Abstract
Racemic chiral O,N-heterocycles containing 2-arylchroman or 2-aryl-2H-chromene subunit condensed with morpholine, thiazole, or pyrrole moieties at the C-3-C-4 bond were synthesized with various substitution patterns of the aryl group by the cyclization of cis- or trans-3-aminoflavanone analogues. The 3-aminoflavanone precursors were obtained in a Neber rearrangement of oxime tosylates of flavanones, which provided the trans diastereomer as the major product and enabled the isolation of both the cis- and trans-diastereomers. The cis- and trans-aminoflavanones were utilized to prepare three diastereomers of 5-aryl-chromeno[4,3-b][1,4]oxazines. Antiproliferative activity of the condensed heterocycles and precursors was evaluated against A2780 and WM35 cancer cell lines. For a 3-(N-chloroacetylamino)-flavan-4-ol derivative, showing structural analogy with acyclic acid ceramidase inhibitors, 0.15 μM, 3.50 μM, and 6.06 μM IC50 values were measured against A2780, WM35, and HaCat cell lines, and apoptotic mechanism was confirmed. Low micromolar IC50 values down to 2.14 μM were identified for the thiazole- and pyrrole-condensed 2H-chromene derivatives. Enantiomers of the condensed heterocycles were separated by HPLC using chiral stationary phase, HPLC-ECD spectra were recorded and TDDFT-ECD calculations were performed to determine the absolute configuration and solution conformation. Characteristic ECD transitions of the separated enantiomers were correlated with the absolute configuration and effect of substitution pattern on the HPLC elution order was determined.
Highlights
The 3-aminoflavanone scaffold 1 is considered an efficient building block for the preparation of condensed chiral O,N-heterocycles 2-4 (Scheme 1), which contain a 2-arylchroman orB1i.oImnoltercoudlesu2c0t2i0o,n10, 1462The 3-aminoflavanone scaffold 1 is considered an efficient building block for the preparation of2co-anrdyel-n2sHed-chchroirmalenOe,Nm-hoeietetyrocfuysceleds a2t-4th(SechCe-m3−eC1-4), bwohnidchwciotnhtaaizninae-2-oarryalzchorleo-mtyapne ohret2e-raorcyyl-c2lHes
The cis- and trans-2-aminoflavanones were utilized for cyclization reactions to condense the 2-aryl-chroman or -2H-chromene subunit with morpholine, thiazole, or pyrrole moieties at the C-3-C-4 bond
Antiproliferative activities of condensed heterocycles and precursors were evaluated against A2780 and WM35 cancer cell lines at 50 μM concentration and IC50 values were determined for the best ones with MTT assay
Summary
The 3-aminoflavanone scaffold 1 is considered an efficient building block for the preparation of condensed chiral O,N-heterocycles 2-4 (Scheme 1), which contain a 2-arylchroman orB1i.oImnoltercoudlesu2c0t2i0o,n10, 1462The 3-aminoflavanone scaffold 1 is considered an efficient building block for the preparation of2co-anrdyel-n2sHed-chchroirmalenOe,Nm-hoeietetyrocfuysceleds a2t-4th(SechCe-m3−eC1-4), bwohnidchwciotnhtaaizninae-2-oarryalzchorleo-mtyapne ohret2e-raorcyyl-c2lHes-. The 3-aminoflavanone scaffold 1 is considered an efficient building block for the preparation of condensed chiral O,N-heterocycles 2-4 (Scheme 1), which contain a 2-arylchroman or. The 3-aminoflavanone scaffold 1 is considered an efficient building block for the preparation of. TToshyela3tedameriinvoatfilvavea5n, orenaeddileyriavvaatiilvaebslecafrnombefloabvtaaninoendesb6yinthtewNoesbteepr sr.eTarhreanNgeebmerenreta[r1r]anogf ethmeenoxt iimnveotlovseysltahtee cdoenrivveartsiivoen5o,frtehaedoilxyimaveatiloasbylleatferoomf aflkaevtaonnoentoesa6rienacttwivoes2tHep-sa.zTirhineeNinetbeerrmreedariaratenignemtheenptriensveonlcveeosftahne acolknovxeirdseiobnasoef, tthhee roixnigm-oepteonsiynlgatoefowfhaickhetpornoedutoceasraenacαt-iavme 2inHo-kaeztiorninee[2in,3t]e.rAmlethdoiautgehinoxthime eptroessyenlactee ooff flanavaalnkoonxeidraec-bEawsee,rethceonrvinegrt-eodpteon3in-agmoinf owflhavicahnopnreodinuaceNseabner αre-aacmtiionnoakseetoanrley a[2s,139].59A[l4t]haonudghisoolaxtiimone otofstyrlaantse-3o-fafmlaivnaonfloanvearnaocn-Ee wraecr-eCcwonevreerrteepdotrote3d-a[m5,i6n]o, ftlhaevasnyonntheeitnicapNoteebnetriarleaocfti3o-namasineoaflrlayvaasno1n95e9s f[o4]r athned pisroelpaatiroantioonf torfancos-n3d-aemnsinedoflOav,Nan-hoenteerroaccy-Cclews ehraesrbepeeonrteudnd[5e,r6u],titlhizeedsy(nStchheetmic epo1)t.enOtianllyofth3epamreipnaorfaltaivoannoofnoexsafzoorltihnee-parnepdairmatiidoanzooflec-ocnodnednesnesdedOd,Ner-hiveatetirvoecsyrcalec-sAhaasnbdereanc-uBnwdearsurteilpizoerdte(dScwhietmh ae f1e)w. RMepoareraotvieorn, ionfthoixsawzoolriknet-heanddiasimterideoaszeolleec-tcivointdyeannsdedsiddee-rpivroadtiuvcetss roafct-hAe aNnedberracr-eBacwtioans irnepthoretepdrewseinthceaoffewaneixnahmerpelnets.CM-2ocrheoirvaelrit,yincetnhtiserwoofrflkatvhaendoinaesstewreeorseesletuctdivieidtyfaunrtdhesirdbey-pmroodduifcytsinogf tthhee rNeaebcteironrecaocntidointioinnsthaendpriessoelnatcieonofoafnthienhdeiaresntetreCo-m2 echriicraplirtoydcuecntste. Reported, in which the reaction conditions are adjusted to stop the transformation at the stage of the 2H-azirine intermediates [7,8,9].
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