i 28%, a proizvodi 125 - 128 u reakcijama ketona 121 i 122 sa (Me3Si)2O2 / TMSOTf, na 0 oC u prinosu 28 – 50% (Shema 24). Utvrđeno je da u reakcijama ketona 119 sa (Me3Si)2O2 / TMSOTf i 121 i 122 sa 30% H2O2 i 50% H2SO4 dominantno nastaju proizvodi Baeyer – Villiger-ove reakcije. Prema drugom postupku sintetisani su tetraoksani 127– 136124 na dva načina: a) hidrolizom 1,25 M rastvorom NaOH u smeši CH2Cl2 / MeOH na sobnoj temperaturi u toku 3 dana (72 – 79%); b) hidrolizom pomoću NaOH u smeši i-PrOH / H2O (3:1, v/v) na temperaturi ključanja u toku 15 min. (90 – 95%, Shema 24). Kiseline 129 i 130 prevedene su preko mešovitog anhidrida u amide 131 – 136 (54 – 81%) kao i prethodno sintetisane amide 127 i 128 (Shema 25). Izolovana su oba predviđena diastereomera a na osnovu spektralnih podataka i analize monokristala derivata 123 X-zracima, pripisana je struktura sintetisanim derivatima: cis-C(2)C(2a) seriji pripadaju derivati 123, 125, 127, 129, 131, 133 i 135, a trans-C(2)C(2a) seriji pripadaju derivati 124, 126, 128, 130, 132, 134 i 136. 2. Razvijen je postupak za sintezu gem-dihidroperoksida derivata holne kiseline (137, 145 i 146, Shema 29) koji uspešno može da se primeni i za dobijanje gemdihidroperoksida jednostavnih cikličnih ketona (149, 150 i 76, Shema 30). Gem-dihidroperoksidi su sintetisani reakcijom odgovarajućeg ketona i 30% H2O2 u smeši CH2Cl2 / CH3CN (1:3, v/v) u prisustvu katalitičkih količina konc. HCl u visokom prinosu (> 90%). Postupak razvijen u toku ovog rada je jednostavniji, ekonomičniji i bitno poboljšan u odnosu na postupke do sada opisane u literaturi (ref. 45, 47, Shema 13). 3. Sintetisana su 53 mešovita tetraoksana derivata holne kiseline, 138 – 144b. Metil-estri 138 dobijeni su kuplovanjem gem-dihidroperoksida 137 sa jednostavnim, supstituisanim i nesusptituisanim, cikličnim ketonima (~ 30%, Shema 27). Reakcija se vrši u dihlormetanu, u prisustvu katalitičkih količina H2SO4. Reakcijom ciklopentanona, cikloheksanona i ciklooktanona dobijen je i izolovan po jedan proizvod, a svaki od prohiralnih 4-metil-, 4-etil-, 4-t-butil- i 4-fenilcikloheksanona daju oba očekivana diastereoizomera. Reakcijama 2,6-dimetil-, 2-metil-cikloheksanona i. mentona proizvodi su izolovani u obliku odgovarajućih smeša. Reakcija gem-dihidroperoksida 137 sa aromatičnim karbonilnim jedinjenjima - 2-furil-metilketon, 4-nitroacetofenon, 6-metoksitetralon-1-on i pmetoksibenzaldehid - nije dala očekivane proizvode. Selektivnom hidrolizom C(24) metil-estarske grupe tetraoksana 138 sa NaOH u smeši i-PrOH / H2O (3:1, v/v) na temperaturi ključanja dobijene su odgovarajuće karboksilne kiseline 139 (72 – 93%), koje su preko mešovitog anhidrida prevedene u odgovarajuće amide 140 – 144b (~ 80%, Shema 28). Na osnovu spektralnih podataka i analize monokristala kiseline 139g X-zracima određena je konfiguracija C(4”) atoma 4”-metil derivata. Utvrđeno je da derivati 138f, 139f i 140f – 143f pripadaju (4”R) seriji, a da derivati 138g, 139g i 140g – 143g pripadaju (4”S) seriji...

