Enantiospecific synthesis of heterocycles linked to purines: different apoptosis modulation of enantiomers in breast cancer cells.
The issue of chiral drug is now a major theme in the design, discovery and development of new drugs. It has been shown for many pharmaceuticals that only one enantiomer contains the desired activity, and the synthesis of such drug molecules in their optically pure form is becoming increasingly important. Mitsunobu reaction was carried out between (R)- and (S)-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol and purines under microwave irradiation. A contraction into a six-membered ring takes place with concomitant inversion at the stereocentre with excellent enatiomeric excesses giving rise to the homochiral 9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purines. The anti-tumour activity of all enantiomers is reported against the caspase-3-deficient MCF-7 and the wild type SKBR-3 human breast cancer cells. The most active homochiral compound displays an IC50 of 1.85 μM and induces inhibition of the translation initiation factor eIF2α. All homochiral compounds included in this study show different apoptotic effects between both enantiomers with levels up to 99%. We have analyzed caspase-mediated apoptotic pathways on enantiomers and racemates. We have found a homochiral derivative that activates the canonical intrinsic caspase-8/caspase-3 apoptotic pathway on the MCF-7 cells, and a racemic compound that induces caspase-2 activation. Moreover, we demonstrate the involvement of caspase activation during cell death induced by these compounds in SKBR-3 cells.
Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja, s/n, 18071 Granada, Spain. jmcampos@ugr.es.
M E
ME
García-Rubiño
A
A
Conejo-García
M C
MC
Núñez
E
E
Carrasco
M A
MA
García
D
D
Choquesillo-Lazarte
J M
JM
García-Ruiz
M A
MA
Gallo
J A
JA
Marchal
J M
JM
Campos
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D008968:Molecular Conformation; D011687:Purines / Q000737:chemistry*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D020717:Eukaryotic Initiation Factor-2B; D006571:Heterocyclic Compounds; D011687:Purines; D053148:Caspase 3; D053181:Caspase 8