Synthesis and anticancer activity of (RS)-9-(2,3-dihydro-1,4-benzoxaheteroin-2-ylmethyl)-9H-purines

Herein are reported the synthesis and anticancer activity against the human breast cancer cell line MCF-7 of a series of substituted (RS)-9-(2,3-dihydro-1,4-benzoxathiin-2-ylmethyl)-9H-purine derivatives and (RS)-9-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-9H-purine derivatives. When the Mitsunobu reaction was carried out between (RS)-2,3-dihydro-1,4-benzoxathiin-3-methanol and the heterocyclic bases 6-chloro-, 2,6-dichloro, and 6-bromo-purines under microwave-assisted conditions, a formal 1,4-sulfur migration takes place through two consecutive oxyranium and episulfonium rings, giving rise to the corresponding (RS)-9-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-9H-purine derivatives, previously reported by us. The most active compound (RS)-2,6-dichloro-9-(2,3-dihydro-1,4-benzoxathiin-2-ylmethyl)-9H-purine shows an IC50 = 2.75 +/- 0.02 mu M. When the cancerous cells were treated with this compound, a significant increase of apoptotic cells (70.08 +/- 0.33%) was obtained in relation to the control ones. The induction of the G(2)/M cell cycle arrest and apoptosis by the three most active compounds is associated with increased phosphorylation of eIF2 alpha in human breast cancer cells. (C) 2011 Elsevier Masson SAS. All rights reserved.