Within this thesis a cholic acid-derived 1,2,4,5- tetraoxacyclohexanes (tetraoxanes) were synthesised and characterised, their in vitro antimalarial activity was evaluated and cytotoxicity determined. In addition, the tetraoxanes reported in this thesis were evaluated as potential antiproliferatives against various cancers cell lines. The results can be summarised as follows: 1.Two procedures for preparation of bis steroidal tetraoxanes were developed: 1) direct peroxyacetalisation of the corresponding 3-keto cholic acid derivatives, 2) transformation of the previously prepared tetraoxanes into its derivatives. 14 bis- Steroidal tetraoxanes, 123-136, were prepared utilising both procedures. Tetraoxanes 123-128 were obtained according to the first procedure. Compounds 123 and 124 were prepared by reacting of ketone 119 with 30% H2O2 / 50% H2SO4 in 25% and 28% yield, respectively, while the compounds 125-128 were obtained from the ketones 121 and 122 using TMS2O2 / TMSOTf at 0 oC, in 28-50% yield (Scheme 24). Ketone 119 with TMS2O2 / TMSOTf, as well as ketones 121 and 122 with 30% H2O2 / 50% H2SO4, afforded as main products the Baeyer-Villiger products. Procedure 2) was utilised for preparation of tetraoxanes 127-136. The carboxylic acids 129 and 130 were obtained by selective hydrolysis of C(24) methyl ester moiety of tetraoxanes 123 and 124, respectively, utilising a) hydrolysis with 1.25 M NaOH/CH2Cl2-CH3OH at r.t. for 3 days (72-79%), and b) hydrolysis with NaOH / i-PrOH-H2O (3:1, v/v) at reflux for 15 min (90-95%, Scheme 24). The acids 129 and 130 were further transformed via their mixed anhydrides into corresponding amides 131-136 (54-81%), as well as into previously synthesised amides 127 and 128 (Scheme 25). Both predicted diastereomers were isolated and their structures was assigned from corresponding spectral data and confirmed by X-ray analysis of tetraoxane 123 monocrystal: compounds 123, 125, 127, 129, 131, 133, and 135 belong to cis-C(2)C(2a) series, and to corresponding trans-C(2)C(2a) series belong the compounds 124, 126, 128, 130, 132, 134, and 136. 2. The procedure developed for the synthesis of cholic acid-derived gem-dihydroperoxides (137, 145, 146, Scheme 29) was also applied for synthesis gemdihydroperoxides of simple cyclic systems (149, 150 and 76, Scheme 30). It embodies the treatment of a ketone with 30% H2O2 in CH2Cl2-CH3CN mixture (1:3, v/v) in the presence of cat. HCl (> 90%). The procedure developed within this thesis represents a significant improvement in terms of simplicity and economy as compared with the known ones (ref. 45, 47, Scheme 13). 3. 53 Mixed tetraoxanes derived from cholic acid were prepared (138-144b). Mixed steroidal tetraoxane methyl esters 138 were synthesised by coupling of gemdihydroperoxide 137 to simple substituted and nonsubstituted cycloalkanones (~30%, Scheme 27). The coupling reaction was performed in dichloromethane in the presence of cat. H2SO4. The reaction of cyclopentanone, cyclohexanone and cyclooctanone afforded only one corresponding tetraoxane each, while the reaction of 4-methyl, 4-ethyl, 4-t-butyl, and 4- phenylcyclohexanone afforded both expected diastereomers each. Aromatic ketones failed to produce a tetraoxane in a reaction with the same dihydroperoxide. Selective hydrolysis of tetraoxanes 138 with NaOH / i-PrOH-H2O as above afforded the corresponding acids 139 (72-93%), which were via their mixed anhydrides transformed into corresponding amides 140-144b (~80%, Scheme 28). The configuration at C(4") in 4"-methyl series was determined by X-ray analysis of tetraoxane acid 139g. It is found that tetraoxanes 138f, 139f, and 140f-143f belong to (4"R)-series, while their respective (4"S) diastereoisomers are 138g, 139g, and 140g-143g...

stеrоidi, tеtrаоksаni, mаlаriја, аntimаlаrici, rаk, pеrоksidi

steroids, tetraoxanes, malaria, antimalarials, cancer, peroxides

547.7:615.31

Steroidi

Tetraoksani

Tekst